2015 Progress 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. , Meeker, John D. , Dolinoy, Dana , Padmanabhan, Vasantha
Current 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 Period Covered by this Report: June 1, 2015 through May 31,2016
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:

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 U.S. 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 will test 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 Protection Center (UM-CEHC) are to:

  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 (body mass index, BMI), sexual maturation and reproductive hormones.
  2. Determine whether EDC mixtures (BPA, phthalates, Pb, Cd) via epigenetic mechanisms induce oxidative stress (tyrosine oxidation products), disrupt metabolic homeostasis (free fatty acids, amino acids, Acyl-carnitine) and lead to changes in gene transcription and metabolic function.
  3. Conduct tissue- and age-specific unbiased epigenomic analyses (DNA methylation, chromatin structure, transcriptomics) to identify a subset of tissue-independent labile genes to serve as biomarkers of exposure-induced metabolic syndrome.
  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.
  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.
  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.

Progress Summary:

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 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 U.S. study population established by MPI Dr. Vasantha Padmanabhan, is included in Project 2 of the UM-CEHC to extend findings from the ELEMENT cohort to a U.S. study population. Whereas Project 1 focuses on 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, 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 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).

During Year 3, we re-recruited ELEMENT participants from our P20 ES01817101/RD834800 (Peterson) plus additional participants from the larger ELEMENT cohorts and completed all T1 visits for the initial target of 400 participants by Year 3, Quarter 4. Based on the success of follow-up, sample size has been expanded to 500 subjects with ongoing recruitment of the additional subjects planned though Quarter 1 of Year 4. We conducted our first two data breaks in December 2015 and May 2016. Progress for Project 1 in Year 3 included continued assessment of maternal urinary concentrations of phthalate metabolites and BPA at multiple time points in pregnancy. This data has been analyzed to examine the relationships between these exposures and sexual maturation and reproductive hormone levels in ~250 boys and girls who previously participated in our P20 study. Among boys, DEHP measure during the 1st trimester was associated with an increase in peripubertal levels of serum estradiol while 2nd trimester MEP was associated with a decrease in estradiol. Several phthalates are associated with a decreased odds of having a Tanner stage > 1 for pubic hair in boys and an increase in BPA during the 2nd trimester is associated with higher odds of testicular volume > 3 ml. Among girls, several phthalates and BPA measured across in utero developed are associated with increased peripubertal levels of serum testosterone. Several phthalates were associated with higher odds of pubic hair development and menarche while BPA during the 2nd trimester was associated with increased odds of having a Tanner stage > 1 for breast development. These findings are currently being submitted for publication in two different manuscripts. In Year 3, Project 1 also began examining associations between trimester specific phthalate and BPA exposure and cognitive and behavioral development. We found that in utero phthalate exposure was associated with increased ADHD symptoms in childhood with differences by sex and timing of exposure. These results will be presented at the International Society of Environmental Epidemiology (ISEE) annual conference held in Rome, Italy, in September 2016. Results from this data, demonstrating child neurodevelopment at ages 2 and 3 is associated with in utero pyrethroid exposure have recently been published in Environmental Research (Watkins et al 2016; Environ Res, 147:307-313).

Progress for Project 2 in Year 3 included completion of analysis of repeat urinary cadmium from ~ 250 women across 3 trimesters of pregnancy and on urine samples from their adolescent offspring originally recruited for our P20 study for ELEMENT and being followed at T1 and T2 in the current P01, as well completion of DNA methylation of candidate genes and of assays of untargeted metabolomics features from P20 samples, along with data pre-management and statistical analysis procedures. The Michigan Mother Infant Pairs (MMIP) completed analysis of urinary phthalates and statistical analysis on targeted metabolomics and its association with epigenetic changes. Another accomplishment in Year 3 was the database construction to concentrate, organize, and clean the data generated by MMIP under the auspices of our Data Management and Modeling Core (DMMC).

ELEMENT Cohorts: In Year 3, urinary analysis of Cd from ~ 250 children at the P20 visit and their mothers during the third trimester was conducted and dietary intake of Cd was estimated using a Cd contamination database. On average, children consumed more dietary Cd than pregnant women and there was a positive association intake of fruits and vegetables among women and potato consumption among children with urinary Cd levels. Preliminary analyses show that prenatal but not postnatal cadmium exposure was negatively associated with adiposity measures in adolescents and results will be presented at the ISEE 2016 Meetings in Rome, Italy, in September 2016. Analysis of DNA methylation of candidate genes in archived cord blood DNA (n = 79) and peri-adolescent DNA (n = 250) was completed and results showed significant associations between peri-adolescent DNA methylation and exposure biomarkers that were gene-, exposure-, time point- and sometimes sex-specific. A manuscript detailing these results has been accepted for publication in Environmental Epigenetics. We also completed untargeted metabolomics features from n = 250 archived fasting serum from adolescents and are currently analyzing this data. Serum-8-isoprostane, a measure of lipid oxidation, was measured in 242 of the P20 samples and preliminary analyses of the association of urinary BPA and 8-isoprostane and the role of diet as an effect modifier are under way.

MMIP Cohort: During Year 3, we completed analysis of urinary phthalates in 68 mother-infant dyads. Findings from these analyses showed that a number of phthalate metabolites were associated with birth size and gestational age in patterns that varied by sex and time of exposure. These results have been accepted for publication in Reproductive Toxicology. Targeted metabolomics in MMIP at first trimester and delivery in maternal blood and infant cord blood and its association with epigenetic changes has been completed. The results demonstrated that lipid metabolism is a key mediator of developmental epigenetic programming, which may impact lifelong offspring health and disease risk. Furthermore, analysis of DNA methylation of candidate genes and LINE1 in 68 cord blood samples is currently in process.

Project 3 is being implemented in the Agouti mouse model. In Years 1-3, six cohorts of mating pairs and litters were established and followed until 10 months of age to assess whether in utero high-fat diets 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, with 6 manuscripts currently being drafted. DNA and RNA have been extracted from liver and visceral white adipose tissue from all 10-month offspring and are currently being assayed for candidate genes involved in hepatic lipid metabolism and oxidative stress response. Preliminary analyses of oxidative stress in PND10 liver suggest that Western diet + BPA exposure results in a more oxidized intracellular environment. We also are testing the hypothesis that early life exposure to BPA and/or variable diet results in altered epigenetic drift as measured by longitudinal DNA methylation at target genes in paired mouse-tail tissue. Findings have been accepted in Reproductive Toxicology and studies in blood using both candidate gene and next-generation sequencing approaches are on going. During Quarter 2 of Year 3, a phthalate exposure study was developed to use the viable yellow agouti mouse model to study how prenatal exposures to phthalates and phthalate mixtures may influence risk of developing metabolic syndrome in adulthood. Exposures began in December 2015 and it is anticipated the animals will be followed through Spring of 2017. 

Data Management and Modeling Core (DMMC): In Year 3, the DMMC not only provided data analysis and modeling to support the three UM-CEHC research projects, but also has remained actively involved in data management. Dr. Peter Song, the Director of the DMMC, and Ms. Lindsey Mitchell, former UM-CEHC Manager, worked closely to create a comprehensive Data Management Plan to regulate and streamline the details of data storage, transfer, use and dissemination. In addition, Dr. Song was funded in Quarter 1 of Year 3 with a R01 statistical methodology grant that focuses on the development of novel statistical methodologies and efficient algorithms to evaluate, interpret and predict environmental risk of early life exposure on child health and development outcomes by using ELEMENT data. Dr. Song also has been involved with the training of masters and doctoral students and post-doctoral fellows. Poster presentations on new statistical models to evaluate associations between change in methylation variability and metabolite features and evaluating functional interactions of Cox proportional hazards model to analyze self-reported sexual maturation data with pre-natal lead exposure were presented at the 2016 International Biometrics Society Eastern North American Region Conference in Austin, TX, in March 2016.

Community Outreach and Translation Core (COTC): In Year 3, the COTC collaborated with other University of Michigan Centers, local, regional and national partners. 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 between UM environmental health-focused center partners and Flint-based colleagues to coordinate responses to the Flint Water Crisis. We also hosted a four-day community viewing and discussion of the documentary series, The Raising of America, with multiple UM partners, in which Dr. Dolinoy is featured in the episode titled “DNA is Not Destiny.” We also advertised relevant webinars and trainings to CEHC affiliates and created a website (http://www.sph.umich.edu/cehc/) and Twitter account (@UMCEHC) that allows us to disseminate our research findings and promote news about children’s environmental health from other Children’s Centers in our network. In Year 3, we also continued to work closely with our Community Advisory Board (CAB) in the Grand Rapids/Kent County, MI, area, including Head Start for Kent County, Healthy Homes Coalition and the Kent County Health Department. We continue to meet monthly with our partners to support their goal of educating the community and creating a stronger platform for addressing children’s environmental health. We finalized the creation of maps illustrating the prevalence and burden of asthma on low-income preschool age children in Kent County, generated talking points and a presentation template. CAB members gave six presentations to community members using the maps, talking points and template in Year 3. 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. At the national level, we have continued to participate in COTC workgroup calls and national/regional meetings. Ms. Lindsey Mitchell, former UM-CEHC COTC Associate Director, and Ms. Meghan Moynihan, PhD Candidate in Nutritional Sciences, attended the 2015 NIEHS/EPA Children’s Centers Annual Meeting in October 2015. In September 2015, Dr. Alison Miller, COTC Director, Dr. Dana Dolinoy, Project 3 PI, and Dr. Peterson, UM CEHC Director, attended the Midwest Children’s Environmental Health Symposium at the University of Illinois to present UM-CEHC activities and learn about research and outreach activities being conducted by the CEHC at the University of Illinois. 

Future Activities:

In Year 4, we plan to expand recruitment of the ELEMENT cohort beyond our initial goal of 400 participants to 500 participants by Quarter 1 of Year 4. The second data collection (T2) on these same P01 participants will begin in Quarter 2 of Year 4. For Project 1, we anticipate publication of two new manuscripts related to Aim 3, evaluating the timing of in utero exposure in relation to peripubertal sexual maturation and reproductive hormone levels. We also will assess the impact of in utero and peripubertal EDC exposure on height and BMI velocity (Aim 1) using anthropometry data from the P20 visit and the first P01 visit (T1). During Year 4, we also will utilize our urinary metals data from ELEMENT mothers and children to address Aim 2 by evaluating how exposure to EDC mixtures during in utero and peripubertal development affect sexual maturation and reproductive hormone levels.

For Project 2, aims related to the ELEMENT cohort, we also will complete laboratory analysis of complete metabolomics data and toxicant concentrations in blood and urine and assess DNA methylation and gene expression at candidate genes. We also will conduct lipidomics analysis of longitudinal fasting blood samples at three timepoints in a subsample of n = 40, funded through Administrative Supplement P01 ES02284403S1. We also will continue to conduct statistical analysis and submit our findings for publication, with a particular emphasis on relating toxicants to metabolomics outcomes and DNA methylation mediators at two sensitive time-periods (e.g., in utero and the pubertal transition). For the MMIP cohort in Project 2, we plan to undertake lipidomics measures and relate it to changes in maternal BPA and phthalate levels. We also will initiate the scope of work for our Administrative Supplement in a subsample of MMIP cohort to examine the effect of repeated exposures to Pb, Cd, BPA and phthalates across pregnancy and adolescence on high-dimensional markers of metabolic homeostasis and potential mediation via changes over time in genome-wide DNA methylation.

For Project 3, in Year 4, we will continue studies on phthalates mixtures and also begin lead and high fat diets in the mice. Also during Year 4, the biospecimens collected in Aim 2 will be used for Aim 3 to assess epigenetic tissue specificity and time-dependent epigenetic drift using genome wide whole methylome, transcriptome and histone mark analysis. The Dolinoy lab has been named a consortium member of the NIEHS TaRGETII Consortium, enabling deeper profiling of epigenomic marks (e.g., ATAC-seq, Chromatin Modifications) within lead and phthalate exposed animals, across multiple tissues and purified cell populations.

The DMMC will continue to provide timely and effective statistical and bioinformatics support for all projects, data management and integration of existing data into a streamlined system. The DMMC also will continue to support the data management, quality controls and integration of databases for conducts of projects and complete another data break in Quarter 1 of Year 4. In Year 4, the DMMC will continue to participate in dissemination of research findings, including writing of manuscripts and presentations. A major focus in Year 4 will be mobilizing for increased data storage capacity due to multiple, large scale datasets being managed at the UM-CEHC as well as developing necessary statistical tools to analyze genome-wide methylation data. The Cox proportional model also will be developed to address the difficulty in analyzing sexual maturation data.

The COTC will continue partnerships in Kent County, Michigan in Year 4 and continue work to actively disseminate findings from our asthma mapping project. This will include presentations at multiple upcoming local and statewide events as well as promotion through social media and articles. We also will be hiring an MPH intern for Summer 2016 to assist in creating materials for dissemination of information related to children’s environmental health, including presentation templates for stakeholders and creating an asset map for community members. We will continue to work with the M-LEEad Center and other UMSPH Centers to disseminate nutrition and lead information to the city of Flint and to our partners in Kent County.


Journal Articles: 93 Displayed | Download in RIS Format

Other center views: All 130 publications 104 publications in selected types All 93 journal articles
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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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    Progress and Final Reports:

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