Combinational Environmental Chemicals Altering Susceptibility for Mammary Cancer

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DESCRIPTION (provided by applicant): Humans are exposed to a complex mixture of environmental chemicals. This is evident from the internal concentrations of these chemicals in humans, such as those from girls recruited via the Breast Cancer and the Environment Research Program. It is the investigators' goal to determine the potential of combinational, low dose exposures to three of these common environmental chemicals, administered orally in rats during the prepubertal period, to alter lifetime mammary cancer susceptibility. The investigators hypothesize that combinational exposure to Bisphenol A (BPA) and di-2-ethylhexyl phthalate (DEHP) will predispose for an additive or synergistic increase in mammary cancer development in a rodent model of mammary cancer. Furthermore, they will investigate the potential of genistein, when administered concurrently, to suppress the ability of BPA and DEHP to increase mammary cancer susceptibility. The specific aims are: 1) to determine if oral, prepubertal exposure to the combination of BPA and DEHP will result in an additive or synergistic increase in chemically-induced mammary cancer in rats, and if dietary genistein will result in negating the effects of BPA and DEHP; 2) to identify genomic signatures, via gene microarrays, from mammary glands of rats exposed to these chemicals to elucidate affected signaling pathways; 3) using the information from the gene array data and MIRA-seq (methylated CpG islands recovery assay coupled with massively parallel sequencing), the investigators will identify candidate DNA methylated genes and determine if prepubertal BPA, DEHP and genistein will effect epigenetic DNA methylation; 4) to investigate in vivo mechanisms of action at the cellular and protein levels (mammary gland morphology, cell proliferation, apoptosis and signaling pathways determined to be differentially regulated via gene array and eipigenetic assays); and 5) to measure concentrations of chemicals in blood and urine of rats exposed, alone or in combination, to BPA, DEHP and/or genistein during the prepubertal period. The identification of early life combinational chemical exposures commonly reported to occur in humans to alter mammary cancer susceptibility will facilitate our understanding of the complex role environmental chemicals play in breast cancer causation and prevention.