Immunotoxicology of Chronic Exposure to Estrogenic Bisphenol-A

描述（由申请人提供）：每年合成约60亿磅双酚A（BPA），使其成为全球产量最高的化学品之一。BPA的最大应用是作为聚碳酸酯塑料制造的起始材料，以及作为饮料和食品罐内衬树脂的成分。 BPA也是除聚碳酸酯以外的塑料的成分，包括聚氯化物和聚对苯二甲酸乙二醇酯，它们也被广泛使用。现在已经确定BPA可以从聚碳酸酯中浸出。 人类通过各种来源接触BPA，其中最重要的是食用受污染的食品。BPA暴露几乎无处不在，在美国95%的尿液样本中都检测到了BPA。在人类母乳、羊水和脐带血中也发现了BPA。由于BPA通过与雌激素受体（ER）、雌激素相关受体（ERR）结合而具有雌激素活性，并且已显示通过GPR 30在细胞水平诱导非基因组事件，因此人们担心，即使在低剂量下，暴露于该化合物也会改变或干扰内分泌信号通路，包括影响免疫系统发育和功能的通路。 这项为期四年的研究计划的总体目标是评估BPA对免疫能力的影响。 具体而言，研究者将检验以下假设：从子宫内开始的慢性低剂量BPA暴露导致成人免疫发育和免疫能力改变，这部分是通过白细胞组成、功能的变化以及通过白细胞雌激素受体（ER）、雌激素相关受体（ERR）和/或雌激素相关受体（ERR）或GPR 30表达的变化介导的。这一假设将使用四个具体目标（SA）进行检验。SA 1旨在确定长期BPA暴露对脾脏中白细胞亚群相对数量和比例的影响。SA 2旨在通过定量对规定刺激的免疫应答来表征长期BPA治疗对白细胞功能的影响。SA 3是为了确定慢性BPA暴露对雌激素受体（ER？和ER？），雌激素相关受体（ERR γ）和GPR 30水平在白细胞亚群。SA 4将确定慢性BPA暴露对已知参与白细胞功能的一组选定雌激素敏感基因的影响。上述具体目标的成功完成将为BPA长期刺激雌激素受体对免疫发育和能力的假定作用提供关键信息。

DESCRIPTION (provided by applicant): 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 the investigators 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. SA3 is to determine the effect of chronic BPA exposure on estrogen receptor (ER? and ER?), 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.