Immunotoxicology of Chronic Exposure to Estrogenic Bisphenol-A

描述(申请人提供)：每年合成约60亿磅的双酚A(BPA)，使其成为世界上产量最大的化学品之一。双酚A最大的应用是作为制造聚碳酸酯塑料的起始材料，以及作为饮料和食品罐头衬里树脂的成分。双酚A也是聚碳酸酯以外的塑料的一种成分，包括聚氯化镍和聚对苯二甲酸乙二酯，这两种塑料也被广泛使用。现在已经很好地证实，双酚A可以从聚碳酸酯中浸出。人类接触双酚A的来源多种多样，其中最重要的是食用受污染的食品。在美国检测的尿样中，95%的尿样中都检测到了双酚A，这证明了双酚A几乎无处不在。在人类母乳、羊水和脐带血中也检测到了双酚A。由于双酚A通过与雌激素受体(ER)和雌激素相关受体(ERR)结合而具有雌激素样活性，并已被证明通过GPR30在细胞水平上诱导非基因组事件，因此人们担心暴露于这种化合物会改变或干扰内分泌信号通路，即使在低剂量下也是如此，包括那些影响免疫系统发育和功能的信号通路。这项为期四年的研究计划的总体目标是评估双酚A对免疫能力的影响。具体地说，研究人员将检验这一假设：从子宫开始的长期低剂量双酚A暴露会导致成人免疫发育和免疫能力的改变，这在一定程度上是通过白细胞成分、功能的变化以及白细胞雌激素受体(ER)、雌激素相关受体(ERR)和/或雌激素相关受体(ERR)或GPR30表达的变化来调节的。这一假设将使用四个特定的目标(SA)进行检验。SA1是为了确定慢性BPA暴露对脾中白细胞亚群的相对数量和比例的影响。SA2是通过量化对特定刺激的免疫反应来表征慢性双酚A治疗对白细胞功能的影响。SA3是为了确定慢性BPA暴露对雌激素受体(ER？和雌激素受体(ER？)、雌激素相关受体(ERRY)和GPR30水平。SA4将定义慢性双酚A暴露对选定的一组与白细胞功能有关的雌激素敏感基因的影响。上述特定目标的成功完成将为BPA对雌激素受体的长期刺激在免疫发育和免疫能力中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.