The objective of this proposal is to determine the mechanism by which prenatal exposure to environmentally relevant levels of the endocrine disrupting chemicals bisphenol A (BPA) and polycyclic aromatic hydrocarbons (PAHs) exert long-term effects on neurobiology, metabolism, immune function and behavior. We propose to examine prenatal exposure to BPA (oral) and PAH (inhaled) in Balb/c mice using a transgenerational breeding design in which the effects can be examined in Fl offspring and F2 grand-offspring. This proposal intends to determine the distinct effects of prenatal BPA and PAH exposure on DNA methylation and gene expression in several tissues (hippocampus, hypothalamus, brain cortex, adipocytes and blood) and the association of these molecular changes with neurobiological and physiological outcomes. Exposure will occur throughout gestation and postnatal mother-infant interactions will be assessed as a potential modulating influence on offspring development. Assessment of male and female Fl and F2 offspring will include weight monitoring, homecage social interactions (PND 30-40), anxiety-like behavior (PND 40), and cognitive functioning (PND 44-60). Adiposity will be quantified following behavioral testing and in the case of BPA exposure, additional exposure groups will be included to examine immune function. Exposure-induced changes in brain cytoarchitecture will be quantified in Fl and F2 offspring at PND 40. The molecular mechanisms driving these effects will be assessed in offspring tissue during fetal development (GD 19) and in adulthood (PND 60). The selection of molecular targets will be based on the results of analysis of tissue collected from the Columbia Center for Children's Environmental Health (CCCEH) cohort with particular focus on genes involved in neurodevelopment and obesity. Methylation analysis will involve pyrosequencing of bisulphite treated DNA samples with mRNA analysis achieved through quantitative RT-PCR. Overall, these studies are designed to confirm and validate the biomarkers determined in the CCCEH human studies of BPA and PAH exposure and to determine the hypothesized link between epigenetic changes in blood with those determined in brain and adipose tissue to determine the possible mechanistic pathways through which long-term effects of exposure are mediated.
These studies will ascertain how environmental exposures may be responsible for multiple diseases across multiple generations. Understanding the mechanisms responsible for the effects of prenatal exposures on adverse health outcomes should validate the suspected dangers in the urban environment, provide important information for risk assessment, and inspire intervention to prevent long-term effects on children's health.
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