Final Report: Lifecourse Exposures & Diet: Epigenetics, Maturation & Metabolic Syndrome

EPA Grant Number: R835436
Center: Lifecourse Exposures & Diet: Epigenetics, Maturation & Metabolic Syndrome
Center Director: Peterson, Karen E.
Title: Lifecourse Exposures & Diet: Epigenetics, Maturation & Metabolic Syndrome
Investigators: Peterson, Karen E. , Padmanabhan, Vasantha
Institution: University of Michigan
EPA Project Officer: Nolt-Helms, Cynthia
Project Period: June 1, 2013 through May 31, 2018 (Extended to May 31, 2019)
Project Amount: $3,651,990
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2012) RFA Text |  Recipients Lists
Research Category: Children's Health , Health

Objective:

Overall Center:

The developmental origins hypothesis relates in utero exposures to endocrine disrupting chemicals (EDCs) to children's physical growth and maturation and the later development of chronic diseases, including metabolic syndrome, a condition affecting up to 25% of US adults and 30% of obese adolescents. Few studies have considered whether subsequent exposures during the pubertal transition may exacerbate impact of prenatal EDC mixtures on growth, maturation and the risk of metabolic syndrome. This center is examining the overarching hypothesis that in utero and peripubertal exposures to mixtures of EDCs (bisphenol A (BPA), phthalates, lead (Pb), cadmium (Cd)) will, via epigenetic mechanisms, lead to changes in gene expression and alter the tempo of physical growth and maturation as well as metabolic function and increase risk of metabolic syndrome. Because nutrients may serve as agonists or antagonists of toxic effects of environmental chemicals, we further hypothesize that dietary intake will modify the impact of EDC mixtures on metabolic outcomes. The Specific Aims of the University of Michigan Children's Environmental Health and Disease Prevention Center (UM-CEHC) are to:

Specific Aim 1: Assess the impact of in utero and peripubertal exposures to mixtures of EDCs (BPA, phthalates, Pb and Cd) on linear growth and weight status, sexual maturation and reproductive hormones.

Specific Aim 2: Determine whether EDC mixtures (BPA, phthalates, Pb, Cd) via epigenetic mechanisms induce oxidative stress, disrupt metabolic homeostasis and lead to changes in gene transcription and metabolic function.

Specific Aim 3: Conduct tissue- and age-specific unbiased epigenomic analyses to identify a subset of tissue-independent labile genes to serve as biomarkers of exposure-induced metabolic syndrome.

Specific Aim 4: Examine the role of dietary intake during pregnancy and adolescence in modifying the impact of EDC mixtures on metabolic homeostasis, oxidative stress and risk of metabolic syndrome.

Specific Aim 5: Foster career development by assisting new investigators in the advancement of their research skills and knowledge in translational and children's environmental health research.

Specific Aim 6: Share current research findings on the role that environmental exposures have on children's health in an accurate, relevant way that allows community members, healthcare professionals, and policy-makers to incorporate this new knowledge into practice for the protection of children's health.

Administrative Core:

Aim 1: Coordinate and integrate the scientific aims of the Projects and Cores, track and evaluate progress and outputs, and ensure successful completion of all Center aims.

Aim 2: Manage Center and University resources to meet the needs and priorities of Projects and Cores.

Aim 3: Act as coordinating center by convening meetings of Project, Core, and subcontract investigators, organize the External Advisory Committee, ensure timely translation of research findings, prepare Center-wide reports, and interface with NIEHS and EPA project officers.

Aim 4: Evaluate the progress and success of the Career Development plan, with specific focus on the career development of Faculty Development Investigator.

Aim 5: Ensure quality control of all stages of research namely study design, establishment of standard operating procedures and study protocols, secure sample and data transfer and management, data analysis, and accurate interpretation I translation of research findings to academic, government, healthcare and community stakeholders.

Community Outreach and Translation Core (COTC):

Aim 1: To develop and evaluate innovative, state-wide translation networks and activities connecting cutting-edge academic research findings to public health practice

Aim 2: To increase the awareness, understanding, and translation of the most recent scientific findings in children's environmental health into practice among families, community members, and community public health practitioners.

Aim 3: To translate children's environmental health research for use by advocacy organizations and policy makers at the local, state, national, and international level in order to advance policies which protect children's health.

Data Management and Modeling Core (DMMC):

Aim 1: To provide statistical and bioinformatics support for all projects, including study design, conduct of statistical analyses, integration with biological information and interpretation of research findings.

Aim 2: To support data management, data quality controls, and integration of databases for conduct of the projects.

Aim 3: To participate in dissemination of research findings, including writing of manuscripts and presentations, and data sharing, and collaborate in dissemination strategies in concert with the Community Outreach and Translation Core.

Project 1: Perinatal and Prepubertal Mixtures, Physical Growth, and Sexual Maturation:

Most, if not all, people in the United States are exposed to phthalates, BPA, and other potential endocrine disrupting chemicals (EDCs), including hormonally active heavy metals, on a daily basis. There is currently much concern that low-level environmental exposures to EDCs may be associated with the recently observed population trends of increased rates of obesity and earlier onset of puberty. Due to widespread exposure to these and other EDCs, the public health significance of this study could be enormous. The specific aims of this research are:

Aim 1: Assess the impact of in utero and peripubertal exposure to EDCs (BPA, phthalates, lead, and cadmium) on linear growth and weight status from birth through adolescence.

Aim 2: Determine the impact of in utero and peripubertal exposures to mixtures of EDCs (phthalates, BPA, lead, and cadmium) on sexual maturation and serum reproductive hormone levels.

Aim 3: Utilize longitudinal models to explore interactions between in utero and peripubertal exposures and determine potential windows of susceptibility for impacts of exposure on child development.

Project 2: Metabolic Consequences of In Utero and Peripubertal Toxicant-Diet Exposures:

Metabolic syndrome affects ~25% of U.S. adults and up to 30% of obese adolescents. Understanding how exposures to EDCs during pregnancy and adolescence may interact with diet to lead to metabolic dysregulation is highly relevant to clinical and public health practice. Results of this study have the potential toinform interventions to reduce health effects of toxicant mixtures in children during key developmental periods. The specific aims of this project are:

Aim 1: Determine the impact of in utero and peripubertal exposures to mixtures of EDCs on biomarkers of metabolic homeostasis and oxidative stress and risk of metabolic syndrome

Aim 2: Determine whether dietary intake modifies the association of in utero and peripubertal EDC exposures with markers of metabolic homeostasis, oxidative stress and risk of metabolic syndrome during the peripubertal period

Aim 3: Determine whether epigenetic changes in a targeted panel of candidate genes regulating metabolism and growth mediate the association of EDC exposures with markers of metabolic homeostasis, oxidative stress and risk of metabolic syndrome during sensitive developmental periods

Project 3: Developmental Exposures and Diet: Epigenetics of Metabolic Syndrome Risk:

It is increasingly recognized that exposures to chemicals affect health and disease by not only mutating genes, but also by modifying the epigenome, alterations to DNA that are heritable and lead to disease when deregulated. The objective of this UM-CEHC Center Project is to identify exposure mixtures and modifiers such as diet and timing of exposure that influence later-life metabolic syndrome risk and reproductive development via epigenetic alterations in order to facilitate children's health risk assessment and disease prevention. The specific aims of this project are:

Aim 1: To assess whether in utero and postnatal high-fat diet modifies the effects of perinatal BPA or Pb exposure on metabolic and hormonal parameters throughout the life course and identify DNA methylation alterations underlying such effects.

Aim 2: To examine the relationship of perinatal exposure to chemical mixtures of phthalates on metabolic and reproductive status throughout the life course and identify key epigenetic labile genes important for metabolic and hormonal homeostasis.

Aim 3: To utilize mouse models of exposures to inform issues of epigenetic tissue specificity and drift with age, inherent complexities in epigenetic epidemiological studies.

Summary/Accomplishments (Outputs/Outcomes):

The University of Michigan Children's Environmental Health and Disease Prevention Center's (UM-CEHC) three research projects are designed to provide scientific integration across shared environmental exposures and interrelated outcomes to examine the impact of endocrine disrupting chemical (EDC) mixtures (BPA, phthalates, Pb, Cd) in utero and during the pubertal transition on physical growth and maturation and leading to alterations in metabolic homeostasis, oxidative stress and metabolic syndrome, using human and animal models. Projects 1 and 2 are human studies, both conducted within the Early Life Exposures in Mexico to ENvironmental Toxicants (ELEMENT) birth cohorts that have been successfully followed for over two decades. In addition to ELEMENT participants overseen by Drs. John Meeker (Project 1) and Karen Peterson (Project 2), the Michigan Mother Infant Pairs (MMIP) cohort, a US study population established by MPI Dr. Vasantha Padmanabhan, is included in Project 2 of the UM-CEHC in order to extend findings from the ELEMENT cohort to a U.S. study population Project 1 focuses on understanding the impact of metals (Cd, Pb) and EDCs (BPA and phthalates) in utero and during peripuberty on children's growth and sexual maturation (Overall Aim 1) in ELEMENT Whereas, Project 2 considers the effect of EDC exposures via epigenetic mechanisms to fetal and peripubertal alterations in metabolic homeostasis and oxidative stress and the potential modifying role of diet (Overall Aims 2, 3, 4) in both the ELEMENT and MMIP cohorts. To parallel the human studies, Project 3 utilizes a mouse model of perinatal environmental exposures to address the influence of perinatal and peripubertal exposure mixtures and diet on life course offspring metabolic status, reproductive development and epigenetic gene regulation (Overall Aims 2, 3, 4).

Accomplishments for Aims 1, 2, 3 and 4 are described under each of the three research projects Activities of the Center and accomplishments for Center Cores in regard to Aim 5 (Training and Career Development) and Aim 6 (Community Outreach and Translation) are summarized below

Administrative Core:

The Administrative Core prioritizes open communication between all study investigators at multiple study locations, which in turn maintains our collaborative relationships and provides an established infrastructure for the UM-CEHC. Through monthly meetings, updates, challenges and opportunities for collaboration between projects are shared and bi-weekly conference calls facilitate communication between investigators at other study locations, e.g., INSP Through these venues, the Administrative Core continuously enhances the efficiency of data collection, maintenance of protocols for protection of human subjects, and the integrity of biospecimens and data management across the Center's projects and cores.

Organizational coordination and management of Center activities has been streamlined by our Center Research Managers, and currently by Ms. Arboleda-Merino. Sample tracking and management was standardized for biological specimens from Project 1 and 2 ELEMENT study visits as well as historical ELEMENT specimens and a barcoding inventory system was implemented in 2018 in order to improve chain of custody of the samples and facilitate their use for future analysis

Throughout the past 5 years, the Administrative Core has also organized External Advisory Committee (EAC) meetings (December 2016 and March 2018) EAC members include: Dr. Virginia Rauh (Columbia University), Dr. Barbara Fiese (University of Illinois at Champaign-Urbana) and Dr. James Hebert (University of South Carolina) EPA Project Officers, Nica Louie and Cynthia Nolt-Helms, as well as Dr. Kimberly Gray from NIEHS, have actively participated in the EAC meetings The EAC, in concert with the project officers, has provided invaluable feedback on the strengths, weaknesses and opportunities of our Center, and have continued to inform our plans moving forward. Several strategies recommended by our EAC, including working closely with our School of Public Health's Marketing and Communications team to develop strategies to increase the publicity and visibility of our Center and the communication of findings to the larger lay and scientific communities, and our local, state and national partners have been implemented in the last 5 years. We also invested in the infrastructure of the ELEMENT inventory with the purchase of an additional freezer and barcoding equipment to accommodate incoming samples. Our Administrative Core also applied for several large grants to continue funding for our ELEMENT and MMIP cohorts; the MMIP cohort, in collaboration with other Michigan based longitudinal cohorts, was awarded the Environmental Influences on Child Health Outcomes (ECHO) funding, and the ELEMENT cohort was awarded the Maintain and Enrich Resource Infrastructure to Existing Environmental Epidemiology Cohorts (R24) in 2017

Community Outreach and Translation Core:

The primary goal of the UM-CEHC Community Outreach and Translation Core (COTC) is to enhance the multiple, diverse stakeholders' understanding of the role that environmental exposures have on children's health and the potential points of prevention and intervention.

Local Partnership: We have maintained our dynamic, community-based participatory research (CBPR) partnership, originally launched in 2010 through our Formative CEHC (P20 ES018171-01/RD834800 (Peterson)) on the theme "Perinatal exposures, epigenetics, child obesity and sexual maturation Our COTC partners include: Head Start for Kent County, Kent County Health Department, and Healthy Homes Coalition of West Michigan, the Asthma Network of West Michigan, and the West Michigan Environmental Council to identify collaborative projects and topics to improve children's environmental health. Throughout the project period, we have met regularly as a large group and in focused, smaller groups to work a number of different projects that have expanded and strengthen relationships with these local partners in Kent County, Michigan Results of these collaborative activities have been translated to programming for children and families, as well as used to create informational materials for community and policy audiences in Michigan Based on community health surveys as well as regular reports from the local health department and the State, our partners identified 2 themes, asthma and a lack of access to education/information related to lead in households, as a prevalent and persistent public health problems in Kent County.

Asthma Mapping Project. Through a collaborative process with Grand Valley State University and our CBPR partners (see above) our team worked to conduct spatial analyses and oversaw the creation of maps illustrating the prevalence and burden of asthma on low-income preschool-age children in Kent County, using data from our Head Start for Kent County partners to generate talking points and a presentation template Our Community Advisory Board (CAB) members have since used these materials to present our findings to the community and other stakeholders to address childhood asthma in Kent County. Furthermore, we collaborated with the CAB to develop a strategic plan for the group that includes a vision and mission statement to strengthen our future collaborations.

Lead Mitigation in the Home Projects. Our partners have a long-standing relationship around lead abatement and environmental housing issues affecting children In close collaboration with the CAB members and Healthy Homes Coalition of West Michigan, we have addressed the issue of lead mitigation in the home in 3 different projects that built on each other in a natural sequence First, we worked with our Head Start and Healthy Homes Partners to develop a survey for parents of low-income children querying the sources they used to obtain information about lead exposure and prevention, as well as any housing-specific concerns Second, based on data from these surveys suggesting that parents preferred to receive information from trusted community members, we developed a peer-delivered, lead education curriculum for parents of young children (the Peer Education Program (PEP)). The project is two-fold: it first trains peer educators from the community, who then deliver the curriculum to parents of children under 5 years of age The curriculum was designed for adult learners and includes information about lead poisoning prevention and remediation specifically in the home environment; developmental information about how normative child behaviors and biology (e.g., toddlers eating paint chips) can increase risk for lead exposure; and demonstrates specific action steps that parents can take (e.g., lead-safe cleaning practices) Educators also connect parents to resources in the community. To date, the curriculum has been delivered by peer educators to 40 families in Grand Rapids and has been translated into Spanish. Dr. Alison Miller, COTC Director, also presented at the 2019 Biennial Meeting of the Society for Research on Child Development (SRCD) in a symposium focused on Community Engagement and reported on the development of and findings from this project. For the third phase of this project, we have continued to deliver the program and refined the educational and evaluation materials for the program based on peer educator and Healthy Homes staff feedback Additional aspects of this expanded project include capacity building to support front-line staff (both peer educators and Healthy Homes staff) though developing supervision and training to prevent staff burnout and manage stress, in collaboration with faculty at the University of Michigan School of Social Work An additional goal to expand this curriculum/program to other agencies that have recently suggested that they are interested in delivering the program to families (e.g., Head Start of Kent County; Washtenaw County Health Department). We are also exploring the possibility of expanding our evaluation to include objective outcome data (e.g., increased child lead testing, reduced child blood lead level). This work involves additional a new faculty member from UM's EHS Department, Dr. Simone Charles. Overall, the lead abatement in the home project has involved and funded six students (including summer internships) from the School of Public Health.

Collaborations with Other UM Centers: Our COTC has also collaborated with other University of Michigan Centers to leverage cross-institutional resources We worked with the Michigan Lifestage Environmental Exposures and Disease (M-LEEaD) Core Center and Dr. Dolinoy, Project 3 PI, to act as a liaison with colleagues in Flint, MI, to coordinate responses to the Flint Water Crisis. Specifically, we worked with the UM Office of Public Health Practice and Public Health Training Center to develop and disseminate nutrition trainings relevant to lead mitigation to community health workers in Flint, MI (https://sph.umich.edu/mphtc/resources.html).

Regional Activities: We have undertaken a number of collaborative activities with other COTC's, mostly with the University of Illinois where Core Director Miller presented our COTC model and projects at a Children's Environmental Health Symposium (2015) and subsequent national presentations at the Society for Research in Child Development (2019). Finally, we have worked with our local PEHSU (Region 5) to develop effective mechanisms to transmit information on children's environmental health needs to families

National Partnerships: In 2012, through our formative UM-CEHC, we initiated collaborations with the Children's Environmental Health Network (CEHN), a national non-profit that works to protect children from environmental health hazards. Through in-person meetings and conference calls with Nse Witherspoon and Carol Stroebel of CEHN, we were able to identify the Eco-Healthy Child Care Program as a project for collaboration.

In 2016, Dr. Dana Dolinoy participated in the Cancer Prevention during Early Life Expert Group convened by the Centers for Disease Control and Prevention that resulted in a published manuscript highlighting opportunities in early life for cancer prevention, including reducing environmental exposures.

Holman, Dawn M., and Natasha D. Buchanan. "Opportunities during early life for cancer prevention: highlights from a series of virtual meetings with experts."Pediatrics138, no. Supplement 1 (2016): S3-S14.

In February 2019, cohosted by the Michigan Lifestage Environmental Exposures and Disease Center (M-LEEaD) Dr. Leo Trasande attended the University Of Michigan School Of Public Health to speak about his recent publication Sicker, Fatter, Poorer: The Urgent Threat of Hormone-Disrupting Chemicals to Our Health and Future... and What We Can Do About It. An in-depth conversation with Dr. Mona Hanna-Attisha, author of the 2018 book What the Eyes Don't See: A Story of Crisis, Resistance, and Hope in an American City followed Dr. Trasande's talk. Here they discussed no only the impact of chemicals on hormones in our bodies, but also the role of environmental exposures in childhood obesity and cardiovascular risk, including as assessment of economic costs to society.

International Partnership: Continuing our now 25-year partnership with the Instituto Nacional de Salud Pública (INSP) through the ELEMENT cohort, we actively focused in the last 5 years on promoting community engagement and translating our research to our ELEMENT study participants and their families in Mexico City. We have worked closely with an anthropologist, Dr. Elizabeth Roberts, who is studying several of the families in the ELEMENT cohort through an NSF-funded grant to inform our strategies for retention and ongoing engagement—including sharing research findings and information with our participants such as, blood lead levels from measurements and personalized charts of weight and height growth since birth. In addition, through several informative posters displayed at ABC-hospital in Mexico City, which focus on Lead toxicity, Eating Habits, Physical Activity, Toxicants and Health Effects, participants are encouraged to learn more about environmental exposure, their effects on the body, and how to prevent possible exposureWe also designed and administered a questionnaire to learn how participants perceive the ELEMENT study and evaluate the acquired environmental toxicant knowledge, in order to assess the project influence on their lifestyles and possible exposures.

In 2019, Dra. Martha Maria Tellez-Rojo, ELEMENT Principal Investigatorat INSP, was part of the planning committee for The International Society for Children's Health and the Environment (ISCHE) 4th international retreat on "Purposeful Research: From Study Design to Prevention" from Jan 8-11, 2019 at the Hacienda Misné in Merida, Yucatan Mexico. ISCHE is a private, non-profit society composed of children's environmental health professionals with the goal of using research, training, policy, clinical care, community outreach, and education to reduce the impact of adverse chemical, physical, biological and social influences on children's health. Through our ongoing partnership with Dr. Tellez-Rojo and her team at INSP, we are committed to the dissemination of our research on environmental and dietary determinants of child obesity and metabolic outcomes, as well as educate and inform public health researchers in Mexico and internationally

Data Management and Modeling Core (DMMC):

Building upon our comprehensive P01 Data Management Plan, which regulates and streamlines the details of data storage, transfer, use and dissemination, our Data Management and Modeling Core (DMMC has provided ongoing biostatistical support and database management for the Center under the direction of Dr. Peter Song. The DMMC team has enhanced investigators' and trainees' study designs and data analysis plans and provided technical consultation in statistical programming, presentation of methods and interpretation of findings for manuscript and poster/presentations at scientific meetings as well as grant applications.

The DMMC also provides active oversight of data management for all UM-CEHC research projects. Over the last 5 years, the DMMC received and fulfilled over 175 data requests from UM-CEHC investigators to support various projects, including student theses, dissertations, scientific manuscripts and proposals. In coordination with our partners at INSP, the DMMC received data from 550 subjects from the first and second study visits in the ELEMENT cohort over six waves of database breaks, and the data is stored and documented in the secured UM data repository. DMMC has created a detailed data management plan that defines clearly procedures of data sharing requested by all UM-CEHC research projects. Over the years, DMMC has also derived new variables from raw data; for example, the normalization of metabolomics data with corrected batch effects and missing data, and measures of confounders of associations of toxicants with health outcomes (total energy intake adjustment for food groups and nutrients, sleep duration and efficiency and physical activity levels from accelerometry data). The DMMC continues to receive new lab results from assays conducted on both MMIP and ELEMENT cohorts and incorporated these into the data repository as well. As part of effort on the data sharing and data coordination, the DMMC has worked closely with our INSP team to prepare and send all data of lab results (including metal, metabolomics, DNA methylation assays) generated in the U.S. to Mexico, ensuring that the entire ELEMENT data are synchronized across the two research centers (UM-CEHC and INSP). All data transfers and storage are performed behind a secure firewall protected by the University of Michigan M+Box

We have also developed a novel toolbox to preprocess untargeted metabolomics data to generate cleaned and normalized data to all projects involving metabolite features. Several key techniques developed for the metabolomics data preprocessing include batch effect normalization, K-nearest neighbor imputation and variable transformations. This toolbox is supporting ongoing preparation and publication of manuscripts relating lead exposure in utero and adolescence to metabolomics.

Finally, Dr. Jong Gyu Baek developed the Newton's Growth Model (NGM), which enables researchers to examine infant BMI growth dynamics of trajectory, velocity, acceleration with relation to in utero exposure to environmental toxicants (BPA and phthalates). NGM is implemented in the Bayesian framework to leverage prior knowledge of infant growth in World Health Organization (WHO). This model was used in Dr. Wei Perng's paper "Associations of the infancy body mass index peak with anthropometry and cardiometabolic risk in Mexican adolescents published in Annals of Human Biology in 2018 (DOI: 10.1080/03014460.2018.1506048) and in a study led by Christina Zhou, MS student in Biostatistics: Late pregnancy urinary phthalate metabolite associations with infant growth characteristic peak deferral: a longitudinal study in Mexico City (under review, JDOHaD).

All Research Projects:

Note: Project 2 examines the relationship of exposures to mixtures of metals (Cd, Pb) and EDCs (BPA and phthalates) in two cohorts during two time periods: pregnancy (MMIP and ELEMENT) and the peripubertal transition (ELEMENT only) to metabolic homeostasis and oxidative stress. Project 1 relates these exposures to physical growth trajectories and sexual maturation and serum reproductive hormone levels in the ELEMENT cohort. To maximize efficient use of resources and quality control, exposure assessment for both Projects 1 and 2 is conducted by Dr. Meeker, PI Project 1, detailed below. Fieldwork involving ELEMENT participants during adolescence for both Projects is overseen by Dr. Peterson and Dr. Tellez-Rojo (INSP subcontract) through Project 2 and is described in more detail there.

Project 1: Perinatal and Prepubertal Mixtures, Physical Growth, and Sexual Maturation

Investigator(s): Dr. John Meeker

Follow-up of ELEMENT participants:

Between 2015 and 2018, we followed-up ELEMENT participants at two different time points (T1 and T2), including those that were re-recruited from our P20 ES01817101/RD834800 (Peterson) plus additional participants from the larger ELEMENT cohorts. We increased our sample size from the initially projected 400 participants to 550 participants for our T1 visit and 520 for T2, as re-recruitment proceeded at a faster pace than originally planned. Approximately 90% and 86% of the P20 participants were re-recruited for each visit, T1 and T2 respectively, in whom we have repeated measures during pregnancy and now repeated measures during adolescence of both exposures and outcomes. Participants were re-recruited according to priority, reflecting the availability of matched archived cord blood and/or prenatal urine and blood samples and the distribution of children's ages needed to ensure information on sexual maturation, reproductive hormones and measures of cardiometabolic risk and metabolomics and oxidative stress markers is collected across the entire pubertal transition.

Exposure and outcome assessment:

Metals have been shown to induce oxidative stress, which plays a role in many health outcomes, including cardiovascular, metabolic, and renal disease, while others have been shown to disrupt the endocrine system, with implications for thyroid function, reproduction, metabolism, and many other health endpoints. Personal care product use has been identified as a potential source of metals exposure among children, but studies have been limited. In the ELEMENT cohort we analyzed the urinary concentrations of 10 metals (aluminum [Al], arsenic, barium [Ba], cadmium, cobalt [Co], lead, manganese [Mn], molybdenum [Mo], nickel [Ni], and zinc [Zn]) in pregnant women (n = 212) and their children (8–14 yr; n = 250) to characterize (1) third trimester urinary metal concentrations as an index of in utero exposure, and (2) among their children between the age of 8–14 years, and finally (3) to evaluate potential associations between children's recent personal care product use and urinary metal concentrations. Metals were detected in 80–100% of urine samples, with significant differences in maternal versus childhood levels but were not strongly correlated. In children, linear regression models including demographic characteristics, BMI z-score, and specific gravity, age were associated with higher Co (6% [95% CI: 2, 10]), while BMI z-score was associated with lower Mo (-6% [95% CI: -11, -1). Significantly higher metal concentrations were observed among users of colored cosmetics (Mo: 42% [95% CI: 1, 99]), deodorant (Ba: 28% [3, 58]), hair spray/hair gel (Mn: 22% [3, 45]), and other toiletries (As: 50% [9, 108]), as well as with an increasing number of personal care products used (As: 7% [3, 11]). However, lower metal concentrations were noted for users of hair cream (As and Zn: -20% [-36, -2] and -21% [-35, -2], respectively), shampoo (Pb: -40% [-62, -7]), and other hair products (Pb: -44% [-65, -9]). Overall, we found that recent use of personal care products among children is associated with exposure to multiple metals Longitudinal studies are needed that collect detailed information on personal care product specifics (e.g., brand, product line) and use patterns (e.g., amount and frequency) and would allow investigation of temporal relationships.

EDCs and growth:

Differences between energy intake and physical activity expenditure are considered the largest risk factors for the development of obesity, but increasing evidence suggests exposures to EDCs such as bisphenol A (BPA) and phthalates are implicated in weight dysregulation. As gestation is a sensitive period for the development of obesity in offspring due to rapid cell differentiation occurring in the fetus, exposures to EDCs during this period are of special concern.

Addressing Aim 1, we evaluated associations between maternal third trimester and concurrent urinary BPA, and individual and summed phthalates metabolites—∑Di(2-ethylhexyl phthalate), ∑high molecular weight, ∑low molecular weight)—with BMI z-score, waist circumference, and sum of triceps and subscapular skinfold thickness in 249 children ages 8–14 years. Prenatal and childhood exposure to phthalates was inversely associated with BMI z-score, waist circumference and skin fold thickness (Yang et al, Environ Res 2017). Prenatal urinary exposure to monobenzyl phthalate (MBzP) was inversely to BMI z-score and child urinary exposure to mono(2-ethylhexyl) phthalate (MEHP) was inversely associated with waist circumference and sum of skinfold thicknesses. In girls, higher concurrent BPA exposure was positively associated with BMI z-score, while higher MEHP was inversely associated with sum of skinfold thickness in boys We also constructed BMI (kg/m2) trajectories from birth to 14 years and evaluated associations with tertiles of third trimester maternal urinary concentrations of BPA and phthalates metabolites. We observed that in utero exposure, to phthalate metabolites differentially influenced the BMI trajectories from birth to 14 years of boys and girls. In girls, the highest level of exposure to MECPP was associated with the highest predicted BMI by age 14, while lower levels of exposure to MiBP, MBzP, MEHP, and MEHHP were associated with the highest predicted BMI in boys (Yang et al, Pediatric Obesity 2018).

Findings from the ELEMENT cohort on maternal phthalate exposure during pregnancy can be related to those seen in U.S. study populations, such as the ongoing Michigan Mother-Infant Pairs cohort (MMIP), where we have also characterized maternal urinary phthalate metabolite concentrations during the prenatal period. MMIP women provided urine and blood samples during their first trimester and at delivery. Urinary phthalate metabolites and serum BPA were measured at both time points, and birth weight, length, head circumference, and gestational age were recorded from medical records. Maternal urinary phthalate metabolite concentrations were not correlated with concentrations measured at delivery, emphasizing the need for repeated phthalate measures during pregnancy to assess prenatal exposure. In addition, maternal DEHP metabolite concentrations were significantly higher at delivery compared to the first trimester, suggesting increased DEHP exposure late in pregnancy. Several phthalate metabolites were associated with birth size and gestational age in patterns that varied by sex and timing of exposure, independent of BPA exposure.

Phthalates, BPA, and sexual maturation:

Phthalates and BPA are known endocrine disruptors and exposure in pregnant mothers and children is ubiquitous. Both phthalates and BPA are classified as endocrine disruptors because of their ability to disrupt hormone action through anti-androgenic and estrogenic mechanisms, respectively. Many studies have examined the relationship between exposure to these compounds and sex hormone levels in adults, including analyses utilizing the NHANES data by our team (Meeker et al, J Clin Endocrinol Metab. 2014), however few studies have measured associations in children, and even fewer have examined the impact of prenatal exposures on sex hormone levels and timing of puberty. Additionally, previous studies have been primarily cross-sectional, although in utero exposure may play an important role in later development. Addressing Aim 2, we have examined phthalate and BPA exposure during two potentially sensitive developmental time points –in uteroand peripubertal – in relation to serum hormone concentrations and physical measures of puberty in boys (Ferguson et al, Reprod Toxicol. 2014) and girls (Watkins et al, Environ Res. 2014) ages 8-14 years For these analyses, phthalate metabolites and BPA were measured in maternal 3rdtrimester and childhood urine. Sex hormones DHEAS, estradiol, inhibin B, SHBG, and total testosterone were measured in serum. In boys, we assessed Tanner stages for genital and pubic hair development, and measured testicular volume using an orchidometer and among girls, we assessed for breast and pubic hair development and collected information on menarche onset. We used linear and logistic regression to model associations between in utero and peripubertal measures of exposure with hormones and sexual maturation, respectively, controlling for covariates.

In boys, we found that prenatal exposure to some phthalates was associated with decreased DHEAS, an early indicator of adrenarche, inhibin B levels, and with increased SHBG. Prenatal exposure to most phthalates and BPA was associated with reduced odds of adrenarche (OR = 0.12–0.65) and slightly reduced odds of pubertal onset (OR = 0.50–0.98). Childhood exposure was not associated with measures of sexual maturation, but some phthalates and BPA were associated with increased SHBG levels and decreased total and free testosterone levels. Conversely in girls, an interquartile range (IQR) increase in in utero urinary MEHP was positively associated with 29% higher DHEAS and 5.3 times higher odds of a Tanner stage >1 for pubic hair development. In utero MBzP and MEP were positively associated with peripubertal testosterone and peripubertal DEHP metabolites were not associated with either hormones or measures of sexual maturation. Our findings suggest that exposure to phthalates during in utero development may impact circulating levels of sex hormones during peri pubescence as well as the timing of sexual maturation in boys and girls.

We also examined the associations between trimester-specific phthalate and BPA exposure in relation to measures of reproductive development among peripubertal boys and girls in the ELEMENT cohort. Exposure and outcome assessment where done as in previous studies, except for measuring maternal urinary phthalate metabolites and BPA in samples collected during the first, second, and third trimesters of pregnancy. To our knowledge, these were the first studies (Watkins et al. Environ Health 2017; Watkins et al. Environmental research 2017) to evaluate maternal urinary phthalate metabolite and BPA concentrations during first, second, and third trimesters of pregnancy, as well as the level and rate of change of exposure across pregnancy, in relation to peripubertal reproductive hormone levels and measures of sexual maturation among their children. We used linear and logistic regression to examine measures of trimester-specific in utero exposure as predictors of peripubertal hormone levels and pubertal onset, respectively. In sensitivity analyses, we evaluated estimated exposure at 7 weeks gestation (middle of the first trimester) and rates of change in exposure across pregnancy in relation to outcomes.

In boys, findings suggest that compared to phthalate exposure early in pregnancy, specifically during the third trimester is associated with reduced odds of adrenarche and a corresponding increase in serum SHBG concentrations. In addition, we observed an increase in peripubertal serum estradiol associated with DEHP exposure specifically in the first trimester of in utero development (Watkins et al, Environ Health, 2017). Meanwhile in girls, we found that testosterone concentrations and breast development were associated with specific phthalates across pregnancy, while markers of adrenarche, such as DHEA-S concentrations and pubic hair development, were associated with specific phthalates measured only during the third trimester (Watkins et al, Environ Res, 2017).

Metals and Sexual Maturation:

Pb is a pervasive toxic metal that remains a public health concern, and is known to have deleterious effects on health, even at relatively low concentrations. Exposure in early life has been associated with growth deficits in infancy and childhood. Growth during adolescence also may be sensitive to effects of exposure to this metal, given the changes in distribution of lean and adipose tissue that vary by sex during puberty. While subtle Pb-related effects on sexual maturation have been reported in animal studies, it remains uncertain whether prenatal Pb exposure is related to timing of sexual maturation in the offspring. Whereas animal studies have consistently shown that prenatal exposure to lead is related to later onset of puberty, findings in human populations are mixed.

Looking to fill this gap, we analyzed this association among 200 girls from the ELEMENT cohort who were followed since the first trimester of gestation. Maternal blood Pb levels were analyzed once during each trimester of pregnancy, and daughters were asked about their first menstrual cycle at a visit between the ages of 9 and 18 years. We estimated hazard ratios (HRs) and 95% confidence intervals (CI) for probability of menarche over the follow-up period using interval-censored Cox models, comparing those with prenatal blood lead level ⩾5 µg/dl to those with prenatal blood lead <5 µg/dl. We also estimated HRs and 95% CI with conventional Cox regression models, which utilized the self-reported age at menarche. In adjusted analyses, we accounted for maternal age, maternal parity, maternal education, and prenatal calcium treatment status. Across trimesters, 36-47% of mothers had blood lead levels ⩾5 µg/dl. Using interval-censored models, we found that during the second trimester only, girls with ⩾5 µg/dl prenatal blood lead had a later age at menarche compared with girls with prenatal blood lead levels <5 µg/dl (confounder-adjusted HR=0.59, 95% CI 0.28-0.90; P=0.05). Associations were in a similar direction, although not statistically significant, in the conventional Cox regression models, potentially indicating measurement error in the self-recalled age at menarche. In summary, higher prenatal lead exposure during the second trimester is associated with later onset of sexual maturation and later age at menarche.

Further, we examined the association of not only prenatal but also early childhood Pb exposure with pubertal stages among 264 boys and 283 girls in ELEMENT (9.8-18.0 years of age). In this study, we aimed to address two research gaps: (1) the lack of studies characterizing multiple sensitive periods of exposure using a longitudinal design and (2) studies focused in boys. We measured maternal bone lead (a proxy for cumulative fetal exposure to lead from maternal bone stores mobilized during pregnancy) at 1 month postpartum. Blood lead was measured annually from 1 to 4 years. Pubertal stage was assessed by a pediatrician. We examined the association between lead and pubertal stages of breast, pubic hair and genitalia using ordinal regression. Age at menarche was evaluated using Cox proportional-hazard models. Multivariate models showed that maternal patella lead and early childhood blood lead were inversely associated with breast growth in girls. Girls with maternal patella lead in the 3rd tertile and child blood lead in the 2nd tertile had a later age at menarche compared with girls in the 1st tertile. Additionally, early childhood blood lead was negatively associated with pubic hair growth in girls. No associations were found in boys. Our data suggest that higher prenatal and early childhood exposure to lead may be associated with delayed pubertal development in girls but not boys. Our findings are consistent with previous analyses and reinforce the reproductive effects of lead for girls. More research still needed in boys.

Recent studies found associations between metals such as Cu, Mn, and Mo and adverse effects on male reproduction, but few studies have measured associations in adolescents, and none have examined the impact of in utero exposures on sex hormone levels and timing of puberty. Therefore, among 132 girls in the ELEMENT cohort, we examined the association between in utero and concurrent exposure to essential and non-essential metals and sex hormone levels, and measures of sexual maturation at age 8 to 13 and again at 14–18 years. We measured urinary concentrations of Al, As, Ba, Cd, Co, Cu, Fe, Mn, Mo, Ni, Sb, Se, and Zn in samples collected from women during their third trimester of pregnancy and from their female children at 8–13 years Higher in utero Zn was associated with increased inhibin B. Several metals at 8–13 years were associated with higher DHEA-S and estradiol, while Ni was positively but Cu was negatively associated with testosterone. In utero Ni, Al, and Cd were associated with slower progression of breast development after adjustment for child age and BMI z-score (Ashrap et al, Environ Res, 2019). These findings suggest that female reproductive development may be vulnerable to the effects of metal exposure and using both Tanner stages and hormone levels may provide clues about underlying mechanisms in two sensitive periods of development.

EDCs and Neurodevelopment:

Exposure to exogenous chemicals such as EDCs can impact endocrine function at multiple sites and through numerous specific modes of actionNeurodevelopmental disorders are prevalent in the United States and worldwide, with evidence that rates of certain disorders such as attention-deficit/hyperactivity disorder and autism spectrum disorders have been increasing in recent years. While it is likely that these trends are attributable to numerous factors including changes in diagnostic practices, there is growing evidence that exposure to EDCs may play a significant role. Sex steroid hormones are vital to central nervous system development. In addressing Aim 3, we have explored interactions between in utero and peripubertal exposures to pesticides, metals, and phthalates and their impacts on child cognitive development

In recent years, pesticide use has increased in Mexico, the United States, and elsewhere, resulting in extensive human exposure. Given the growing concern that pregnant women and their developing fetus may be particularly vulnerable populations, we characterized prenatal urinary concentrations of 3-phenoxybenzoic acid (3-PBA; a non-specific metabolite of several pyrethroids insecticides and biomarker of exposure to the fetus) during the third trimester of pregnancy in 187 mother-child pairs from the ELEMENT cohort. We also measured 3-PBA during the first, second, and third trimester in a small subgroup (n=21) to assess variability across pregnancy. We examined associations between third trimester 3-PBA concentrations and children's scores on the Mental Development Index (MDI) and Psychomotor Development Index (PDI) from the Bayley Scales for Infant Development (BSID-IIS) at 24 and 36 months of age. 3-PBA was detected in 46% of all urine samples, with similar detection rates and geometric mean concentrations across pregnancy among the 21 participants who provided repeat samples. Participants in the medium and high 3-PBA categories (≥LOD) had lower MDI scores at 24 months compared to those in the low 3-PBA category (

Attention Deficit Hyperactivity Disorder (ADHD) is the most commonly diagnosed and studied cognitive andbehavioral disorderin school-age children. The etiology of ADHD and ADHD-related behavior is unclear, but genetic and environmental factors, such as pesticide exposure, have been hypothesized. Looking at the prenatal period as a potential window of susceptibility, we have explored the relationship between in utero exposure to chlorpyrifos, chlorpyrifos-methyl, and/or 3,5,6-trichloro-2-pyridinol (TCPY) and ADHD in school-age ELEMENT children using TCPY as a biomarker of exposure. We also explored the temporal reliability of maternal urinary TCPY concentrations across trimesters among a subset of the ELEMENT mothers. To explore associations with ADHD-related outcomes in children, third trimester urinary TCPY concentrations were measured in the same mother-child pairs described above. Child neurodevelopment was assessed using Conners' Parental Rating Scales-Revised (CRS-R), Conners' Continuous Performance Test (CPT), and Behavior Assessment System for Children-2 (BASC-2) when the children were 6–11 years of age. Multivariable linear regression models were used to test relationships for all children combined and stratified by sex. Intraclass correlation coefficients (ICC) calculations were based on random effects models. The ICC was 0.41 for uncorrected TCPY and ranged from 0.29 to 0.32 for specific gravity-corrected TCPY. We did not observe any statistically significant associations between tertiles of maternal TCPY concentrations and ADHD-related outcomes in children. However, compared to the lowest tertile we found suggestive evidence for increased ADHD index in the highest TCPY tertile in boys and increased attention problems for the middle tertile in girls.

Lead exposure has previously also been reported to be associated with ADHD or ADHD symptoms. Higher blood Pb levels have been observed in children with ADHD, and positive associations between blood Pb and increased likelihood of ADHD symptoms or ADHD diagnosis have been observed in studies using various behavioral scales in cross-sectional studies. However, the associations between Pb exposure and ADHD subtypes are inconsistent and understudied and the mechanism of lead contributing to the risk of ADHD, especially regarding the different behavior subtypes, remains unclear. In a sample of 578 Mexican children 6-13 years of age from the ELEMENT cohort, we have explored the association between concurrent Pb exposure and the prevalence of ADHD behaviors regarding three subtypes: hyperactivity, inattention, and the combination of hyperactivity and inattention. We measured concurrent blood Pb levels using inductively coupled plasma mass spectrometry (ICPMS) and administered the Conners' Rating Scales-Revised (CRS-R) to mothers to evaluate their children's ADHD symptoms. We imputed missing values for blood Pb levels and used segmented regression models adjusted for relevant covariates to model the nonlinear relationship between blood lead and ADHD symptoms. Mean ± SD blood lead levels were 3.4 ± 2.9 μg/dL. We found that concurrent blood lead was associated with hyperactive and impulsive behaviors in 6- to 13-year-old children. However, the association did not exhibit a linear relationship. We observed a trend of worsening responses associated with increasing blood Pb levels below approximately 5 μg/dL, followed by a plateau or slightly decreasing trend when blood Pb level was > 5 μg/dL. We did not observe any association between concurrent blood Pb and inattentiveness or overall ADHD symptoms. Our study concurs with previous studies demonstrating an association of concurrent Pb exposure with ADHD-symptoms. However, this association was attenuated when levels were > 5 μg/dL, which may explain why behavior problems are not often linked with lead exposure on an individual basis, given the lack of a clear dose–response relationship at levels more typically characterized as "elevated. The potential impact of low-level lead exposure on a population basis is large and raises a serious public health concern particularly in areas where environmental lead contamination continues.

We also have evaluated in utero and peripubertal phthalate exposure in relation to ADHD symptoms within the ELEMENT population at two different time points in development: 6-12 and 9-18 years of age. In utero MCPP and SDBP were associated with increased self-report of inattention and hyperactivity in childhood (6-12 years), but we found no relationships between in utero phthalate exposure and parent-reported ADHD behaviors or performance on the CPT (Watkins et al., ISEE 2016, manuscript in prep). However, in utero MCPP, SDBP, and MBzP levels were associated with poorer performance on the CPT in adolescence (9-18 year), indicating inattention (Watkins et al. ISEE 2018, manuscript in prep). In addition, adolescent SDEHP exposure was associated with CPT scores indicating higher inattention among both boys and girls.

Project 2: Metabolic Consequences of In Utero and Peripubertal Toxicant-Diet Exposures

Investigator(s): Dr. Karen Peterson and Dr. Vasantha Padmanabhan

ELEMENT Exposure and outcome assessment:

We completed exposure assessments for 405 ELEMENT adolescents for phthalates, phenols, a 16-metal panel, and blood lead levels. These exposures were also assessed from 180 archived maternal urines We also completed analysis of untargeted metabolomics and conventional markers of metabolic risk (e.g. insulin, glucose, lipids; blood pressure and anthropometry) in 405 adolescents as well as targeted metabolomics (amino acids and acyl carnitine) on a subset 208 participants. Candidate gene DNA methylation analysis (LINE-1, H19, HSD11B2, PPARA) was completed for 385 of these adolescents; epigenome-wide analysis of DNA methylation at >850,000 CpG sites via the Infinium MethylationEPIC BeadChip was completed using DNA from 322 blood leukocyte or cord blood leukocyte samples from three time periods (in utero, early and late adolescence).

MMIP Assessment of toxicant exposures and physiological biomarkers:

Extensive exposure assessment, molecular and metabolic phenotyping was completed on samples from subsets of MMIP mothers and newborns, including urine, blood, and plasma from women collected during the first trimester and at term and plus umbilical cord blood, placenta, and cord collected from infants at delivery. Concentrations of unconjugated BPA and BPA glucuronide were measured in matching plasma from 80 MMIP families using a methodology validated in the NIEHS-funded Round Robin study (Vandenberg et al, Environ. Health 2014). Maternal urinary concentrations of nine phthalate metabolites were also quantified in 68 of the same women at NSF International in Ann Arbor, MI, revealing a range of exposure levels. Among a subset of 56 MMIP mothers, exposure analysis was expanded to include quantification of concentrations of 12 phthalate metabolites, 12 phenols, and 17 trace elements and toxic metals in first trimester urine. Biomarkers of oxidative stress and inflammation were measured in MMIP biospecimens along with targeted and untargeted assessment of the metabolome and lipidome. Epigenetic (DNA methylation) and transcriptomic (gene expression) assessment of samples from MMIP neonates were also completed using targeted and genome-wide approaches.

Methods for epigenetic assessment:

In both ELEMENT and MMIP, we examined whether epigenetic changes underlie the associations between EDC exposures, metabolic homeostasis, oxidative stress, and birth outcomes, child adiposity, pubertal timing We originally designed and tested pyrosequencing assays to quantify DNA methylation at 12 genes, and utilized the best performing 6 in downstream analyses: two imprinted loci (IGF2, H19), an estrogen receptor gene (ESR1), peroxisome proliferator-activated receptor alpha (PPARA), hydroxysteroid 11-beta dehydrogenase 2 (HSD11B2), and LINE-1 repetitive elements. DNA methylation was quantified via pyrosequencing at these optimized regions in (cord) blood leukocyte samples from ELEMENT (at birth, in early adolescence, and late adolescence) and MMIP. Epigenetic analysis was expanded to quantify DNA methylation at >850,000 CpG sites throughout the genome including within all known genes via the Infinium MethylationEPIC beadarray in subsets of samples from both ELEMENT (cord blood, blood) and MMIP (cord blood, placenta). Gene expression was evaluated in some of these samples via RT-qPCR and/or next generation sequencing (RNA-seq).

Aim 1-ELEMENT:

Phthalates metabolites and metabolic markers

Metabolic processes are vulnerable to environmental perturbations during stages characterized by hormonal fluctuations and rapid maturation of organ systems, e.g., in utero and during puberty. Addressing Aim 1, within 249 ELEMENT participants ages 8-14, we found higher concentrations of the phthalate metabolite MEHP were associated with a decrease in sum of skinfold thickness in boys while BPA exposure was associated with an increase in BMI z-score in girls among children who had not entered puberty. (Yang et al, Environ. Res. 2017) Since serum lipid concentrations track from childhood into adulthood, we also examined relations of in utero and peripubertal BPA and phthalate exposure with peripubertal serum triglycerides, total cholesterol, LDL-C, and HDL-C), adjusting for age, sex, and urinary specific gravity. In utero EDC exposure was not related to lipid profile during peripuberty, but we observed sex-specific associations with concurrent phthalate exposure. In boys, higher urinary levels of MCPP, MEP, and ΣDBP at 8–14 years was related to lower total cholesterol and LDL-C, while MBzP was associated with higher HDL-C. In girls, higher urinary ΣDEHP correlated with lower LDL-C (Perng et al, Environ. Res. 2017). Overall, these findings suggest associations of EDCs with obesity and cardiometabolic outcomes depend on timing of exposure, as well as sex and pubertal status.

Phthalate exposure also has been associated with hormonal mechanisms involved in metabolic homeostasis. Among 250 ELEMENT adolescents, we found that phthalate metabolites and BPA were associated with metabolism biomarkers at age 8-14 years in patterns that varied by sex, pubertal status, and exposure timing. In utero MEP was associated with lower insulin secretion among pubertal boys and higher leptin among girls. In utero DEHP was associated with higher IGF-1 among pubertal girls; peripubertal DEHP was associated with higher IGF-1, insulin secretion, and resistance among prepubertal girls. In contrast, peripubertal DBP, MBzP, and MCPP were associated with lower IGF-1 among pubertal boys. Peripubertal BPA was associated with higher leptin in boys. In conclusion, we observed that urinary phthalate metabolites and BPA measured during both in utero and peripubertal development were associated with markers of glucose and lipid metabolism at age 8–14 years in patterns that varied by both sex and pubertal status. (Watkins et al, JCEM 2016).

Metals (Pb & Cd) and metabolic risk components

Lead (Pb) exposure remains a public health concern and exposure in early life has been associated with growth deficits in infancy and childhood. Growth during adolescence also may be sensitive to effects of exposure to lead, given the changes in distribution of lean and adipose tissue that vary by sex during puberty Previous ELEMENT studies reported that prenatal Pb, reflected by maternal patella Pb, is associated with a lower weight trajectory among 0- to 5-year-old girls We investigated the associations of prenatal and early-life exposure to maternal bone lead at 1 mo postpartum and cumulative blood lead from 1 to 4 years with indices of adiposity. Prenatal but not childhood lead exposure was significantly associated with a decrease in child BMI z-score, waist circumference, sum of skinfolds and body fat percentage at ages 8–16 years, highlighting the role of early lead exposure in the fetal programming of child growth (Liu et al, Int. J. Hyg. Environ. Health 2019).

Prospective studies have related prenatal Cd exposure to growth deficits in early childhood, but it is not known whether effects of prenatal exposure on growth persist into adolescence. We examined whether prenatal and concurrent Cd exposures are related to adiposity among 185 participants ages 8-15 years. Maternal third trimester and adolescent urines were analyzed for Cd using an Inductively Coupled Plasma Mass Spectrometer (ICPMS). We found prenatal cadmium exposure was negatively associated with measures of abdominal and peripheral adiposity in girls, but not in boys. An IQR increase in prenatal Cd was associated with percent decreases in BMI z-score (−27%, p = 0.01), waist circumference (−3%, p = 0.01), and subscapular (−11%, p = 0.01), suprailiac (−11%, p = 0.02), and triceps (−8%, p < 0.01) skinfold thickness. Results emphasize sex-dependent effects of in utero Cd exposure on adiposity in adolescence (Moynihan et al, Frontiers Pub Health 2019).

Aim 1-MMIP:

In utero EDC exposures and birth outcomes

We measured unconjugated BPA and BPA glucuronide in 80 sets of matching MMIP plasma samples (maternal first trimester, term, and in cord blood), and related BPA concentrations to birth outcomes. A 10-fold increase in maternal first trimester unconjugated BPA was associated with 183 g lower birth weight when male and female pregnancies were combined and 607 g lower birth weight with only female pregnancies, as well as with increased gestational length: 2.2 days for all pregnancies and 3.7 days for only female pregnancies. The impact of early pregnancy BPA levels on reducing birth weight highlights the risk posed by developmental exposure to BPA (Veiga-Lopez et al, J Clin Endocrinol Metab. 2015). We then examined associations between 9 phthalate metabolites in first trimester and term maternal urine samples with infant size and gestational age. DEHP metabolite concentrations were significantly higher at delivery compared to the first trimester, and a number of phthalate metabolites were associated with birth size and gestational age in patterns that varied by sex and timing of exposure (Watkins et al, Reprod Toxicol. 2016).

After exposure assessment was expanded to include 12 phenols, 12 phthalate metabolites, and 17 elements/metals in a subset of 56 first trimester maternal urine samples, we reported detection of an average of 30 toxicants per woman in the first trimester. Self-reported fast food consumption was associated with several phthalate metabolites, phenols, and metals, and canned food consumption was correlated with bisphenol F Mono (3-carboxypropyl) phthalate was significantly associated with higher birth weight and Fenton z-score while the opposite was observed for bisphenol S. Estimated femur length from ultrasonography in mid-pregnancy was significantly inversely associated with arsenic, barium and lead. Overall, this study was one of the first to evaluate birth outcomes with respect to emerging endocrine disrupting chemicals and to examine associations between toxicants and fetal biometrics (Goodrich et al, J Dev Orig Health Dis. 2019).

In utero EDC exposures and biomarkers of oxidative stress and inflammation

Given associations between gestational exposures and fetal and pregnancy outcomes, we profiled oxidative stress and inflammatory biomarkers to investigate possible mechanisms underlying the effects of toxicants Matched samples from human pregnancies (n=24) during the first trimester and at term, as well as cord samples were used to determine the impact of BPA on free fatty acid and oxidative stress dynamics. Mothers exposed to higher BPA during early to mid-pregnancy and their matching term cord samples displayed increased 3-nitrotyrosine, a marker of nitrosative stress. Maternal samples had increased palmitic acid, which was positively correlated with 3-nitrotyrosine. These findings provided evidence of the induction of nitrosative stress by prenatal BPA in both the mother and the fetus at time of birth and is thus supportive of the use of maternal 3-nitrotyrosine as a biomarker for offspring health (Veiga-Lopez et al, Endocrinology 2015). Associations between 41 first trimester exposures (phenols, phthalates, and trace elements/metals) and oxidative stress, e.g., nitrotyrosine, dityrosine, chlorotyrosine in first trimester, term plasma and cord blood plasma, using principal components analysis. We found an inverse relationship between levels of maternal/cord oxidative stress markers and individual exposures overall. For example, maternal term nitrotyrosine was inversely associated with gestational age. Nevertheless, both direct and inverse associations were evident in sex-specific analyses. In the same 56 families, 12 cytokines were measured in first trimester and cord plasma and related to exposures (individually and as mixtures) and birth outcomes. We reported positive associations between cytokines and gestational age or birth weight. For example, first trimester cytokines (MIP-1alpha, IL-8, TNF-alpha) were positively associated with birth weight. We also reported associations between individual exposures and weighted exposure mixtures with cytokines. For example, first trimester BPA was positively associated with maternal tem MCP-1 (Kelly et al, Sci Rep. 2019).

Maternal and neonatal metabolite profiles

The offspring metabolome may be reprogrammed early in development and may serve as a marker of early risk for metabolic related diseases later in life. Using targeted metabolomics and quantitative DNA methylation analyzed in 1st trimester, delivery and cord blood plasma, we found very long chain fatty acids, medium chain acylcarnitines, and histidine were: (1) stable in maternal plasma from pregnancy to delivery, (2) significantly correlated between maternal and child samples, and (3) the top 10% of maternal metabolites correlated with infant DNA methylation, suggesting maternal metabolites related to infant DNA methylation are tightly controlled. Global DNA methylation was highly correlated across maternal and child samples, suggesting circulating maternal lipids are related to epigenetic programming (Marchlewicz et al, Scientific Reports 2016).

Aim 2-ELEMENT:

Growing evidence suggests that diet modifies susceptibility to toxicants through effects on absorption, distribution, and toxicity, via down-regulation of signaling pathways involved in the inflammatory response, protection against oxidative stress, and competitive binding with toxicants Cadmium is a ubiquitous, toxic metal with modifiable exposure sources including cigarette smoking and diet. In ELEMENT, we estimated DCd intake in 192 mothers during the third trimester of pregnancy and in 223 adolescents, and estimated DCd using the US Total Diet Survey. Sources of DCd were similar between pregnant women and children, were correlated with UCd among those without a maternal history of smoking and showed that fruits and vegetables were the primary source of DCd and were positively associated with UCd. (Moynihan et al, Science Total Environ 2016)

Dental caries is an important public health problem in Mexico, a country also faced with high exposure to toxicants including Pb. A limited number of population-based studies have examined the potential associations between Pb exposure and dental caries risks in adolescence, but to our knowledge, none have assessed the associations of Pb exposure at multiple sensitive life periods. In addition, among dietary factors, sugar-sweetened beverage (SSB) consumption is most strongly and consistently associated with higher risk of dental caries, thus making the interaction between Pb exposure and SSB intake in relation to caries risk in adolescence a concern. In a group of 386 ELEMENT children ages 10-18 years, we found that while Pb exposure during sensitive developmental periods was not statistically significantly associated with caries risk after accounting for confounders among our cohort, evidence from stratified analysis suggested a Pb-caries association among children with high SSB intake. Associations among those with lower SSB intake were roughly half those of the higher group and not statistically significant (Wu et al, Science of the Total Environment 2019).

Aim 3-ELEMENT:

Targeted DNA methylation and EDC exposures during sensitive developmental periods

Recent studies suggest that perinatal Pb changes DNA methylation patterns among rodentsand is associated with differences in DNA methylation in humans, but the impact ofin uteroPb exposure on the epigenome of neonates is understudied. We examined the association between DNA methylation (in LINE-1, IGF2, H19 and HSD11B2) and Pb concentrations in umbilical cord blood, maternal tibia and patella), in 247 mother-infant pairs in the ELEMENT cohort. IGF2andHSD11B2 methylation was higher among those with higher maternal patella Pb levels. Sex-specific trends between Pb and DNA methylation were observed among girls including a 0.23% increase in HSD11B2 methylation with 10 μg/g higher patella Pb, but not among boys To explore the effects of concurrent Pb exposure in the adolescence and to include additional EDCs to our analysis (BPA, and nine phthalates metabolites) described above, we also examined their association leukocyte DNA methylation at LINE-1 repetitive elements and IGF2,H19, andin adolescence. Pb was only associated with LINE-1 hypomethylation during pregnancy (P= 0.04), while early childhood Pb was related to H19 hypermethylation (P= 0.04). Concurrent MEHP was associated withHSD11B2hypermethylation. Sex-specific associations, particularly among males, were also observed. Principal component analysis was employed to examine exposure mixtures; this method largely corroborated the findings of the single exposure models. Overall, findings emphasize that environment-epigenetic relationships vary by chemical, exposure timing, and sex.

Our prior research in ELEMENT identified associations between phthalate exposure and DNA methylation ofH19andHSD11B2(Goodrich et al. Environ Epignetics, 2016) as well as between phthalate exposure and weight status and adiposity at one childhood time point (Yang et al. Environ Res. 2017; Yang et al. Pediat Obes. 2018). Extending these studies to include trimester-specific measures and repeat measures of adiposity in ELEMENT children, we evaluated DNA methylation at H19andHSD11B2are mediators between phthalate exposures in sensitive developmental periods and BMI-for-age z-score, skinfolds thicknesses, and waist circumference. Urinary phthalate metabolite concentrations were quantified in mothers at each of the 3 trimesters and in children at the first peri-adolescent study visit. Blood leukocyte DNA methylation at H19 and HSD11B2 was quantified during the first adolescent visit, and adiposity was measured at the first visit and ~3 years later among 223 ELEMENT participants (n = 109 boys, 114 girls). Even though the analysis was underpowered to detect mediation pathways with small to medium effect sizes, there was suggestive evidence for DNA methylation as a mediator between phthalate exposure and adiposity (Sobel p > 0.05). For example, among girls, the positive associations between trimester 1 or trimester 2 MiBP and adiposity may be explained in part by the indirect effect of increased H19 methylation. On the other hand, accounting for DNA methylation may reveal stronger direct relationships between exposures and outcomes in cases when epigenetic change may be protecting against the effects of exposure. Among girls, controlling for H19 methylation revealed a stronger inverse association between T3 MBzP and skinfold thickness or BMI-for-age. Our results show that phthalate exposures during pregnancy and in early adolescence have sex-specific associations with DNA methylation and sex- and exposure timing-specific associations with repeat measures of adolescent adiposity. This highlights the importance of considering epigenetics as a mediator not only in the traditional sense but also as a biological buffer that may influence susceptibility to effects from toxicant exposures.

Aim 3-MMIP:

Targeted DNA methylation and in utero EDC exposures

We examined associations between first trimester exposures to nine phthalate metabolites and BPA and cord blood leukocyte DNA methylation at IGF2, H19, PPARA, ESR1, and LINE-1 repetitive elements in 116 MMIP offspring. MCPP was inversely associated with DNA methylation at LINE-1, IGF2, and PPARA. PPARA DNA methylation was the most sensitive to exposures with decreased methylation associated with MBzP, MCPP, and metabolites of DEHP. Gene expression of PPARA was inversely correlation with DNA methylation, suggesting a functional implication of changes to DNA methylation at PPARA.

Epigenome-wide DNA methylation and in utero EDC exposures

High-throughput ‘omics' platforms such as epigenomics and transcriptomics offer unparalleled opportunities to identify genes associated with in utero exposures that may give insight into processes by which chemicals influence early development. Thus, we expanded beyond candidate gene DNA methylation analysis and quantified DNA methylation at >850,000 CpG sites via the Infinium MethylationEPIC, a widely-used method in epidemiological studies DNA methylation was assessed via the EPIC in 114 MMIP cord blood leukocyte samples and 36 placenta samples with the help from additional funding sources. Transcriptomic analysis (RNA-seq) was also completed on 43 of the cord blood leukocyte samples. We are currently utilizing these data to identify differentially methylated and/or expressed genes in cord blood and placenta by first trimester exposures to phenols, phthalates, and metals. We are also examining whether genes with altered regulation are associated with birth outcomes and the metabolome and planning to expand the genome-wide DNA methylation and transcriptome analyses to a total of 200 MMIP neonates to increase our statistical power to identify key genes

Project 3: Developmental Exposures and Diet: Epigenetics of Metabolic Syndrome Risk

Investigator(s): Dr. Dana Dolinoy

Using the human-relevant, yellow agouti (Avy) mouse model, Project 3 has worked on mirroring three exposures (bisphenol A—BPA, phthalates, lead) and outcomes in our human cohorts (ELEMENT and MMIP) to study the role of perinatal exposures on nutrient-toxicant interactions, offspring life course metabolic status, reproductive development, and epigenetic regulation. Seven cohorts of mating pairs and litters were established and followed until 10 months of age to assess whether in utero High-Fat Diets (HFD) modify the effects of perinatal BPA exposure on metabolic, hormonal and oxidative stress parameters throughout the life course, and to identify DNA methylation alterations underlying such effects (Aim 1). Oral exposure to one of six diets: Control, Western HFD, Mediterranean HFD or each diet with 50 µg BPA/kg added, occurred pre-gestation through lactation. All mice were weaned onto the Control diet, thus isolating exposure to the perinatal period. In addition to usual phenotyping measures (such as body weight, relative organ weights, serum hormone levels), two primary metabolic phenotypes were investigated: hepatic steatosis (lipid accumulation in the liver) and oxidative response.

Non-alcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease among youth in the United States. This recent rise of NAFLD may be partially due to perinatal programming, where in utero exposures alter the lifelong health trajectory of offspring. To examine the role of HFD and BPA, on perinatal programming of NAFLD across the life course, we developed a longitudinal mouse model that uses a human-relevant dose of oral BPA coupled with intake of Western or Mediterranean style diets in dams, from pre-gestation through lactation. We assessed hepatic steatosis via quantification of hepatic triglycerides (TGs) and metabolic health via body weight, relative organ weights, and serum hormone levels in dams and offspring, at postnatal day 10 (PND10) and 10-months. We found that perinatal BPA did not affect hepatic TGs in either dams or offspring, but both high fat experimental diets (Western and Mediterranean) were associated with hepatic TGs levels in dams and PND10 males.

Hepatic histology from 10-month offspring highly correlated with hepatic TG levels, validating the TG findings. Hepatic 8-isoprostane (8-iso) levels differed by perinatal exposure in PND10 and 10-month offspring, but alterations were age and sex-specific. Perinatal HFD and BPA minimally influenced offspring redox parameters (EhGSH, EhCys, S-glut), suggestive of greater homeostatic control of these parameters compared to lipid oxidation. Dam metabolic phenotype significantly altered offspring hepatic steatosis and oxidative response, even when perinatal HFD and BPA did not, emphasizing the critical role of the maternal environment on offspring health. The unexpected lack of protection exerted by the Mediterranean diet, suggests the beneficial effect observed in adult human studies may not apply to perinatal exposure. Greater impact of HFDs compared to BPA highlights the need to conduct toxicant-nutrient interaction studies. Sex-specific effects were observed, emphasizing the importance of investigating perinatal programming in all offspring.

Supplementary Study [funded by NIEHS]: Supplementary Study: White adipose tissue (WAT) plays an important role in obesity pathophysiology. Redox signaling underlies several aspects of WAT physiology; however, the thiol redox environment of WAT has not yet been fully characterized. Dietary and endocrine disrupting chemical (EDC) exposures during development can transiently impact the cellular redox environment, but it is unknown whether these exposures can reprogram the WAT thiol redox environment. To characterize the WAT thiol redox environment, we took a descriptive approach and measured thiol redox parameters using high-performance liquid chromatography in mouse mesenteric (mWAT), gonadal (gWAT) and subinguinal (sWAT) depots. We found that thiol redox environment is important for WAT physiology and that mesenteric WAT redox potentials are reprogrammed by developmental exposure to HFDs and EDCs (Neier et al, J. Nutr. Biochem 2019).

Developmental exposure to phthalates has been implicated as a risk for obesity; however, epidemiological studies have yielded conflicting results and mechanisms are poorly understood. An additional layer of complexity in epidemiological studies is that humans are exposed to mixtures of many different phthalates. Addressing Aim 2, we utilize our mouse model of perinatal exposure to investigate the effects of three phthalates, diethylhexyl phthalate (DEHP), diisononyl phthalate (DINP) and dibutyl phthalate (DBP), on body weight and organ weights in weanling mice. In addition to individual phthalate exposures, we employed two mixture exposures: DEHP + DINP and DEHP + DINP + DBP. Phthalates were administered through phytoestrogen free chow at the following exposure levels: 25 mg DEHP/kg chow, 25 mg DBP/kg chow and 75 mg DINP/kg chow. The viable yellow agouti (Avy) mouse strain, along with measurement of tail DNA methylation, was used as a biosensor to examine effects of phthalates and phthalate mixtures on the DNA methylome. We found that female and male mice perinatally exposed to DINP alone had increased body weights at postnatal day 21 (PND21), and that exposure to mixtures did not exaggerate these effects. Perinatal exposures to DINP and a mixture of all three phthalates were associated with increased body weights in females. In males, phthalate-related body weight effects at PND21 were more pronounced in Avy/a mice than in a/a mice, with more exposure groups exhibiting significant differences v. controls in Avy/a mice than in a/a mice (Neier et al, J. Dev. Orig. Health Dis. 2019).

Additionally, several organs and tissues were collected from fasted a/a mice at PND21; females exposed to DINP and DEHP + DINP had increased relative liver weights at PND21, and females exposed to a mixture of DEHP + DINP + DBP had increased relative gonadal fat weight. Phthalate-exposed Avy/a offspring exhibited altered coat color distributions and sexually dimorphic alterations in DNA methylation at intracisternal A-particles (IAPs), repetitive elements in the mouse genome. In this study, developmental exposures to phthalates in the perinatal window influenced body weight, liver weight and gonadal fat weight in mice at weaning. Interestingly, females appeared to be more sensitive than males with respect to alterations in relative liver and gonadal fat weights. Tail IAP DNA methylation at the Avy locus and on a global level was altered by developmental phthalate exposures, presenting the possibility that epigenetic alterations link early-life exposures and potential later life health outcomes. These findings provide evidence that developmental exposures to phthalates influence body weight and organ weight changes in early life and are associated with altered DNA methylation at IAPs (Neier et al, J. Dev. Orig. Health Dis. 2019).

To further understand the extent to which developmental phthalate and phthalate mixture exposures impact metabolism across the life, our team expanded on our previous mouse model of perinatal exposure to longitudinally evaluate long-term metabolic impacts of perinatal exposures. Multiple metabolic phenotyping measures, including body composition, glucose tolerance, energy expenditure (EE), and food intake, were taken at two time points, early adulthood (2 months) and later adulthood (8 months), so that effects could be assessed in a longitudinal manner. Additionally, plasma adipokines (Leptin, MCP-1, PAI-1, resistin, IL-6 and TNF-α) were measured at 10 months of age. We found that female mice, but not male mice, exposed to DEHP-only and DINP-only gained more weight across time than control females. Longitudinally, females perinatally exposed to DEHP only had increased body fat percentage and decreased lean mass percentage compared with controls, whereas females perinatally exposed to DINP only had impaired glucose tolerance. Perinatal phthalate exposures also modified the relationship between body fat percentage and plasma adipokine levels at 10 months in females.

Building upon the metabolic phenotyping findings presented above, we hypothesized that early life exposures to phthalates resulted in long-lasting impacts on PPAR target gene expression in the liver by decreasing promoter region DNA methylation to influence metabolism across the life course. To investigate this hypothesis, we utilized liver tissue collected from a previously established mouse model of perinatal exposures to DEHP-only, DINP-only, and DEHP+DINP. We used transcriptomics (RNA-seq) in liver collected in early postnatal life at the end of the exposure period (PND21) and at 10 months of age, long after the exposure had ceased, to screen for PPAR target genes that were persistently activated by developmental phthalate exposures. We then measured promoter region DNA methylation levels for candidate PPAR target genes to elucidate the role of DNA methylation. Differential expression analyses comparing hepatic gene expression in exposed groups versus controls, stratified by age and sex, revealed that PND21 females perinatally exposed to DINP-only had evidence of reprogrammed PPAR target genes in the liver that suggested upregulation of fatty acid biosynthesis. Pathway analyses revealed several metabolic pathways in the liver that were potentially reprogrammed by perinatal phthalate exposures. Within the most significantly enriched hepatic pathway for DINP females, acetyl-CoA metabolic process, there were 13 significant genes and 10 of those are PPAR target genes. Notably, females perinatally exposed to DEHP-only and DEHP+DINP also exhibited differences in PPAR target gene expression, although these differences were less consistent than those observed in DINP-only females (Neier et al, Endocrinology 2019).

Since PPARs can recruit TET enzymes to de-methylate promoter region DNA of PPAR target genes, we measured CpG methylation levels in the promoter regions of Acly, Fasn, and Cs in the livers collected from mice at PND21 and 10 months of age. Females perinatally exposed to phthalates had altered DNA methylation levels in the promoter regions of Cs, Acly, and Fasn. Interestingly, promoter DNA methylation was increased at the Fasn locus in both PND21 and 10-month females perinatally exposed to DINP, indicating that this gene may have been epigenetically reprogrammed.

Overall, we found that perinatal exposures to phthalates were associated with altered hepatic gene expression and promoter region DNA methylation in PPAR target genes in female mice at both PND21 and 10 months. Pathway enrichment analyses of RNA-seq data indicated that pathways regulated by PPARs were altered in DINP-only female livers at PND21 and 10 months of age, indicating that these pathways were potentially reprogrammed by perinatal exposure to DINP. The 10 PPAR target genes that were significant in the top enriched pathway, acetyl-CoA metabolic process, indicated a shift in utilization of acetyl-CoA to fatty acid metabolism. Furthermore, the gene responsible for fatty acid biosynthesis, Fasn, had persistently altered levels of promoter region DNA methylation in the livers of females perinatally exposed to DINP. Up-regulation of these genes that suggest increased fatty acid biosynthesis could result in a predisposition towards increased fatty acid biosynthesis in the liver. If those fatty acids are used for triglyceride synthesis and subsequent storage in the liver, or are exported to circulation as free fatty acids, then this could increase the susceptibility of developing insulin resistance, NAFLD, or coronary heart disease. Thus, reprogramming of these genes by developmental phthalate exposures may play a role in long-term risk of metabolic syndrome. Interestingly, females perinatally exposed to a mixture of DEHP + DINP exhibited few persistent changes in gene expression and DNA methylation relative to females perinatally exposed to DINP-only, providing further evidence of complex longitudinal effects following developmental exposures to phthalate mixtures.

Environmental factors, including exogenous exposures and nutritional status, can affect DNA methylation across the epigenome, but effects of exposures on programmed age-dependent methylation changes and stochastic epigenetic drift remain unclear. We collectively refer to environmentally-induced shifts in age-dependent methylation and epigenetic drift as "environmental deflection (see our 2017 review on the topic, described below). Addressing Aim 3, we examined evidence for tissue specificity of epigenetic changes and environmental deflection by toxicants and diet in this aim using matched mouse samples across tissues and/or time from the mouse models described in Aims 1 and 2

To investigate longitudinal changes in DNA methylation and to assess whether perinatal environmental exposure to the representative metal, Pb, accelerates the rate of change in DNA methylation in 3 imprinted genes (Igf2, Igf2r, H19) and the transposon-containing metastable epialleleCabpIAP, isogenic mice were exposed perinatally to Pb acetate at four concentrations, 0 ppm (control), 2.1 ppm (low), 16 ppm (medium), and 32 ppm (high) prior to conception through weaning, and were followed until 10 months of age. Absolute values of DNA methylation CabpIAP and three imprinted loci (Igf2, Igf2r, and H19) were obtained from tail tissue in paired samples.

DNA methylation levels in the controls increased over time at the imprinted Igf2 and Igf2r loci but not at the imprinted H19 locus or the CabpIAP metastable epiallele. Pb exposure was associated with accelerated DNA hypermethylation in CabpIAP and moderated hypermethylation in Igf2r and with marginally accelerated hypermethylation at H19. Overall, the presence and magnitude of age-related methylation change was locus-dependent, and environmental deflection of this change was mediated by perinatal Pb exposure, in some, but not all, loci. Assessing drift in isogenic mice eliminates confounding factors such as genetic heterogeneity and age cohort effects and allows for rigorous control of environmental and dietary conditions. The results of this study indicate that the DNA methylation of metastable epialleles and imprinted genes is not stable from childhood to adulthood. At the same time, perinatal lead exposure alters the rate and direction of change in DNA methylation that occurs during aging (Faulk et al, Epigenetics 2014)

We also tested the hypothesis that early-life exposure to bisphenol A (BPA) and/or variable diet results in environmental deflection, as measured longitudinally via target loci methylation in paired mouse tail tissue (3 wks/10 mos old) from the mouse model described in Aim 1. Methylation was quantified at two repetitive elements (LINE-1, IAP), two imprinted genes (Igf2, H19), and one non-imprinted gene (Esr1) in isogenic mice developmentally exposed to Control, Control+BPA (50μg/kg diet), Mediterranean, Western, Mediterranean+BPA, or Western+BPA diets. Across age, DNA methylation levels significantly decreased at LINE-1, IAP, and H19, and increased at Esr1. Igf2 demonstrated Western diet-specific changes in early-life methylation, and IAP showed marginal negative modification of the rate of change (environmental deflection) in Western and Western+BPA. Thus, DNA methylation changes across age, and developmental nutritional exposures can alter age-related DNA methylation patterns (Kochmanski et al, Reproductive Toxicol. 2017).

Previous work indicates that DNA methylation status changes as a function of age in humans and animal models, a process described as "age-related methylation. Recent reports have shown nutrient- and toxicant-mediated shifts away from the baseline rate of age-related methylation, a concept we have termed "environmental deflection. We tested the hypothesis that developmental exposure to bisphenol A (BPA), variable diet, and/or physical activity results in deflection of age-related methylation, as measured via longitudinal target loci methylation in matched mouse blood (2, 4, and 10 months of age). This study utilizes the mouse model from Aim 1 and tests the same hypothesis as Kochmanski et al. 2017 in another tissue type that is commonly used in human epigenetic studies (blood). DNA methylation levels were quantified at LINE-1, IAP, Igf2, H19, and Esr1 in isogenic mice exposed to Control, Control+BPA (50 µg/kg diet), Western, or Western+BPA diets. All exposures began two weeks prior to mating and continued through gestation and lactation. Longitudinal spontaneous physical activity was measured prior to each blood draw using an integrated open-circuit calorimetry system. Across age, DNA methylation levels in blood significantly increased at Esr1, but did not show significant changes at the other loci. LINE-1 demonstrated significant negative deflection of age-related methylation by Western diet exposure, and Esr1 demonstrated significant negative deflection by both Western diet and physical activity. Combined, our results suggest that age-related methylation is a gene-specific biological process that is sensitive to both early-life environmental factor exposures and life-course behaviors such as physical activity (Kochmanski et al, Environ Epigenet2018).

To better characterize whether toxicant-induced DNA methylation changes are driven by changes in 5-methylcytosine (5mC) or 5-hydroxymethylcytosine (5hmC) and to move beyond a candidate gene approach, we quantified hydroxymethylation and methylation levels in blood using two genome-wide sequencing methods -- hydroxymethylated DNA immunoprecipitation sequencing (hMeDIP-seq) and enhanced reduced representation bisulfite sequencing (eRRBS) in blood samples from the same mouse model and lifecourse stages. Specifically, matched blood samples from 2, 4, and 10-month mice from the control and BPA diet groups were used. Analysis of hMeDIP-seq and eRRBS data facilitated the identification of new candidate regions with persistent epigenetic change across time by developmental exposures. Specifically, we identified 5,950 genomic regions that were differentially hydroxymethylated when comparing perinatally-exposed BPA mice to control mice. Twelve of these regions were in known imprinted genes including Gnas. The differential hydroxymethylation persisted across time (through 10 months of age) even after the exposure ceased. In the case of Gnas, gene expression at 10 months of age was higher in the BPA group, suggesting a functional effect of this persistent epigenetic change (Kochmanski et al, Environ Health Perspect. 2018)

DNA methylation at cytosine-phosphate-guanine (CpG) dinucleotides changes as a function of age in humans and animal models, a process that may contribute to chronic disease development. Recent studies have investigated the role of an oxidized form of DNA methylation – 5hmC– in the epigenome, but its contribution to age-related DNA methylation remains unclear. We tested the hypothesis that 5hmC changes with age, but in a direction opposite 5mC, potentially playing a distinct role in aging. To characterize epigenetic aging, genome-wide 5mC and 5hmC were measured in longitudinal blood samples (2, 4, and 10 months of age) from isogenic mice using two sequencing methods – hMeDIP-seq and eRRBS. Examining the epigenome by age, we identified 28,196 unique differentially methylated CpGs (DMCs) and 8,613 differentially hydroxymethylated regions (DHMRs). Mouse blood showed a general pattern of epigenome-wide hypermethylation and hypo-hydroxymethylation with age. Comparing age-related DMCs and DHMRs, 1,854 annotated genes showed both differential 5mC and 5hmC, including one gene – Nfic – at five CpGs in the same 250 bp chromosomal region. At this region, 5mC and 5hmC levels both decreased with age. Reflecting these age-related epigenetic changes, Nfic RNA expression in blood decreased with age, suggesting that age-related regulation of this gene may be driven by 5hmC, not canonical DNA methylation. Combined, our genome-wide results show age-related differential 5mC and 5hmC, as well as some evidence that changes in 5hmC may drive age-related DNA methylation and gene expression (Kochmanski et al, Epigenetics 2018).

In 2017, Project 3 team members were invited by Toxicological Sciences to write a Contemporary Review on epigenetics. We focused on a concept relevant to Aim 3 - Environmental Deflection: The Impact of Toxicant Exposures on the Aging Epigenome (Kochmanski et al, Toxicol Sci. 2017; doi: 10.1093/toxsci/kfx005). Epigenetic drift and age-related methylation have both been used in the literature to describe changes in DNA methylation that occurs with aging. However, ambiguity remains regarding the exact definition of both terms, and neither of these fields of study explicitly considers the impact of environmental factors on the aging epigenome. Recent twin studies have demonstrated longitudinal, pair-specific discordance in DNA methylation patterns, suggesting an effect of the environment on age-related methylation and/or epigenetic drift. Supporting this idea, other new reports have shown clear environment- and toxicant-mediated shifts away from the baseline rates of age-related methylation and epigenetic drift within an organism, a process we now term "environmental deflection." By defining and delineating environmental deflection, this contemporary review aimed to highlight the effects of specific toxicological factors on the rate of DNA methylation changes that occur over the life course. To inform future epigenetics-based toxicology studies, a field of research now classified as toxicoepigenetics, we provided clear definitions and examples of "epigenetic drift" and "age-related methylation," summarize the recent evidence for environmental deflection of the aging epigenome and discuss the potential functional effects of environmental deflection.


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Journal Article Baek J, Sancehz BN, Berrocal VJ, Sanchez-Vaznaugh EV. Distributed lag models: examining associations between the built environment and health. Epidemiology 2016;27(1):116-124. R835436 (2016)
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  • Journal Article Baek J, Sanchez-Vaznaugh EV, Sanchez BN. Hierarchial distributed-lag models: exploring varying geographic scale and magnitude in associations between built environment and health. American Journal of Epidemiology 2016;183(6):583-592. R835436 (2016)
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  • Journal Article Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children's Environmental Health Studies: The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives 2017;125(4):511-526. R835436 (Final)
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  • Journal Article Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. Small-magnitude effect sizes in epigenetic end points are important in children's environmental health studies:the Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives 2017;125(4):511-526. R835436 (2017)
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  • Journal Article Small Magnitude Effect Sizes in Epigenetic Endpoints are Important in Children's Environmental Health Studies:The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives 2017; 125(4):511-526. R835436 (Final)
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  • Journal Article Cantonwine DE, Hauser R, Meeker JD. Bisphenol A and human reproductive health. Expert Review of Obstetrics & Gynecology 2013;8(4):329-335. R835436 (2014)
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  • Journal Article Cantoral A, Tellez-Rojo MM, Levy TS, Hernandez-Avila M, Schnaas L, Hu H, Peterson KE, Ettinger AS. Differential association of lead on length by zinc status in two-year old Mexican children. Environmental Health 2015;14:95 (7 pp.). R835436 (2015)
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  • Journal Article Cantoral A, Tellez-Rojo MM, Ettinger AS, Hu H, Hernandez-Avila M, Peterson K. Early introduction and cumulative consumption of sugar-sweetened beverages during the pre-school period and risk of obesity at 8-14 years of age. Pediatric Obesity 2016;11(1):68-74. R835436 (2014)
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  • Journal Article Chavarro JE, Watkins DJ, Afeiche MC, Zhang Z, Sanchez BN, Cantonwine D, Mercado-Garcia A, Blank-Goldenberg C, Meeker JD, Tellez-Rojo MM, Peterson KE. Validity of self-assessed sexual maturation against physician assessments and hormone levels. The Journal of Pediatrics 2017;186:172-178.e3. R835436 (2016)
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  • Journal Article Chen Y-H, Ferguson KK, Meeker JD, McElrath TF, Mukherjee B. Statistical methods for modeling repeated measures of maternal environmental exposure biomarkers during pregnancy in association with preterm birth. Environmental Health 2015;14(1):9 (13 pp.). R835436 (2014)
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  • Journal Article Faulk C, Liu K, Barks A, Goodrich JM, Dolinoy DC. Longitudinal epigenetic drift in mice perinatally exposed to lead. Epigenetics 2014;9(7):934-941. R835436 (2014)
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  • Journal Article Ferguson KK, Peterson KE, Lee JM, Mercado-Garcia A, Blank-Goldenberg C, Tellez-Rojo MM, Meeker JD. Prenatal and peripubertal phthalates and bisphenol A in relation to sex hormones and puberty in boys. Reproductive Toxicology 2014;47:70-76. R835436 (2014)
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  • Journal Article Ferguson KK, McElrath TF, Chen Y-H, Loch-Caruso R, Mukherjee B, Meeker JD. Repeated measures of urinary oxidative stress biomarkers during pregnancy and preterm birth. American Journal of Obstetrics & Gynecology 2015;212(2):208.e1-208.e8. R835436 (2014)
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  • Journal Article Ferguson KK, McElrath TF, Cantonwine DE, Mukherjee B, Meeker JD. Phthalate metabolites and bisphenol-A in association with circulating angiogenic biomarkers across pregnancy. Placenta 2015;36(6):699-703. R835436 (2015)
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  • Journal Article Ferguson KK, Meeker JD, Cantonwine DE, Chen Y-H, Mukherjee B, McElrath TF. Urinary phthalate metabolite and bisphenol A associations with ultrasound and delivery indices of fetal growth. Environment International 2016;94:531-537. R835436 (2016)
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  • Journal Article Fortenberry GZ, Meeker JD, Sanchez BN, Barr DB, Panuwet P, Bellinger D, Schnaas L, Solano-Gonzalez M, Ettinger AS, Hernandez-Avila M, Hu H, Tellez-Rojo MM. Urinary 3,5,6-trichloro-2-pyridinol (TCPY) in pregnant women from Mexico City:distribution, temporal variability, and relationship with child attention and hyperactivity. International Journal of Hygiene and Environmental Health 2014; 217(2-3):405-412. R835436 (2014)
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  • Journal Article Goodrich JM, Sanchez BN, Dolinoy DC, Zhang Z, Hernandez-Avila M, Hu H, Peterson KE, Tellez-Rojo MM. Quality control and statistical modeling for environmental epigenetics: a study on in utero lead exposure and DNA methylation at birth. Epigenetics 2015;10(1):19-30. R835436 (2014)
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  • Journal Article Goodrich JM, Dolinoy DC, Sanchez BN, Zhang Z, Meeker JD, Mercado-Garcia A, Solano-Gonzalez M, Hu H, Tellez-Rojo MM, Peterson KE. Adolescent epigenetic profiles and environmental exposures from early life through peri-adolescence. Environmental Epigenetics 2016;2(3):dvw018 (11 pp.). R835436 (2016)
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  • Journal Article Goodrich JM, Chou HN, Gruninger SE, Fraznblau A, Baus N. Exposures of dental professionals to elemental mercury and methylmercury. Journal of Exposure Science and Environmental Epidemiology 2016;26(1):78-85. R835436 (2016)
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  • Journal Article Huang S, Hu H, Sanchez BN, Peterson KE, Ettinger AS, Lamadrid-Figueroa H, Schnaas L, Mercado-Garcia A, Wright RO, Basu N, Cantonwine DE, Hernandez-Avila M, Tellez-Rojo MM. Childhood blood lead levels and symptoms of attention deficit hyperactivity disorder (ADHD):a cross-sectional study of Mexican children. Environmental Health Perspectives 2016;124(6):868-874. R835436 (2016)
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  • Journal Article Jansen EC, Zhou L, Song PXK, Sanchez BN, Mercado A, Hu H, Solano M, Peterson KE, Tellez-Rojo MM. Prenatal lead exposure in relation to age at menarche: results from a longitudinal study in Mexico City. Journal of Developmental Origins of Health and Disease 2018;9(4):467-472. R835436 (2017)
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  • Journal Article Jansen EC, Zhou L, Perng W, Song PXK, Tellez-Rojo MM, Mercado A, Peterson KE, Cantoral A. Vegetables and lean proteins-based and processed meats and refined grains-based dietary patterns in early childhood are associated with pubertal timing in a sex-specific manner: a prospective study of children from Mexico City. Nutrition Research 2018;56:41-50. R835436 (2017)
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  • Journal Article Kasper N, Peterson KE, Zhang Z, Ferguson KK, Sanchez BN, Cantoral A, Meeker JD, Tellez-Rojo MM, Pawlowski CM, Ettinger AS. Association of bisphenol A exposure with breastfeeding and perceived insufficient milk supply in Mexican women. Maternal and Child Health Journal 2016;20(8):1713-1719. R835436 (2015)
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  • Journal Article Kochmanski JJ, Marchlewicz EH, Cavalcante RG, Perera BPU, Sartor MA, Dolinoy DC. Longitudinal effects of developmental bisphenol A exposure on epigenome-wide DNA hydroxymethylation at imprinted loci in mouse blood. Environmental Health Perspectives 2018;126(7):077006 (16 pp.). R835436 (2017)
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  • Journal Article Kochmanski J, Montrose L, Goodrich JM, Dolinoy DC. Environmental deflection: the impact of toxicant exposures on the aging epigenome. Toxicological Sciences 2017;156(2):325-335. R835436 (2016)
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  • Journal Article Kochmanski J, Marchlewicz EH, Savidge M, Montrose L, Faulk C, Dolinoy DC. Longitudinal effects of perinatal bisphenol A and variable diet exposures on epigenetic drift in mice. Reproductive Toxicology 2017;68:154-163. R835436 (2016)
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  • Journal Article Kochmanski J, Marchlewicz EH, Dolinoy DC. Longitudinal effects of developmental bisphenol A, variable diet, and physical activity on age-related methylation in blood. Environmental Epigenetics 2018;4(3):dvy017 (10 pp.). R835436 (2017)
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  • Journal Article Lewis RC, Meeker JD. Biomarkers of exposure to molybdenum and other metals in relation to testosterone among men from the United States National Health and Nutrition Examination Survey 2011-2012. Fertility and Sterility 2015;103(1):172-178. R835436 (2014)
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  • Journal Article Lewis RC, Johns LE, Meeker JD. Serum biomarkers of exposure to perfluoroalkyl substances in relation to serum testosterone and measures of thyroid function among adults and adolescents from NHANES 2011-2012. International Journal of Environmental Research and Public Health 2015;12(6):6098-6114. R835436 (2014)
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  • Journal Article Lewis RC, Johns LE, Meeker JD. Exploratory analysis of the potential relationship between urinary molybdenum and bone mineral density among adult men and women from NHANES 2007-2010. Chemosphere 2016;164:677-682. R835436 (2016)
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  • Journal Article Liu Y, Peterson KE. Maternal exposure to synthetic chemicals and obesity in the offspring: recent findings. Current Environmental Health Reports 2015;2(4):339-347. R835436 (2015)
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  • Journal Article Marchlewicz EH, Dolinoy DC, Tang L, Milewski S, Jones TR, Goodrich JM, Soni T, Domino SE, Song PXK, Burant C, Padmanabhan V. Lipid metabolism is associated with developmental epigenetic programming. Scientific Reports 2016;6:34857 (13 pp.). R835436 (2016)
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  • Journal Article Meeker JD, Ferguson KK. Urinary phthalate metabolites are associated with decreased serum testosterone in men, women, and children from NHANES 2011-2012. The Journal of Clinical Endocrinology and Metabolism 2014;99(11):4346-4352. R835436 (2014)
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  • Journal Article Montrose L, Padmanabhan V, Goodrich JM, Domino SE, Treadwell MC, Meeker JD, Watkins DJ, Dolinoy DC. Maternal levels of endocrine disrupting chemicals in the first trimester of pregnancy are associated with infant cord blood DNA methylation. Epigenetics 2018;13(3):301-309. R835436 (2017)
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  • Journal Article Moynihan M, Peterson KE, Cantoral A, Song PXK, Jones A, Solano-Gonzalez M, Meeker JD, Basu N, Tellez-Rojo MM. Dietary predictors of urinary cadmium among pregnant women and children. Science of the Total Environment 2017;575:1255-1262. R835436 (2016)
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  • Journal Article Neier K, Marchlewicz EH, Dolinoy DC, Padmanabhan V. Assessing human health risk to endocrine disrupting chemicals: a focus on prenatal exposures and oxidative stress. Endocrine Disruptors (Austin);2015;3(1):e1069916 (8 pp.). R835436 (2015)
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  • Journal Article Omoike OE, Lewis RC, Meeker JD. Association between urinary biomarkers of exposure to organophosphate insecticides and serum reproductive hormones in men from NHANES 1999-2002. Reproductive Toxicology 2015;53:99-104. R835436 (2015)
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  • Journal Article Peretz J, Vrooman L, Ricke WA, Hunt PA, Ehrlich S, Hauser R, Padmanabhan V, Taylor HS, Swan SH, VandeVoort CA, Flaws JA. Bisphenol A and reproductive health: update of experimental and human evidence, 2007-2013. Environmental Health Perspectives 2014;122(8):775-786. R835436 (2014)
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  • Journal Article Perng W, Watkins DJ, Cantoral A, Mercado-Garcia A, Meeker JD, Tellez-Rojo MM, Peterson KE. Exposure to phthalates is associated with lipid profile in peripubertal Mexican youth. Environmental Research 2017;154:311-317. R835436 (2016)
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  • Journal Article Perng W, Fernandez C, Peterson KE, Zhang Z, Cantoral A, Sanchez BN, Solano-Gonzalez M, Tellez-Rojo MM, Baylin A. Dietary patterns exhibit sex-specific associations with adiposity and metabolic risk in a cross-sectional study in urban Mexican adolescents. The Journal of Nutrition 2017;147(10):1977-1985. R835436 (2017)
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  • Journal Article Perng W, Hector EC, Song PXK, Tellez Rojo MM, Raskind S, Kachman M, Cantoral A, Burant CF, Peterson KE. Metabolomic determinants of metabolic risk in Mexican adolescents. Obesity (Silver Spring) 2017;25(9):1594-1602. R835436 (2017)
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  • Journal Article Sanchez-Vaznaugh EV, Sanchez BN, Crawford PB, Egerter S. Association between competitive food and beverage policies in elementary schools and childhood overweight/obesity trends: differences by neighborhood socioeconomic resources. JAMA Pediatrics 2015;169(5):e150781 (17 pp.). R835436 (2014)
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  • Journal Article Silver MK, Lozoff B, Meeker JD. Blood cadmium is elevated in iron deficient U.S. children: a cross-sectional study. Environmental Health 2013;12(1):117 (9 pp.). R835436 (2014)
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  • Journal Article Somers EC, Monrad SU, Warren JS, Solano M, Schnaas L, Hernandez-Avila M, Tellez-Rojo MM, Hu H. Antinuclear antibody prevalence in a general pediatric cohort from Mexico City: discordance between immunofluorescence and multiplex assays. Clinical Epidemiology 2017;9:1-8. R835436 (2016)
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  • Journal Article Sun Z, Tao Y, Li S, Ferguson KK, Meeker JD, Park SK, Batterman SA, Mukherjee B. Statistical strategies for constructing health risk models with multiple pollutants and their interactions: possible choices and comparisons. Environmental Health 2013;12(1):85 (19 pp.). R835436 (2014)
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  • Journal Article Tao Y, Sanchez BN, Mukherjee B. Latent variable models for gene-environment interactions in longitudinal studies with multiple correlated exposures. Statistics in Medicine 2015;34(7):1227-1241. R835436 (2014)
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  • Journal Article Trentacosta CJ, Davis-Kean P, Mitchell C, Hyde L, Dolinoy D. Environmental contaminants and child development. Child Developmental Perspectives 2016;10(4):228-233. R835436 (2016)
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  • Journal Article Vandenberg LN, Gerona RR, Kannan K, Taylor JA, van Breemen RB, Dickenson CA, Liao C, Yuan Y, Newbold RR, Padmanabhan V, vom Saal FS, Woodruff TJ. A round robin approach to the analysis of bisphenol A (BPA) in human blood samples. Environmental Health 2014;13(1):25 (20 pp.). R835436 (2014)
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  • Journal Article Veiga-Lopez A, Pennathur S, Kannan K, Patisaul HB, Dolinoy DC, Zeng L, Padmanabhan V. Impact of gestational bisphenol A on oxidative stress and free fatty acids: human association and interspecies animal testing studies. Endocrinology 2015;156(3):911-922. R835436 (2014)
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  • Journal Article Veiga-Lopez A, Kannan K, Liao C, Ye W, Domino S, Padmanabhan V. Gender-specific effects on gestational length and birth weight by early pregnancy BPA exposure. Journal of Clinical Endocrinology and Metabolism 2015;100(11):E1394-E1403. R835436 (2015)
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  • Journal Article Watkins DJ, Tellez-Rojo MM, Ferguson KK, Lee JM, Solano-Gonzalez M, Blank-Goldenberg C, Peterson KE, Meeker JD. In utero and peripubertal exposure to phthalates and BPA in relation to female sexual maturation. Environmental Research 2014;134:233-241. R835436 (2014)
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  • Journal Article Watkins DJ, Peterson KE, Ferguson KK, Mercado-Garcia A, Tamayo y Ortiz M, Cantoral A, Meeker JD, Tellez-Rojo MM. Relating phthalate and BPA exposure to metabolism in peripubescence: the role of exposure timing, sex, and puberty. Journal of Clinical Endocrinology & Metabolism 2016;101(1):79-88. R835436 (2015)
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  • Journal Article Watkins DJ, Fortenberry GZ, Sanchez BN, Barr DB, Panuwet P, Schnaas L, Osorio-Valencia E, Solano-Gonzalez M, Ettinger AS, Hernandez-Avila M, Hu H, Tellez-Rojo MM, Meeker JD. Urinary 3-phenoxybenzoic acid (3-PBA) levels among pregnant women in Mexico City: distribution and relationships with child neurodevelopment. Environmental Research 2016;147:307-313. R835436 (2015)
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  • Journal Article Watkins DJ, Milewski S, Domino SE, Meeker JD, Padmanabhan V. Maternal phthalate exposure during early pregnancy and at delivery in relation to gestational age and size at birth: a preliminary analysis. Reproductive Toxicology 2016;65:59-66. R835436 (2016)
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  • Journal Article Watkins DJ, Sanchez BN, Tellez-Rojo MM, Lee JM, Mercado-Garcia A, Blank-Goldenberg C, Peterson KE, Meeker JD. Impact of phthalate and BPA exposure during the in utero windows of susceptibility on reproductive hormones and sexual maturation in peripubertal males. Environmental Health 2017;16(1):69 (10 pp.). R835436 (2016)
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  • Journal Article Watkins DJ, Sanchez BN, Tellez-Rojo MM, Lee JM, Mercado-Garcia A, Blank-Goldenberg C, Peterson KE, Meeker JD. Phthalate and bisphenol A exposure during in utero windows of susceptibility in relation to reproductive hormones and pubertal development in girls. Environmental Research 2017;159:143-151. R835436 (2017)
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  • Journal Article Wu J, Wen XW, Faulk C, Boehnke K, Zhang H, Dolinoy DC, Xi C. Perinatal lead exposure alters gut microbiota composition and results in sex-specific body weight increases in adult mice. Toxicological Sciences 2016;151(2):324-333. R835436 (2016)
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  • Journal Article Yang TC, Peterson KE, Meeker JD, Sanchez BN, Zhang Z, Cantoral A, Solano M, Tellez-Rojo MM. Bisphenol A and phthalates in utero and in childhood: association with child BMI z-score and adiposity. Environmental Research 2017;156:326-333. R835436 (2016)
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  • Journal Article Yang TC, Peterson KE, Meeker JD, Sanchez BN, Zhang Z, Cantoral A, Solano M, Tellez-Rojo MM. Exposure to bisphenol A and phthalates metabolites in the third trimester and BMI trajectories. Pediatric Obesity 2018;13(9):550-557. R835436 (2017)
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  • Journal Article Zhang Z, O’Neill MS, Sanchez BN. Using a latent variable model with non-constant factor loadings to examing PM2.5 constituents related to secondary inorganic aerosols. Statistical Modeling 2016;16(2):91-113. R835436 (2016)
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  • Journal Article Zhou Y, Wang P, Wang X, Zhu J, Song PX. Sparse multivariate factor analysis regression models and its applications to integrative genomics analysis. Genetic Epidemiology 2017;41(1):70-80. R835436 (2016)
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  • Journal Article Shimpi PC, More VR, Paranjpe M, Donepudi AC, Goodrich JM, Dolinoy DC, Rubin B, Slitt AL. Hepatic lipid accumulation and Nrf2 expression following perinatal and peripubertal exposure to bisphenol A in a mouse model of nonalcoholic liver disease. Environmental health perspectives 2017;125(8):087005. R835436 (Final)
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  • Journal Article McCabe C, Anderson OS, Montrose L, Neier K, Dolinoy DC. Sexually dimorphic effects of early-life exposures to endocrine disruptors:sex-specific epigenetic reprogramming as a potential mechanism. Current environmental health reports 2017;4(4):426-38. R835436 (Final)
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  • Journal Article Banu SK, Stanley JA, Taylor RJ, Sivakumar KK, Arosh JA, Zeng L, Pennathur S, Padmanabhan V. Sexually dimorphic impact of chromium accumulation on human placental oxidative stress and apoptosis. Toxicological Sciences 2017;161(2):375-87. R835436 (Final)
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  • Journal Article Jansen EC, Dunietz GL, Chervin RD, Baylin A, Baek J, Banker M, Song PX, Cantoral A, Rojo MM, Peterson KE. Adiposity in adolescents:the interplay of sleep duration and sleep variability. The Journal of pediatrics 2018;203:309-16. R835436 (Final)
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  • Journal Article Kochmanski J, Marchlewicz EH, Cavalcante RG, Sartor MA, Dolinoy DC. Age-related epigenome-wide DNA methylation and hydroxymethylation in longitudinal mouse blood. Epigenetics 2018;13(7):779-92. R835436 (Final)
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  • Journal Article Wu Y, Peterson KE, Sánchez BN, Dolinoy DC, Mercado-Garcia A, Téllez-Rojo MM, Goodrich JM. Association of blood leukocyte DNA methylation at LINE-1 and growth-related candidate genes with pubertal onset and progression. Epigenetics 2018;13(12):1222-33. R835436 (Final)
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  • Journal Article Banu SK. Chromium Burden in Human Placenta:Author (s) Responses to Thompson et al. Toxicological Sciences 2018;165(2):270-1. R835436 (Final)
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  • Journal Article Axson EL, Peterson KE, Tellez-Rojo MM, Goodrich JM, Meeker J, Mercado-García A, Solano M, Needham BL. Sex differences in telomere length are not mediated by sex steroid hormones or body size in early adolescence. Gender and the Genome 2018;2(3):68-75. R835436 (Final)
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  • Journal Article Wang T, Pehrsson EC, Purushotham D, Li D, Zhuo X, Zhang B, Lawson HA, Province MA, Krapp C, Lan Y, Coarfa C. The NIEHS TaRGET II Consortium and environmental epigenomics. Nature biotechnology 2018;36(3):225. R835436 (Final)
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  • Journal Article Lewis RC, Meeker JD, Basu N, Gauthier AM, Cantoral A, Mercado-García A, Peterson KE, Téllez-Rojo MM, Watkins DJ. Urinary metal concentrations among mothers and children in a Mexico City birth cohort study. International journal of hygiene and environmental health. 2018;221(4):609-15. R835436 (Final)
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  • Journal Article Neier K, Marchlewicz EM, Bedrosian LD, Dolinoy DC, Harris C. Characterization of the mouse white adipose tissue redox environment and associations with perinatal environmental exposures to bisphenol A and high-fat diets. The Journal of nutritional biochemistry 2019;1(66):86-97. R835436 (Final)
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  • Journal Article Wu Y, Sánchez BN, Goodrich JM, Dolinoy DC, Cantoral A, Mercado-Garcia A, Ruiz-Narváez EA, Téllez-Rojo MM, Peterson KE. Dietary exposures, epigenetics and pubertal tempo. Environmental Epigenetics 2019;5(1):dvz002. R835436 (Final)
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  • Journal Article Perng W, Tamayo-Ortiz M, Tang L, Sánchez BN, Cantoral A, Meeker JD, Dolinoy DC, Roberts EF, Martinez-Mier EA, Lamadrid-Figueroa H, Song PX. Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) Project. BMJ open 2019;9(8):e030427. R835436 (Final)
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  • Journal Article Liu Y, Téllez-Rojo MM, Sánchez BN, Zhang Z, Afeiche MC, Mercado-García A, Hu H, Meeker JD, Peterson KE. Early lead exposure and pubertal development in a Mexico City population. Environment international. 2019;125:445-51. R835436 (Final)
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  • Journal Article Kelley AS, Banker M, Goodrich JM, Dolinoy DC, Burant C, Domino SE, Smith YR, Song PX, Padmanabhan V. Early pregnancy exposure to endocrine disrupting chemical mixtures are associated with inflammatory changes in maternal and neonatal circulation. Scientific reports 2019;9(1):5422. R835436 (Final)
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  • Journal Article Neier K, Cheatham D, Bedrosian LD, Gregg BE, Song PXK, Dolinoy DC. Longitudinal metabolic impacts of perinatal exposure to phthalates and phthalate mixtures in mice." Endocrinology 2019;160(7):1613-1630. R835436 (Final)
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  • Journal Article Perng W, Tang L, Song PX, Tellez-Rojo MM, Cantoral A, Peterson KE. Metabolomic profiles and development of metabolic risk during the pubertal transition:a prospective study in the ELEMENT Project. Pediatric research 2019;85(3):262. R835436 (Final)
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  • Journal Article Neier K, Cheatham D, Bedrosian LD, Dolinoy DC. Perinatal exposures to phthalates and phthalate mixtures result in sex-specific effects on body weight, organ weights and intracisternal A-particle (IAP) DNA methylation in weanling mice. Journal of developmental origins of health and disease 2019;10(2):176-87. R835436 (Final)
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  • Journal Article Rodríguez-Carmona Y, Cantoral A, Trejo-Valdivia B, Téllez-Rojo MM, Svensson K, Peterson KE, Meeker JD, Schnaas L, Solano M, Watkins DJ. Phthalate exposure during pregnancy and long-term weight gain in women. Environmental research 2019;169:26-32. R835436 (Final)
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  • Journal Article Moynihan M, Telléz-Rojo MM, Colacino J, Jones AD, Song PX, Cantoral A, Mercado-Garcia A, Peterson K. Prenatal cadmium exposure is negatively associated with adiposity in girls not boys during adolescence. Frontiers in Public Health 2019;7:61. R835436 (Final)
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  • Journal Article Wu Y, Jansen EC, Peterson KE, Foxman B, Goodrich JM, Hu H, Solano-González M, Cantoral A, Téllez-Rojo MM, Martinez-Mier EA. The associations between lead exposure at multiple sensitive life periods and dental caries risks in permanent teeth. Science of the Total Environment 2019;654:1048-55. R835436 (Final)
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  • Journal Article Perng W, Tang L, Song PX, Goran M, Tellez Rojo MM, Cantoral A, Peterson KE. Urate and Nonanoate Mark the Relationship between Sugar-Sweetened Beverage Intake and Blood Pressure in Adolescent Girls:A Metabolomics Analysis in the ELEMENT Cohort. Metabolites 2019;9(5):100. R835436 (Final)
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  • Journal Article Jansen EC, Dunietz GL, Dababneh A, Peterson KE, Chervin RD, Baek J, O'Brien L, Song PX, Cantoral A, Hu H, Téllez-Rojo MM. Cumulative Childhood Lead Levels in Relation to Sleep During Adolescence. Journal of clinical sleep medicine:JCSM:official publication of the American Academy of Sleep Medicine 2019. R835436 (Final)
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  • Journal Article Goodrich JM, Ingle ME, Domino SE, Treadwell MC, Dolinoy DC, Burant C, Meeker JD, Padmanabhan V. First trimester maternal exposures to endocrine disrupting chemicals and metals and fetal size in the Michigan Mother–Infant Pairs study. Journal of developmental origins of health and disease 2019:1-2. R835436 (Final)
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  • Journal Article Perera BP, Svoboda L, Dolinoy DC. Genomic tools for environmental epigenetics and implications for public health. Current Opinion in Toxicology 2019. R835436 (Final)
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  • Journal Article Marchlewicz E, Djuric Z, Sanchez B, Peterson K, Dolinoy D. Impact of Prenatal Exposure to Humanized High Fat Diets on Murine Metabolic Phenotype. The FASEB Journal. 2015;29(1):754-3. R835436 (Final)
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  • Journal Article Ashrap, Pahriya, Sánchez BN, Martha M, Téllez-Rojo, Niladri Basu, Tamayo-Ortiz M, Peterson KE, Meeker JD, and Watkins DJ. In utero and peripubertal metals exposure in relation to reproductive hormones and sexual maturation and progression among girls in Mexico City. Environmental research (2019):108630, https://www.sciencedirect.com/science/article/pii/S001393511930427X. R835436 (Final)
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  • Journal Article Anderson OS, Kim JH, Peterson KE, Sanchez BN, Sant KE, Sartor MA, Weinhouse C, Dolinoy DC. Novel epigenetic biomarkers mediating bisphenol A exposure and metabolic phenotypes in female mice. Endocrinology158, no. 1 (2017):31-40. https://academic.oup.com/endo/article/158/1/31/2751111. R835436 (Final)
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  • Journal Article Dou JF, Farooqui Z, Faulk CD, Barks AK, Jones T, Dolinoy DC, Bakulski KM. Perinatal Lead (Pb) Exposure and Cortical Neuron-Specific DNA Methylation in Male Mice. Genes 2019(4):274. R835436 (Final)
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  • Journal Article Jansen EC, Dolinoy DC, O’Brien LM, Peterson KE, Chervin RD, Banker M, Téllez-Rojo MM, Cantoral A, Mercado-Garcia A, Sanchez B, Goodrich JM. Sleep duration and fragmentation in relation to leukocyte DNA methylation in adolescents. Sleep 2019. R835436 (Final)
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  • Journal Article Perera BP, Faulk C, Svoboda LK, Goodrich JM, Dolinoy DC. The role of environmental exposures and the epigenome in health and disease. Environmental and molecular mutagenesis 2019. R835436 (Final)
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  • Supplemental Keywords:

    Children's Health, Human Health, Health Effects, Children's environmental health, prenatal exposure, environmental risks, epigenetics, maternal exposure, Mexican, Bisphenol A, phthalates, lead, cadmium, cumulative effects, toxics, metals, epidemiology, metabolic syndrome, oxidative stress, animal exposure, agouti mouse, animal phenotyping, mixtures, metabolic homeostasis

    Relevant Websites:

    Progress and Final Reports:

    Original Abstract
  • 2013 Progress Report
  • 2014 Progress Report
  • 2015 Progress Report
  • 2016 Progress Report
  • 2017 Progress Report