The period of intrauterine development is a """"""""critical window"""""""" where environmental exposures can profoundly influence the life course. Interactions between the environment and genes, whose expression is choreographed and highly influenced by the environment, significantly impact health outcomes of the developing child. Much of this interaction occurs in the placenta, a highly complex organ which serves as the site for nutrient, water, and waste exchange, immune-endocrine regulation, and environmental regulation between the mother and child. Modifications of these actions can have profound effects. For example, inappropriate downregulation of IL-10, a critical anti-inflammatory cytokine, has been related to preterm birth, and work from Project 3 in the Brown SBRP has demonstrated that exposures to PCBs in IL-10 deficient murine models leads to preterm birth. Environmental exposures, such as PCBs, have long term health consequences for intrauterine exposed children, suggesting that these exposures contribute to the phenomenon of """"""""fetal programming"""""""". These effects are thought to be elicited molecularly as alterations to the cellular epigenome, although the precise molecular character of these epigenetic alterations has yet to be elucidated. Again, the placenta, as a regulator of fetal development, reflects these exposures, as exposures can lead to stable downregulation of specific genes, as well as to alterations to the DMA methylation status of specific genomic regions. Therefore, in this Project, we hypothesize that environmental exposure to persistent PCBs in-utero results in adverse pregnancy outcomes that are modified by genetic variation at the IL-10 gene locus, and further, that the molecular mechanism by which PCB exposures act is epigenetic and that these alterations can serve as biomarkers, defining a """"""""molecular footprint"""""""" of intrauterine exposure captured in the placenta.
We aim to (1) examine the associations between prenatal PCB exposure, preterm birth, and fetal growth restriction;(2) assess whether functional haplotypes of the IL-10 gene promoter modify the association between PCB exposure and preterm birth or fetal growth restriction;and (3) identify a signature of gene promoter methylation alterations in human placenta as novel biomarkers of preterm birth, fetal growth restriction, and PCB exposure using genome-wide assays of DNA methylation. This will be done as part of a newly established population-based longitudinal birth cohort for Rhode Island, capturing a population of 32,000 mother-infant pairs. This unique and powerful resource provides one of the most profound environments for examining these questions.
The over-arching goal of this Superfund Basic Research Program is to address health concerns, and to design novel remediation techniques, related to mixed exposures arising from contaminated lands and buildings, using Rhode Island as a model for appropriate research, educational, and training interventions. This projects works toward that goal by examining the health effects of environmental exposures to the population of Rhode Island.
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