Grantee Research Project Results
2011 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: April 1, 2011 through March 31,2012
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:
Overweight and obesity in children have increased significantly over the past few decades. Many attempts have been made to reverse this trend through school food reforms, clinical counseling of at risk youth, camps and group clinics that focus on lifestyle and behavior change. However, CEHC research offers a new perspective on the childhood obesity dilemma. Recent environmental health research suggests that early life exposure to environmental toxins, such lead, bisphenol A, and phthalates, which we are studying at the UM-CEHC, may also affect child growth trajectories, body mass index (BMI), and the tempo of sexual maturation.
If an association between in utero or early life exposure to lead, bisphenol A, or phthalates with child growth, development, and/or sexual maturation, is demonstrated, this information can be used to inform future policies for decreasing exposure to substances related to obesity and the multitude of associated co-morbidities. Knowledge of environmental exposures that are associated with adverse health effects also can be used by physicians, public health workers, and community activists to educate the general public about ways to avoid these exposures.
The specific aims of this Center are:
- 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 to examine the epigenetic mechanisms, e.g. 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.
Progress Summary:
The following Research Project tasks were completed this year:
- INSP field study staff in Mexico were hired, trained, and standardized for study-specific questionnaires and measures, including a three-day anthropometry and Tanner staging intensive course with study consultant, Dr. Jorge Chavarro.
- Recruitment began in September 2011 with more than 100 participant visits completed in Year 2.
- Hormone analyses of the first 53 study participants were completed in December 2011; analyses for an additional 56 participants are under way.
- Assay design for candidate gene methylation at key growth related genes was completed.
- Archived DNA samples (n=390) from ELEMENT cohorts, from which UM-CEHC participants are being recruited, were identified. DNA was bisulfite converted and pyrosequencing of four candidate genes (IGF-1, H19, IGF2R, 11ss-HSD2) is complete for the first 300 samples.
- Archived cord blood samples (n=203), from the UM-CEHC recruitment pool of ELEMENT cohort participants, were identified. Bisulfite confersion and pyrosequencing of these samples will occur over the next three months, in conjunction with current DNA collected during study visits.
- Complete study data for the first 109 participants were transmitted via secure internet connection from the field study location in Mexico City to investigators at the UM-SPH.
- Data cleaning and initial analyses have begun with data from the first 109 participants.
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 with exposure via water: control (0 ppm lead) and three exposure groups (3.7 ppm, 27 ppm, or 55ppm). 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.
- Animal colony expansion for this study began in late 2010. Six control litters, eight low (3.7 ppm) dose, eight medium (27 ppm) dose, and eight high (55 ppm) dose litters currently are included in the study. An additional four to six litters per group are planned over the next four months.
- DNA methylation assays for the Avy and Cabp metastable alleles has been conducted on all study animals. Candidate genes assay design is being optimized for the remaining candidate genes (IGF2, H19, IGF2R).
Preliminary analysis of Pilot Project 1 findings suggests:
- Statistically significant shifts in the coat color distribution of the viable yellow agouti mice toward the yellow phenotype in both the medium and high lead dose groups compared to controls. This suggests that maternal exposure to lead at these doses decreases DNA methylation at the Avy allele, an established biosensor for maternal exposure and offspring epigenetic effects.
- DNA methylation at both Avy and Cabp is decreased in the medium and high lead exposure groups compared to control offspring.
Specific Aim 2:
The following Pilot Project 1 tasks related to Specific Aim 2 were completed this year:
- 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 occur at three time points throughout life (3, 6, and 9 months).
- Pilot funds from the Michigan Nutrition and Obesity Research Center (NORC, NIH DK089503) were received in 2010 to conduct these physiological, hormonal, and epigenetic studies following dose-dependent maternal exposure to BPA, a chemical of interest in the UM-CEHC. In utero exposure to BPA via maternal diet at 50 ng (n=20), 50 μg (n=21), or 50 mg (n=18) and analysis at all three time points is complete in these mice.
Preliminary analysis of Pilot Project 1 findings suggests:
- Life-course analysis of BPA exposed mice indicates in utero BPA exposure is associated with hyperactive and possibly lean phenotypes based on the following significant differences between mice exposed to 50 mg BPA vs. controls: increased oxygen consumption (males at 3 months, females at 9 months), higher carbon dioxide production (females at 6 months), increased vertical activity (3 months in males, 3 and 9 months in females), increased ambulatory activity (females at 9 months). Female offspring exposed to 50 ng and 50 μg BPA in utero displayed marginally significant decreases in body weight and percent body fat. These findings make it necessary to further evaluate BPA as a potential human obesogen.
The following Pilot Project 2 tasks were completed this year:
- All Pilot Project 2 aims depend on human participant recruitment, which is progressing ahead of schedule (See Research Project).
- A product-use and activity questionnaire to predict BPA and phthalate concentrations was developed for this Mexican cohort. The questionnaire was shared with collaborators at INSP, translated into Spanish, and approved by Institutional Review Boards at both institutions.
- A full inventory of archived maternal urine samples from pregnancy in the ELEMENT study available for measurement of BPA and phthalates has been conducted. This inventory provided crucial input for UM-CEHC recruitment; assessment of BPA and phthalate exposures both in utero and at current levels are important to developmental outcomes of interest.
- The relationship between the UM-CEHC and NSF International strengthened over the past year. This partnership provides both current state-of-the-art and cost-efficient laboratory support and a foundation for future collaborations. Pilot Project 2 personnel worked with NSF chemists to develop and validate the methods for BPA and phthalate analysis.
- Urine specimens from the first 50 UM-CEHC participants and a matched, archived sample of maternal urine from pregnancy when the child was in utero currently are being analyzed at NSF International.
Future Activities:
- Study recruitment continues as a UM-CEHC priority; recruitment completion is expected in the summer of 2012.
- DNA methylation analysis of candidate genes in archived, cord blood DNA and DNA from current blood samples will be completed in Year 3.
- Hormone analyses in current blood samples will be completed in Year 3.
- Data analysis will become an increasing priority in Year 3 as an emphasis on manuscript preparation and publication increases over the next year.
- Submission of an R21 investigating the long-term metabolic consequences of environmental exposures (to lead, BPA, and phthalates) during the pregnancy for both the mother and adolescent offspring is awaiting funding. This project will build on the UM-CEHC by re-recruiting participants to investigate the impact of perinatal exposures on (1) hyperglycemia during pregnancy, (2) markers of insulin resistance and metabolic syndrome in adolescents.
- In utero lead exposure is expected to be complete by the fall of 2012.
- Epigenetic analysis of candidate genes will be completed in Year 3.
- Metabolic assessments of a/a offspring at 3, 6, and 9 months will continue into Year 3. Hormone levels in plasma collected at day 22 and 10 months will be analyzed. A five-hour fasting glucose tolerance test to measure insulin sensitivity has been added to the original proposal at the 9-month assessment.
- Animals exposed in utero to BPA will be assessed for BPA-induced epigenetic changes via promoter tiling arrays with funding from the NORC pilot grant. Epigenetic results will be analyzed in combination with metabolic parameters to determine if epigenetic mechanisms mediate the effects of BPA exposure on measured phenotypes.
- 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. Frontal cortex tissues from 10-month old, sacrificed mice will be separated into neuronal nuclei and non-neuronal nuclei. Differential DNA methylation in the neuronal cell population compared to non-neuronal cells globally and in the promoter regions of four candidate genes (Adam17, Bace1, Aph1a, Drd1a) are expected. Methylation levels as well as spontaneous activity levels are expected to differ in lead-exposed compared to non-exposed mice. This is the first neuron-specific environmental epigenetics study conducted in any species and will contribute to the field of cell-type specific epigenetics.
- Urine analysis for BPA and phthalate exposure will continue in Year 3, on current samples collected from UM-CEHC study participants and archived maternal urine samples from pregnancy.
- Data analysis for Pilot Project 2 aims is beginning and will continue throughout Year 3.
- With the completion of recruitment expected in the summer of 2012, final data analysis and manuscript preparation will be a focus in the second half of Year 3. Related analyses and papers are ongoing as UM-CEHC data are being generated.
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, prenatal exposure, environmental risks, exposure assessment, epigenetics, maternal exposure, Mexican, lead, bisphenol A, phthalates, animal exposure, agouti mouse, animal phenotyping, 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.