Immunotoxicology of Chronic Exposure to Estrogenic Bisphenol-A

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Approximately 6 billion pounds of bisphenol A (BPA) is synthesized each year making it one of the highest volume chemicals produced worldwide. The greatest applications of BPA are as a starting material in the manufacturing of polycarbonate plastic and as a component in the resin that lines beverage and food cans. BPA is also a constituent of plastics other than polycarbonates including polynil chloride and polyethylene terephthalate, which are also widely used. It is now well established that BPA can leach from polycarbonate. Human exposure to BPA occurs through a variety of sources with consumption of contaminated food products being the most important. BPA exposure is virtually ubiquitous as evidenced by its detection in 95% of urine samples tested in the US. BPA has also been detected in human breast milk, amniotic fluid and cord blood. Because BPA possesses estrogenic activity by binding to estrogen receptors (ER), estrogen related receptors (ERR), and has been shown to induce non-genomic events at the cellular level through GPR30, there is concern that exposure to this compound can alter or interfere with endocrine signaling pathways, even at low doses, including those affecting immune system development and function. The overall goal of this four-year research plan is to evaluate the effects of BPA on immune competence. Specifically we will test the hypothesis: Chronic low dose BPA exposure, beginning in utero, results in altered immune development and immune competence in the adult, which is mediated, in part, through changes in leukocyte composition, function and through changes in estrogen receptor (ER), estrogen related receptor (ERR) and/or estrogen related receptor (ERR) or GPR30 expression by leukocytes. This hypothesis will be tested using four specific aims (SA). SA1 is to determine the effects of chronic BPA exposure on the relative number and proportion of leukocyte subpopulations in the spleen. SA2 is to characterize the effect of chronic BPA treatment on leukocyte function by quantification of immune responses to defined stimuli. SAS is to determine the effect of chronic BPA exposure on estrogen receptor (ERa and ERp), estrogen-related receptor (ERRy) and GPR30 levels in leukocyte subpopulations. SA4 will be to define the effect of chronic BPA exposure on a selected suite of estrogen sensitive genes known to be involved in leukocyte function. The successful completion of the aforementioned specific aims will provide critical information on the putative role of long-term stimulation of estrogen receptors by BPA on immune development and competence.