Grantee Research Project Results
2013 Progress Report: Perinatal Exposures, Epigenetics, Child Obesity & Sexual Maturation
EPA Grant Number: R834800Center: Center for Research on Early Childhood Exposure and Development in Puerto Rico
Center Director: Alshawabkeh, Akram
Title: Perinatal Exposures, Epigenetics, Child Obesity & Sexual Maturation
Investigators: Peterson, Karen E.
Current Investigators: Peterson, Karen E. , Dolinoy, Dana , Meeker, John D.
Institution: University of Michigan
EPA Project Officer: Hahn, Intaek
Project Period: August 9, 2010 through August 8, 2014
Project Period Covered by this Report: August 9, 2012 through August 8,2013
Project Amount: $1,335,311
RFA: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
- To characterize the effect of lead, bisphenol A and phthalates on weight gain and status (BMI) and the development of obesity in early/mid childhood and on pubertal timing assessed by Tanner staging and hormonal biomarkers.
- To utilize lead as a model toxicant, examine the epigenetic mechanisms, for example, DNA methylation of four key growth-regulating genes, associated with perinatal exposure and potential modification of the development of obesity and pubertal timing.
- To enhance career development by assisting new investigators and trainees in the advancement of their research skills and knowledge in translational and children’s environmental health research.
- To involve key stakeholders in Michigan and Mexico via a Community Engagement Plan aimed to educate and inform study participants, policy makers and public health decision makers on children’s environmental health exposures of concern.
- To apply research findings, infrastructure and partnerships gained through the Formative P20 Center to the development of a full P01 Children’s Environmental Health Center at the University of Michigan.
- To describe the relationship of prenatal lead exposure to sexual maturation.
- To describe the association of prenatal lead exposure with childhood weight gain and status.
- To examine the relationship of prenatal lead exposure to cord blood DNA methylation levels in four genes associated with early growth.
- To develop a mouse model of dose-dependent maternal lead effects on the fetal epigenome.
- To examine the relationship of prenatal lead exposure to physiological parameters and hormonal status throughout the life course.
- To compare urinary concentrations of BPA and phthalate metabolites from pregnant women and adolescents in Mexico City with those measured in the U.S. general population.
- To explore the association between BPA and phthalate exposure and birth outcomes.
- To investigate the relationship between early-life (in utero) exposure to BPA and phthalates and measures of weight, body mass index and growth in infancy and early childhood.
- To explore the association between exposure to BPA and phthalates in early life (in utero) and in adolescence with stages of sexual maturation and relevant endocrine markers in Mexican youth.
- To determine predictors of BPA and phthalate exposure among adolescents in Mexico City.
Progress Summary:
- Study recruitment was completed and surpassed the initial target of 200 participants. A total of 250 participants were recruited (118 males and 132 females).
- Data collected from participants aged ~7-15 years included biological specimens (blood and urine); anthropometry (height, weight, waist circumference and skinfolds); questionnaires (food frequency, physical activity and exposure assessment); and a physical exam by a physician, including Tanner staging and a self-report Tanner staging questionnaire.
- Laboratory analysis of hormones was completed December 2012 at the University of Michigan Diabetes Research Center (DRC).
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Statistical analysis examining the effect of lead exposure in different sensitive periods (in utero, early childhood and concurrently in peripuberty [7-15 yr of age]) in relation to:
- Reproductive hormones and observed and self-reported Tanner stages of secondary sexual characteristics;
- Metabolic risk syndrome components and targeted biomarkers of metabolic homeostasis.
- The relationship of BPA and phthalates measured in the third trimester urines on the development of cardiometabolic outcomes was explored.
- All laboratory analyses for two studies investigating the associations between prenatal Pb exposure and cord blood DNA methylation levels were completed.
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Additional statistical analyses utilizing the P20 sample included:
- Examination of the association of preterm birth (< 37 weeks gestational age) with BMI, obesity and waist circumference in adolescence, using a developmental origins framework.
- Consideration of other predictors of obesity in adolescence in a population undergoing the nutrition transition (e.g., dietary quality).
Analysis of Research Project findings suggest:
- That infancy is the window of greatest sensitivity to lead exposure and that lead is associated with measures of elevated cardiometabolic risk in adolescence that vary by sex, for example, elevated serum lipids in girls and higher fasting glucose in boys. In addition, preliminary data analyses suggest that both lead and BPA exposure may be associated with a lean rather than an obese phenotype but a greater cardiometabolic risk in adolescent girls.
RD834800C002: In Utero Lead Exposure: Fetal Epigenome and Life-Course Physiologic Effects
Progress is described by Specific Aim, below.
Specific Aim 1:
The following Pilot Project 1 tasks related to Specific Aim 1 were completed this year:
- Maternal lead exposure in the viable yellow agouti mouse model began in the summer of 2011 and ended summer 2012 with exposure via water: control (0 ppm lead) and three exposure groups (2.1 ppm, 16 ppm, or 32 ppm). Water used for control animals and to make stock lead solutions was sent to NSF International (Ann Arbor, MI) for objective verification of lead-free water content. For further quality control, lead stock solutions also were sent to NSF International for verification of expected lead levels; minor adjustments were subsequently made to solutions to attain the desired lead levels.
- At 3 weeks of age, wean weight was recorded and tail tips for DNA isolation and epigenetic analyses were collected from all mice.
- Results were analyzed and published.
- Dose- and sex-specific responses in weanling body weight and DNA methylation indicate that lead acts on the epigenome in a locus-specific fashion, dependent on the genomic feature hosting the CpG site of interest and that sex is a factor in epigenetic response.
- Lean Avy offspring (a/a genotype only) began life-course evaluations of body composition, spontaneous activity, energy expenditure and food intake at the Michigan Metabolomics and Obesity Center, Animal Phenotyping Core this past year. These evaluations occurred at 3 time points throughout life (3, 6 and 9 months).
- Epigenetic drift was measured in in a/a genotype mice exposed perinatally to lead (Pb) acetate at four concentrations: 0 ppm, 2.1 ppm, 16 ppm and 32 ppm.
- Pilot funds from the Michigan Nutrition and Obesity Research Center (NORC, NIH DK089503) were received in 2010 to conduct physiological, hormonal and epigenetic studies following dose-dependent maternal exposure to BPA, a chemical of interest in the UM-CEHC. Instead of terminating the mouse BPA study at post-natal day 22, the life-course evaluation of physiological parameters was able to be continued.
- Results were analyzed and published.
- Pb: Exposed females and males exhibited increased energy expenditure as compared to controls (p < 0.0001 for both). In females, horizontal activity differed significantly from controls (p = 0.02) over the life course. Overall, food intake increased in exposed females and males (p < 0.0008 and p < 0.0001, respectively) with significant linear trends at 9 months in females (p = 0.01) and 6 months in males (p < 0.01). Body weight was significantly increased in males at the medium and high exposures (p = 0.001 and p = 0.006). Total body fat differed among exposed females and males (p < 0.0001 and p < 0.0001, respectively). Insulin response was significantly increased in medium exposure males (p < 0.05). Perinatal Pb exposure at blood lead levels between 4.1 mg/dL and 32 mg/dL is associated with increased food intake, body weight, total body fat, energy expenditure, activity and insulin response in mice. Physiological effects of developmental Pb exposure persist and vary according to sex and age.
- DNA methylation levels in the controls increased over time at the imprinted Igf2 and Igf2r loci (both p = 0.0001), but not at the imprinted H19 locus or the CabpIAP metastable epiallele. Pb exposure was associated with accelerated DNA hypermethylation in CabpIAP (p = 0.0209) and moderated hypermethylation in Igf2r (p = 0.0447) and with marginally accelerated hypermethylation at H19 (p = 0.0847). The presence and magnitude of epigenetic drift was locus-dependent, and enhancement of drift was mediated by perinatal Pb exposure in some, but not all, loci.
- BPA: Overall, exposed females and males exhibited increased energy expenditure (p < 0.001 and 0.001) throughout the life course. In females, horizontal and vertical activity increased (p = 0.07 and 0.06) throughout the life course. Generally, body composition measures were not different throughout the life course in exposed females or males (all p > 0.44), although body fat and weight decreased in exposed females at particular ages (all p < 0.08). Milligram-exposed females had improved glucose, insulin, adiponectin and leptin profiles (all p < 0.10). Thus, life-course analysis illustrates that BPA is associated with hyperactive and lean phenotypes.
- Data were collected from more participants (N = 250) than originally proposed (N = 200) as described above in the P20 Research Project.
- We found that self-reported use of a number of personal care products in the 48 hours prior to urine sample collection was associated with exposure to multiple phthalates among children in the study. In boys, cologne use was associated with multiple phthalates, while in girls the use of colored cosmetics (make-up), deodorant, conditioner and other hair care products were important for exposure. Among girls, the number of personal care products used associated with significantly increased MEP concentrations. Since exposure to phthalates in children may be associated with endocrine-related effects, reduced or delayed use of certain personal care products (e.g., cologne/perfume, colored cosmetics) in children may be warranted.
- Associations between archived maternal third trimester urinary measures of BPA and 9 phthalate metabolites with peripubertal (aged 8-14 years) BMI z-score, waist circumference and triceps skinfold were analyzed with continuous and quartile measures of metabolites. A cross-sectional study of adolescent urinary concentrations of BPA and phthalate metabolites with these outcome measures was also assessed. Results indicated sexually dimorphic, nonmonotonic relationships between both maternal and peripubertal urinary metabolites with peripubertal measures. Additionally, direction of association with outcomes differed by timing of urinary measures, and significant findings were negative and occurred with second or third quartiles of metabolites.
- Associations between in utero or peripubertal exposure to EDCs and sexual maturation were examined. Among boys, we found that in utero exposure to certain phthalates was associated with reduced odds of pubertal onset (pubarche and gonadarche) and increased levels of serum SHBG. While childhood exposure to phthalates was not associated with pubertal onset, DEHP metabolites were associated with decreased free T (and increased SHBG). Overall, findings appear to be consistent with anti-androgenic properties of multiple phthalates in males reported in animal and very limited human studies to date. Among girls, in utero MEHP levels were associated with increased odds of pubarche, along with increased serum concentrations of DHEAS (adrenarche) and inhibin B. Childhood low molecular weight phthalates were associated with increased odds of puberty (pubarche, thelarche or menarche). Our results are consistent with previous animal and limited human cross-sectional studies.
- Self-reported use of personal care products (e.g., cologne, colored cosmetics, deodorant, conditioner and other hair care products) in the 48 hours prior to urine sample collection was associated with exposure to multiple phthalates among boys and girls. We also found nonmonotonic relationships of phthalates and BPA exposures with measures of fat mass and distribution (BMI, skinfolds, waist) that differed by sex and timing of exposure. Additionally, phthalates were related to measures of pubertal onset and reproductive hormones, results that were consistent with previous animal and limited human cross-sectional studies.
Future Activities:
- Statistical analyses, manuscript preparation and submission.
- Validation of self-reported sexual maturation in Mexican youth in relation to M.D.-observed Tanner stages and reproductive hormones related to secondary sexual characteristics.
- Statistical analyses will examine associations between prenatal and early childhood lead exposure and DNA methylation levels during peripuberty. The impact of early lead exposure on methylation drift between birth and the peri-adolescent time points at the four candidate regions is being evaluated.
- Funding has been received to expand to a 5-year P01 CEHC. A newly established Michigan Mother-Infant Pairs (MMIP) cohort will be included along with the ELEMENT cohort to examine how EDC mixtures perturb metabolic homeostasis, clarify the role of diet in amplifying or negating such effects, illustrate the epigenetic and transcriptional changes involved, and inform the design of future interventions to modify metabolic consequences of EDC exposures both in utero and during the pubertal transition.
- Build upon these P20 Pilot Project 1 data in Project 3 of the 5-year P01 Children’s Environmental Health Center to investigate the hypothesis that perinatal exposure to BPA/phthalates/Pb mixture results in epigenetic alterations in critical DNA control elements and disrupts physiologic status throughout the life course, events that are subject to modification by diet and continued peripubertal exposure.
- Additional Pilot Funds from the UM P30 NIEHS Core Center were obtained to utilize brain tissue from the lead-exposed mice in the UM-CEHC Pilot Project 1.
- With funding from the NORC Pilot grants, animals exposed in utero to BPA are being assessed for BPA-induced epigenetic changes via promoter tiling arrays. Epigenetic results will be analyzed in combination with already collected physiological parameters to determine if epigenetic mechanisms mediate the effects of BPA exposure on the measured phenotypes.
- The findings from Pilot Project 2 of the P20 Formative Children’s Center serve as a perfect launching point for the newly funded P01 CEHC to examine these relationships in greater depth by expanding sample size, increasing the number of time points exposure is assessed, and exploring the effects of exposure to mixtures (lead, BPA, phthalates, and cadmium) on repeated measures of physical growth and sexual maturation throughout the pubertal transition.
Journal Articles: 28 Displayed | Download in RIS Format
Other center views: | All 72 publications | 33 publications in selected types | All 28 journal articles |
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Afeiche M, Peterson KE, Sanchez BN, Cantonwine D, Lamadrid-Figueroa H, Schnaas L, Ettinger AS, Hernandez-Avila M, Hu H, Tellez-Rojo MM. Prenatal lead exposure and weight of 0- to 5-year-old children in Mexico City. Environmental Health Perspectives 2011;119(10):1436-1441. |
R834800 (2011) R834800 (2012) |
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Afeiche M, Peterson KE, Sanchez BN, Schnaas L, Cantonwine D, Ettinger AS, Solano-Gonzalez M, Hernandez-Avila M, Hu H, Tellez-Rojo MM. Windows of lead exposure sensitivity, attained height, and body mass index at 48 months. The Journal of Pediatrics 2012;160(6):1044-1049. |
R834800 (2012) R834800 (2013) |
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Anderson OS, Sant KE, Dolinoy DC. Nutrition and epigenetics:an interplay of dietary methyl donors, one-carbon metabolism and DNA methylation. The Journal of Nutritional Biochemistry 2012;23(8):853-859. |
R834800 (2012) R834800 (2013) |
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Anderson OS, Nahar MS, Faulk C, Jones T, Liao C, Kannan K, Weinhouse C, Rozek RS, Dolinoy DC. Epigenetic responses following maternal dietary exposure to physiologically relevant levels of bisphenol A. Environmental and Molecular Mutagenesis 2012;53(5):334-342. |
R834800 (2012) |
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Anderson OS, Peterson KE, Sanchez BN, Zhang Z, Mancuso P, Dolinoy DC. Perinatal bisphenol A exposure promotes hyperactivity, lean body composition, and hormonal responses across the murine life course. The FASEB Journal 2013;27(4):1784-1792. |
R834800 (2012) R834800 (2013) |
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Cantonwine D, Meeker JD, Hu H, Sanchez BN, Lamadrid-Figueroa H, Mercado-Garcia A, Fortenberry GZ, Calafat AM, Tellez-Rojo MM. Bisphenol A exposure in Mexico City and risk of prematurity:a pilot nested case control study. Environmental Health 2010;9:62. |
R834800 (2011) R834800 (2012) |
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Dolinoy DC, Faulk C. Introduction: the use of animals models to advance epigenetic science. ILAR Journal 2012;53(3-4):227-231. |
R834800 (2013) |
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Eng DS, Lee JM, Gebremariam A, Meeker JD, Peterson K, Padmanabhan V. Bisphenol A and chronic disease risk factors in US children. Pediatrics 2013;132(3):e637-e645. |
R834800 (2013) |
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Faulk C, Dolinoy DC. Timing is everything: the when and how of environmentally induced changes in the epigenome of animals. Epigenetics 2011;6(7):791-797. |
R834800 (2011) R834800 (2012) R834800 (2013) |
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Faulk C, Barks A, Dolinoy DC. Phylogenetic and DNA methylation analysis reveal novel regions of variable methylation in the mouse IAP class of transposons. BMC Genomics 2013;14:48. |
R834800 (2013) |
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Faulk C, Barks A, Liu K, Goodrich JM, Dolinoy DC. Early-life lead exposure results in dose- and sex-specific effects on weight and epigenetic gene regulation in weanling mice. Epigenomics 2013;5(5):487-500. |
R834800 (2013) |
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Faulk C, Barks A, Sanchez BN, Zhang Z, Anderson OS, Peterson KE, Dolinoy DC. Perinatal lead (Pb) exposure results in sex-specific effects on food intake, fat, weight, and insulin response across the murine life-course. PLoS One 2014;9(8):e104273. |
R834800 (2013) |
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Ferguson KK, Loch-Caruso R, Meeker JD. Urinary phthalate metabolites in relation to biomarkers of inflammation and oxidative stress: NHANES 1999-2006. Environmental Research 2011;111(5):718-726. |
R834800 (2011) R834800 (2012) |
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Ferguson KK, Loch-Caruso R, Meeker JD. Exploration of oxidative stress and inflammatory markers in relation to urinary phthalate metabolites: NHANES 1999-2006. Environmental Science & Technology 2012; 46(1):477-485. |
R834800 (2011) R834800 (2012) |
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Ferguson KK, Hauser R, Altshul L, Meeker JD. Serum concentrations of p,p’-DDE, HCB, PCBs and reproductive hormones among men of reproductive age. Reproductive Toxicology 2012;34(3):429-435. |
R834800 (2013) |
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Fortenberry GZ, Hu H, Turyk M, Barr DB, Meeker JD. Association between urinary 3,5,6-trichloro-2-pyridinol, a metabolite of chlorpyrifos and chlorpyrifos-methyl, and serum T4 and TSH in NHANES 1999-2002. Science of the Total Environment 2012;424:351-355. |
R834800 (2013) |
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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. |
R834800 (2013) R835436 (2014) R835436 (2015) R835436 (2017) |
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Kordas K, Ettinger AS, Bellinger DC, Schnaas L, Téllez Rojo MM, Hernández-Avila M, Hu H, Wright RO. A dopamine receptor (DRD2) but not dopamine transporter (DAT1) gene polymorphism is associated with neurocognitive development of Mexican preschool children with lead exposure. The Journal of Pediatrics 2011;159(4):638-643. |
R834800 (2011) R834800 (2012) |
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Lamadrid-Figueroa H, Téllez-Rojo MM, Angeles G, Hernández-Ávila M, Hu H. Bias correction by use of errors-in-variables regression models in studies with K-X-ray fluorescence bone lead measurements.Environmental Research 2011;111(1):17-20. |
R834800 (2011) R834800 (2012) |
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Lewis RC, Meeker JD, Peterson KE, Lee JM, Pace GG, Cantoral A, Tellez-Rojo MM. Predictors of urinary bisphenol A and phthalate metabolite concentrations in Mexican children. Chemosphere 2013;93(10):2390-2398. |
R834800 (2013) |
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Meeker JD, Ferguson KK. Relationship between urinary phthalate and bisphenol A concentrations and serum thyroid measures in U.S. adults and adolescents from National Health and Nutrition Examination Survey (NHANES) 2007-2008. Environmental Health Perspectives 2011;119(10):1396-1402. |
R834800 (2011) R834800 (2012) |
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Meeker JD, Calafat AM, Hauser R. Urinary phthalate metabolites and their biotransformation products: predictors and temporal variability among men and women. Journal of Exposure Science and Environmental Epidemiology 2012; 22(4):376-386. |
R834800 (2012) |
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Meeker JD. Exposure to environmental endocrine disruptors and child development. Archives of Pediatrics and Adolescent Medicine 2012;166(10):952-958. |
R834800 (2012) R834800 (2013) |
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Sánchez BN, Hu H, Litman HJ, Téllez-Rojo MM. Statistical methods to study timing of vulnerability with sparsely sampled data on environmental toxicants. Environmental Health Perspectives 2011;119(3):409-415. |
R834800 (2011) R834800 (2012) |
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Tellez-Rojo MM, Cantoral A, Cantonwine DE, Schnaas L, Peterson K, Hu H, Meeker JD. Prenatal urinary phthalate metabolites levels and neurodevelopment in children at two and three years of age. Science of the Total Environment 2013;461-462:386-390. |
R834800 (2013) |
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Weinhouse C, Anderson OS, Bergin IL, Vandenbergh DJ, Gyekis JP, Dingman MA, Yang J, Dolinoy DC. Dose-dependent incidence of hepatic tumors in adult mice following perinatal exposure to bisphenol A. Environmental Health Perspectives 2014;122(5):485-491. |
R834800 (2013) |
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Wickerham EL, Lozoff B, Shao J, Kaciroti N, Xia Y, Meeker JD. Reduced birth weight in relation to pesticide mixtures detected in cord blood of full-term infants. Environment International 2012;47:80-85. |
R834800 (2012) |
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Zhang A, Hu H, Sánchez BN, Ettinger AS, Park SK, Cantonwine D, Schnaas L, Wright RO, Lamadrid-Figueroa H, Tellez-Rojo MM. Association between prenatal lead exposure and blood pressure in children. Environmental Health Perspectives 2011;120(3):445-450. |
R834800 (2011) R834800 (2012) |
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Supplemental Keywords:
Children’s health, human health, health effects, children’s environmental health, environmental risks, exposure assessment, epigenetics, maternal exposure, Mexico, lead, bisphenol A, phthalates, animal exposure, agouti mouse, animal phenotyping, abnormal sexual maturation, age-related differences, environmental risks, perinatal exposure, biological response, childhood obesity, assessment of exposure, dietary exposure, dietary factors, developmental disorders, RFA, Health, Scientific Discipline, INTERNATIONAL COOPERATION, HUMAN HEALTH, Exposure, Biochemistry, Children's Health, Environmental Policy, Biology, abnormal sexual maturation, age-related differences, biological response, environmental risks, perinatal exposure, epigenetics, childhood obesity, assessment of exposure, children's environmental health, dietary exposure, dietary factors, developmental disordersProgress and Final Reports:
Original Abstract Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834800C001 In Utero Lead Exposure: Fetal Epigenetics and Life-Course Physiologic Effects
R834800C002 Impacts of Life-stage Exposures to BPA and Phthalates on Growth and Development
The 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.