Epidemiological and animal studies now firmly establish that environmental exposures during eariy embryonic development play a critical role in disease susceptibility in later-life. Moreover, such exposures during gestation have been directly linked with subsequent disease formation through epigenetic mechanisms. Little research, however, has considered the combined effects of perinatal and peripubertal , exposures on life course metabolic syndrome risk and reproductive development. Utilizing an established mouse model of perinatal exposures and focusing on bisphenol A (BPA), phthalates, and lead (Pb) as representative toxicants, we focus on the influence of perinatal and peripubertal exposures on offspring metabolic status and epigenetic gene regulation. Specifically, we will investigate whether perinatal exposure to BPA/phthalates/Pb mixture results in epigenetic alterations and disrupts life course physiologic status, events that are subject to modification by diet and continued peripubertal exposure. First, capitalizing on our mouse models of physiologically relevant maternal toxicant levels, we will assess whether pregnancy and postnatal high-fat diet modifies the effects of perinatal BPA or Pb exposure on life course physiological parameters. Second, we will use sophisticated mouse phenotyping to examine the relationship of perinatal and peripubertal exposure to chemical mixtures on metabolic and reproductive status and identify key epigenetic labile genes important for metabolic homeostasis and hormonal regulation. Finally, animal models are well-poised to elucidate complex relationships among exposures, epigenetic tissue specificity, and timedependent epigenetic drift. Thus, we will conduct unbiased lineage specific whole methylome, transcriptome, and histone mark analysis at multiple time points. Results of these comprehensive studies will elucidate issues of tissue specificity and drift with age, inherent complexities in conducting epigenetic epidemiological studies. Knowledge from this project is crucial for deciphering the role of epigenetic programming by early exposures in the pathogenesis of diseases, including metabolic syndrome and reproductive success, and for the development of novel epigenetic-based diagnostic and therapeutic strategies for human diseases.
It is increasingly recognized that exposures to chemicals affect health and disease by not only mutating genes, but.also by modifying the epigenome, alterations to DNA that are heritable and lead to disease when deregulated. The objective of this POl Center Project is to identify exposure mixtures and modifiers such as diet and timing of exposure that influence later-life metabolic syndrome risk and reproductive development via epigenetic alterations in order to facilitate children's health risk assessment and disease prevention.
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|Sánchez, Brisa N; Kim, Sehee; Sammel, Mary D (2017) Estimators for longitudinal latent exposure models: examining measurement model assumptions. Stat Med 36:2048-2066|
|Yuan, Ye; Meeker, John D; Ferguson, Kelly K (2017) Serum polybrominated diphenyl ether (PBDE) concentrations in relation to biomarkers of oxidative stress and inflammation: The National Health and Nutrition Examination Survey 2003-2004. Sci Total Environ 575:400-405|
|Zhou, Yan; Wang, Pei; Wang, Xianlong et al. (2017) Sparse multivariate factor analysis regression models and its applications to integrative genomics analysis. Genet Epidemiol 41:70-80|
|Perng, Wei; Fernandez, Carmen; Peterson, Karen E et al. (2017) Dietary Patterns Exhibit Sex-Specific Associations with Adiposity and Metabolic Risk in a Cross-Sectional Study in Urban Mexican Adolescents. J Nutr 147:1977-1985|
|Perng, Wei; Watkins, Deborah J; Cantoral, Alejandra et al. (2017) Exposure to phthalates is associated with lipid profile in peripubertal Mexican youth. Environ Res 154:311-317|
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