Grantee Research Project Results
2017 Progress Report: Lifecourse Exposures & Diet: Epigenetics, Maturation & Metabolic Syndrome
EPA Grant Number: R835436Center: Center for Research on Early Childhood Exposure and Development in Puerto Rico
Center Director: Alshawabkeh, Akram
Title: Lifecourse Exposures & Diet: Epigenetics, Maturation & Metabolic Syndrome
Investigators: Peterson, Karen E. , Padmanabhan, Vasantha
Institution: University of Michigan
EPA Project Officer: Hahn, Intaek
Project Period: June 1, 2013 through May 31, 2018 (Extended to May 31, 2019)
Project Period Covered by this Report: June 1, 2017 through May 31,2018
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 , Human 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 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 Protection Center (UM-CEHC) are to:
- 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.
- 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.
- 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.
- 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.
- Foster career development by assisting new investigators in the advancement of their research skills and knowledge in translational and children's environmental health research.
- 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).
The University of Michigan Medical School Institutional Review Board has reviewed and approved the Human Subjects Protocol for both ELEMENT, through November 14, 2018, and MMIP, through November 5, 2018.
During Year 5, we have continued to re-recruit ELEMENT participants from our P20 ES01817101/RD834800 study population (PI: Peterson) plus additional participants from the larger ELEMENT cohorts and are now close to completing our T2 visit, which begin in July 2017. As of August 2018, we have completed 446 of our targeted 550 T2 visits.
Progress for Project 1 in Year 5 includes the completion of exposure assessments in urine samples from the first visit for measurements of phthalates and phenols (n = 415). Additionally, during this past year, we have completed analysis of cadmium, and 16 metals in archived trimester 3 urines and of EDCs in trimester 1 and 2 urines of 250 mothers. In ELEMENT, we found associations between urinary BPA and different phthalate metabolites with measures of weight status and adiposity that differed by timing of exposure, sex, and pubertal status. Prenatal phthalate exposure was inversely associated with BMI z-score, waist circumference and skinfold thicknesses in adolescence in our cohort. Additionally, childhood BPA exposure was found to be positively associated with skinfold thicknesses in girls, while increased childhood MEHP exposure was inversely related to skinfolds in boys [Yang et al, Environmental Research, 2017]. Looking at BMI trajectories from birth to 14 year of age, we also observed that 3rd trimester phthalates exposure was associated with sex-specific differences in BMI trajectories, with the highest predicted BMI trajectories being observed in the third tertile exposure for females and in the first and second tertile exposure for males [Yang et al, Pediatric Obesity, 2018]. It was also found that in utero, BPA and phthalates exposure was associated with higher peripubertal serum testosterone, and higher odds of adrenarche in girls [Watkins et al, Environmental Research, 2017]. We also examined prenatal lead exposure in relation to age of menarche in girls, finding that during the 2nd trimester only, girls whose mothers had ≥5 µg/dL prenatal blood lead reported a later age at menarche compared to girls with prenatal blood lead levels < 5 µg/dL (confounder-adjusted HR = 0.59, 95% CI 0.28 to 0.90; P = 0.05) [Jansen et al, J Dev Orig Health Dis. 2018].
Progress for Project 2 in Year 5 included the completion of untargeted metabolomics and conventional markers of metabolic risk (e.g. insulin, glucose, lipids; blood pressure and anthropometry) in 405 of the T1 visit samples in the ELEMENT cohort. During this year, we also completed candidate gene analysis of DNA methylation in samples from the T1 visit to perform longitudinal assessments of changes in DNA methylation over time at these genes. Data analysis is occurring in parallel using an epigenome-wide analysis of DNA methylation at > 850,000 CpG sites via MethylationEPIC in 322 blood leukocyte samples from three time periods in the ELEMENT (in utero, early and late adolescence. Exposure analysis of EDCs (12 phthalates, 12 phenols), 17 metals, and inflammatory markers in first trimester samples from 56 families in the MMIP cohort were previously completed in Year 4. We also completed untargeted metabolomics and lipidomics in first trimester and term maternal samples and cord blood in 56 mother-child dyads. DNA methylation at > 850,000 CpG sites in 54 cord blood leukocyte and 40 placenta DNA samples was also done, and we used RNA-seq to profile gene expression in 43 of these cord blood samples. Now during Year 5, we conducted statistical analyses of these data to relate exposures to birth outcomes, metabolite, inflammatory, and DNA methylation profiles in MMIP newborns.
ELEMENT Cohorts: As described under Project 1, we began data collection for the second P01 follow up visit and have completed 446 visits as of August 2018. In the ELEMENT cohort, we found that urinary phthalate metabolite and BPA concentrations in utero and at 8-14 years of age were associated with markers of metabolic homeostasis, which were dependent on sex and puberty status (Watkins et al, J Clin Endocrinol Metab. 2016). Furthermore, we reported that metabolites of lipids, amino acids and carbohydrate metabolism were associated with metabolic risk in girls while lipid pathways were related to metabolic risk in boys through untargeted metabolomics (Perng et al, Obesity 2017). Additionally, concurrent levels of MCPP, MEP and metabolites of DBP corresponded with lower total cholesterol and low- density lipoprotein (LDL) in 8-14 year old boys, and higher urinary metabolites of DEHP were correlated with lower LDL in girls (Perng et al, Environ Res., 2017) .
Under Aim 2, Project 2, we also looked at the effects of dietary patterns and specific micronutrients during critical windows (pregnancy, adiposity rebound (3 years of age) and adolescence) on metabolic health in peripuberty. We found that diets high in vegetables, fruit, fish, chicken and legumes protected against metabolic risk in boys, while diets high in processed meats, traditional Mexican fried foods, and sugar sweetened beverages were associated with higher adiposity in girls (Perng et al, J Nutr., 2017). We also found that these same dietary patterns were related to pubertal onset, with higher vegetable and lean meats related to lower odds of B4 Tanner staging in girls, and higher processed meats and refined grains were positively associated with testicular volume > 3 mL in boys (Jansen et al, Nutrition Research, 2018). Prenatal consumption of micronutrients in mid to late pregnancy were associated with pubertal development in boys, with selenium, zinc, phosphorus, thiamin and riboflavin associated with increased odds for higher stages of genital development and pubic hair growth while vitamins C and D are negatively associated with genital development (Liu, under review, Nutrition Research, 2018). In work paralleling experiments in the viable agouti mouse model, we created a Mediterranean Diet Score (MDS) based on data from the Food Frequency Questionnaire to examine the potential for MDS to modify effects of BPA exposures. In this study, maternal MDS score during pregnancy modified the effect of prenatal BPA on adolescent metabolic health outcomes, with trimester 2 MDS*BPA interaction impacting these health effects the most (Marchlewicz, 2018 (Dissertation). In addition, maternal diet during pregnancy modified the effect of BPA on adolescent metabolic health outcomes in a sex specific manner. In boys, the interaction of maternal MDS*BPA altered metabolic risk score and in girls, MDS*BPA decreased 8-isoprostane levels, a marker of inflammation (Marchlewicz, 2018). A manuscript is currently in preparation.
As noted above, we completed untargeted metabolomics in 405 of the T1 visit samples, along with conventional markers of metabolic risk in the ELEMENT cohort. We also completed candidate gene analysis of DNA methylation in the latest adolescent time period. We continued analysis of DNA methylation data at > 850,000 CpG sites, quantified via the Infinium MethylationEPIC, in 322 blood leukocyte samples (from the same children at birth, early adolescence and late adolescence). We have observed associations between prenatal Pb exposure and DNA methylation at birth. We also observed associations between DNA methylation and prenatal BPA exposure with evidence that the association persists into adolescence at some loci.
MMIP Cohort: During Year 5, we complemented the untargeted metabolomics and lipidomics in first trimester, term maternal, and cord blood samples in 56 mother-child dyads. We also performed exposure analysis of phthalates, metals, and phenols, and DNA methylation analysis of cord blood with analysis of twelve inflammatory markers in this same set of samples, as well as DNA methylation at > 850,000 CpG sites via the Infinium MethylationEPIC BeadChip in 40 placenta samples. Expanding upon our past work in targeted analyses that found maternal long chain fatty acids, medium chain acylcarnitines, and histidine were correlated with infant DNA methylation at candidate genes [Marchlewicz et al, Scientific Reports, 2016], we are examining relationships between exposures, the untargeted metabolome, lipidome, DNA methylation across the epigenome, inflammatory markers, and birth outcomes. Preliminary results of these analyses were presented at several conferences in 2017-2018 including the Society for Reproductive Investigation, the NIH CHEAR Grantee Meeting, and the Defining Precision Nutrition Symposium. Analyses will be continued and completed during the no-cost extension period. Example results thus far include an association between bisphenol S exposure and decreased birth weight, associations between first trimester BPA exposure and DNA methylation at 47 CpG sites, and associations between first trimester exposures and inflammatory markers. In the continuation of targeted analyses, we published on the associations between maternal first trimester urinary levels of DEHP metabolites, MBzP and MCPP with hypomethylation of PPARa in cord blood DNA [Montrose et al, Epigenetics, 2018].
Project 3 is being conducted in a human-relevant mouse model. During Year 5: (1) experiments investigating nutrient toxicant interactions among high fat diets (HFD) and bisphenol A (BPA) were completed and submitted for publication; (2) experiments involving phthalate mixtures and metabolic impacts were completed, and (3) the epigenetic impact of exposures across the life-course were evaluated.
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. Maternal pregnancy diet and endocrine disrupting chemical exposure have been identified as drivers of perinatal programming. However, the potential for maternal diet to modify the impact of perinatal chemical exposure is not well understood. Project 3 Aim 1 examined whether perinatal exposure to two common environmental toxicants, BPA and HFDs, would affect NAFLD incidence in offspring. A longitudinal mouse exposure study was used to investigate this hypothesis and to evaluate the translation of findings to Projects 1 and 2.
Oral exposure to one of six diets: Control, Western HFD, Mediterranean HFD or each diet with 50g BPA/kg added, occurred pre-gestation through lactation. All mice were weaned onto the Control diet, thus isolating exposure to the perinatal period. Offspring NAFLD was assessed via hepatic steatosis and hepatic oxidative response at postnatal day 10 (PND10) and 10-months. Hepatic triglyceride (TG) levels were altered by perinatal HFD in dams, but in offspring perinatal exposures affected metabolic outcomes not hepatic TGs. 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 impacted 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. This research suggests that perinatal BPA and HFD exposure may be insufficient to induce perinatal programming of NAFLD. These results were presented by Marchlewicz et al at the Society of Toxicology and Gordon Research Conference and are currently in submission.
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. Here, we utilize an established 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 (A vy ) 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. 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 A vy /a offspring exhibited altered coat color distributions and altered DNA methylation at intracisternal A-particles (IAPs), repetitive elements in the mouse genome. 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 DOHaD Journal 2018).
Administration and Cores:
Administrative Core: In Year 5, we continued to use the organizational structure we have created to ensure clear and consistent communication among Center researchers, Core Directors, trainees and staff. This is achieved through monthly meetings where updates, challenges and opportunities for collaboration between projects are shared. Bi-weekly conference calls are also held to facilitate communication between investigators at other study locations. The new Center Manager, visited our fieldwork site in Mexico City in June 2018 to ensure smooth coordination of enhanced biorepository and sample management protocols and coordination of remaining ELEMENT field work.
Data Management and Modeling Core (DMMC):
The DMMC has provided extensive support to data management and data analysis to various projects conducted by the PIs. Specifically, the DMMC has updated the Data Management Plan protocol to address specific issues related to data collection, data storage, data processing and data sharing in the P01 projects. To date, the DMMC has integrated the P01-related data from the ELEMENT T1 and T2 visits and all new laboratory analysis results for Projects 1 and 2 into the database housed at UM-SPH. The DMMC also meets weekly to discuss various issues concerning data processing, modeling and analysis for mediation analysis, missing data imputation, multiple comparisons, growth trajectory analysis [Yang et al, Pediatric Obesity, 2018], data harmonization, and survival modeling for sexual maturation outcomes. In addition, the DMMC derived new variables from raw data for the P01 projects; for example, the normalization of metabolomics data with corrected batch effects and missing data, total energy intake adjustment for food groups and nutrients in ELEMENT, sleep duration and efficiency and physical activity levels from accelerometry data and MET scores based on self-reported PA items. Additionally, the DMMC has conducted data processing that included total energy intake (TEI) adjustment for food groups and nutrients in ELEMENT food frequency questionnaires; extracting tooth contour from dental imaging data; preprocessing accelerometry data for analyses on sleep and physical activity; computation of the Dietary Inflammatory Index; computing MET Scores based on physical activity questionnaires; and preprocessing metabolomics data to address batch effects and missing data. Modeling and analysis included providing modeling help for mediation analysis, missing data imputation, multiple comparison [Tao et al, Statistics in Medicine, 2015] , trajectory analysis [Yang et al, Pediatric Obesity, 2018], data harmonization and survival modeling; conducting analyses for relating exposures to EDCs on BMI, growth curve, sleep patterns, metabolic profiles, methylation29 and time to sexual maturation.
Additionally, in preparation for his transition out of the DMMC, Dr. Lu Tang worked on developing tutorials and data documentation to serve as training materials for Ms. Irena Chen who assumed this role in August 2018. Specific training plan for Ms. Chen included: (1) review of the data management protocols (DMP), including the tutorial of standard data procedures, such as fulfilling data requests; (2) walkthrough of data and documentations, and step-to-step data release, beginning from the historical data and to the most recent data; (3) training on software and data management tools, such as the use of R, SAS, U Drive and MBox.
Community Outreach and Translation Core (COTC):
Our Community Outreach and Translation Core (COTC) worked in Year 5 with the UM Office of Public Health Practice and Public Health Training Center to develop and disseminate nutrition trainings to community health workers in Flint, MI (https://sph.umich.edu/mphtc/resources.html) as part of lead mitigation education efforts. Furthermore, we have collaborated closely with our Community Advisory Board in Grand Rapids, MI, to design and implement a community driven project focused on lead abatement education for parents of young children.
Since April 2018, our team has been collaborating with the Healthy Homes Coalition and Kent County Health Department personnel to develop a Peer Education Program (PEP) that focuses on providing volunteer community parents educational materials on lead and lead mitigation techniques that they can share with families with young children in their communities in the form of a scheduled home visit. We have developed this interactive curriculum in collaboration with the Healthy Homes Coalition, and multiple students have participated in this project. We plan to have a finalized curriculum by mid-October, conduct Peer educator trainings during late fall and early winter, and begin home visits by early spring 2019. We are also developing evaluation tools to assess partnership outcomes and program outcomes (e.g., participant satisfaction, number of families served; change in understanding and skills around lead exposure and abatement in the home among parents with young children). We have submitted an abstract as part of a proposed symposium on community engagement to the Society for Research on Child Development (SRCD) to report on the development of and findings from this project.
Future Activities:
As part of the 12-month no-cost extension period (June 1, 2018 – May 31, 2019), we are completing the following activities reflected in our scope of work and scientific aims for the center.
Project 1:
We will complete pending laboratory analyses during Q1 of 12-month extension period. During this upcoming year, we will complete the remaining statistical analyses and manuscripts relating EDC exposures, including blood lead and BPA/phthalates levels, and relate these to sexual maturation outcomes, including changes in reproductive hormones that reflect progression of secondary sexual characteristics from early to late adolescence (T1 and T2 visits). Finally, we will complete modeling the impact of mixtures of EDCs and metals on maturation outcomes as well as height trajectories.
Project 2:
ELEMENT Cohorts: During this upcoming year, we will continue to conduct candidate gene analyses in the ELEMENT cohort and investigate associations between exposures, DNA methylation and metabolic risk outcomes and untargeted metabolomics (Aims 2 & 3). We will examine if DNA methylation changes over time in the same individuals in the candidate gene and epigenome-wide datasets and associated toxicants across time, termed “epigenetic deflection” (Aim 2 & 3). Additionally, we will conduct statistical analyses of the relationship of candidate gene methylation in utero and adolescence with onset and progression of sexual maturation, both potential mediators of toxicant associations with metabolic syndrome risk score in adolescence. We will also investigate changes in metabolomics profiles with dietary exposures, progression of obesity and insulin resistance in early and later puberty (Aims 2 & 3). Finally, we will utilize the Dietary Inflammatory Index to characterize dietary patterns and examine effect modification of associations between EDC and metals (lead) exposures in pregnancy and adolescence of markers of inflammation and metabolic homeostasis (metabolomics, metabolic syndrome components) (Aims 2 & 3).
MMIP Cohort: In this no cost-extension period, we plan to complete exposure assessments for phthalates and phenols on first trimester maternal urinary samples from the remaining participants and complete statistical analysis relating epigenome-wide DNA methylation data in cord blood samples to first trimester exposures to phthalates and phenols (Aim 2 & 3).
Project 3:
We are utilizing mouse brain tissue (10 months of age) to validate previously documented BPA-related differential DNA hydroxymethylation at imprinted genes in blood. In the same brain samples, we are using RT-qPCR to measure gene expression for imprinted genes with documented differential DNA hydroxymethylation by BPA exposure as well as ox-bis-seq to evaluate 5-hmC levels at imprinted genes and metabolic target genes at both 3 weeks and 10 months of age.
Journal Articles: 66 Displayed | Download in RIS Format
Other center views: | All 97 publications | 73 publications in selected types | All 66 journal articles |
---|
Type | Citation | ||
---|---|---|---|
|
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) R835436 (2017) |
Exit Exit |
|
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) R835436 (2017) |
Exit Exit Exit |
|
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) R834515 (Final) R836159 (2018) |
|
|
Buxton M, Perng W, Tellez-Rojo M, Rodriguez-Carmona Y, Cantoral A, Sanchez B, Rivera-Gonzalez L, Gronlund C, Scivappa N, Hebert J, O'Neill M, Peterson K. Particulate matter exposure, dietary inflammatory index and preterm birth in Mexico city, Mexico. ENVIRONMENTAL RESEARCH 2020;189(109852). |
R835436 (Final) |
Exit Exit |
|
Cantonwine DE, Hauser R, Meeker JD. Bisphenol A and human reproductive health. Expert Review of Obstetrics & Gynecology 2013;8(4):329-335. |
R835436 (2014) R835436 (2015) R835436 (2017) |
Exit |
|
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) R835436 (2017) |
Exit Exit |
|
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) R835436 (2015) R835436 (2016) R835436 (2017) |
Exit Exit Exit |
|
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) R835436 (2017) |
Exit Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit Exit Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit Exit Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit |
|
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) R835436 (2017) |
Exit Exit Exit |
|
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) R835436 (2017) R834513 (Final) R836155 (2017) R836155 (2020) R836155C003 (2017) |
Exit Exit Exit |
|
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) R835436 (2015) R835436 (2017) R834800 (2013) |
Exit Exit Exit |
|
Fossee E, Zamora A, Peterson K, Cantoral A, Perng W, Tellez-Rojo M, Torres-Olascoaga L, Jansen E. Prenatal dietary patterns in relation to adolescent offspring adiposity and adipokines in a Mexico City cohort. JOURNAL OF DEVELOPMENTAL ORIGINA OF HEALTH AND DISEASE 2023;PII S2040174422000678:1-10 |
R835436 (Final) |
Exit |
|
Goodman C, Bashash M, Green R, Song P, Peterson K, Schnass L, Mercado-Garcia A, Martinez-Medina S, Hernandez-Avila M, Martiniz-Mier A, Tellez-Rojo M, Hu H, Till C. Domain-specific effects of prenatal fluoride exposure on child IQ at 4, 5, and 6-12 years in the ELEMENT cohort. ENVIRONMENTAL RESEARCH 2022;211:112993. |
R835436 (Final) |
Exit Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit Exit |
|
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) R835436 (2017) |
Exit Exit |
|
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) R835436 (2017) |
Exit Exit |
|
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) R835436 (2017) |
|
|
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) |
Exit |
|
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) |
Exit |
|
Jansen E, Burgess H, Chervin R, Dolinoy D, Tellez-Rojo M, Cantoral A, Olasocoaga-Torres L, Lee J, Dunietz G, O'Brien L, Peterson K. Sleep duration and timing are prospectively linked with insulin resistance during late adolescence. OBESITY 2023;31(4):912-922. |
R835436 (Final) |
Exit |
|
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) R835436 (2016) R835436 (2017) |
Exit Exit |
|
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) |
|
|
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) R835436 (2017) |
Exit Exit |
|
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) R835436 (2017) |
Exit Exit Exit |
|
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) |
Exit Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit Exit Exit |
|
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) R835436 (2015) R835436 (2017) R836155 (2020) R836155C003 (2017) |
Exit Exit Exit |
|
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) R835436 (2017) |
Exit Exit Exit |
|
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) R835436 (2017) |
Exit Exit |
|
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) R835436 (2017) |
Exit Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit Exit |
|
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) |
Exit |
|
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) R835436 (2017) |
Exit Exit Exit |
|
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) R835436 (2017) |
Exit Exit |
|
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) R835436 (2017) |
Exit Exit Exit |
|
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) R835436 (2015) R835436 (2017) R834593C001 (Final) R835434 (2013) R835434 (2014) |
|
|
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) R835436 (2017) |
Exit Exit Exit |
|
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) |
Exit Exit |
|
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) |
Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit Exit |
|
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) R835436 (2017) |
Exit Exit Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit Exit |
|
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) R835436 (2017) |
Exit Exit |
|
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) R835436 (2015) R835436 (2017) R834678C001 (Final) |
Exit Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit Exit |
|
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) R835436 (2017) |
Exit Exit Exit |
|
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) R835436 (2015) R835436 (2017) |
Exit Exit Exit |
|
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) R835436 (2016) R835436 (2017) |
Exit Exit |
|
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) R835436 (2016) R835436 (2017) R836155 (2017) R836155 (2020) R836155C003 (2017) |
Exit Exit Exit |
|
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) R835436 (2017) R834513 (Final) |
Exit Exit Exit |
|
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) R835436 (2017) R835436 (Final) |
Exit Exit |
|
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) |
Exit Exit Exit |
|
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) R835436 (2017) |
Exit Exit |
|
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) R835436 (2017) |
Exit Exit Exit |
|
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) |
Exit Exit |
|
Zamora A, Peterson K, Goodrichy J, Tellez-Roho M, Song P, Meeker J, Dolinoy D, Torres-Olascoaga L, Cantoral A, Jansen E. Associations between exposure to phthalates, phenols, and parabens with objective and subjective measures of sleep health among Mexican women in midlife: a cross-sectional and retrospective analysis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH 2023;Epub |
R835436 (Final) |
Exit |
|
Zamora A, Jansen E, Goodrich J, Tellez-Rojo M, Song P, Meeker J, Dolinoy D, Torres O, Cantoral A, Peterson K. Cross-sectional associations between phthalates, phenols, and parabens with metabolic syndrome risk during early-to-mid adolescence among a cohort of Mexican youth. ENVIRONMENTAL SCIENCE 2023;116706 |
R835436 (Final) |
Exit |
|
Zhang K, Buxton M, Rodriguez-Carmona Y, Peterson K, Liu Y, Burgess H, Cantoral A, Tellez-Rojo M, Torres-Olasconaga L, Arboleda-Merino L, Jansen E. Duration, timing, and consistency of sleep in relation to inflammatory cytokines in Mexican adolescents. SLEEP MEDICINE 2022;100:103-111. |
R835436 (Final) |
Exit Exit |
|
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) R835436 (2017) |
Exit Exit |
|
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) R835436 (2017) |
Exit |
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2016 Progress Report
- 2015 Progress Report
- 2014 Progress Report
- 2013 Progress Report
- Original Abstract
66 journal articles for this center