Immunotoxicology of Chronic Exposure to Estrogenic Bisphenol-A

每年大约有60亿磅的双酚A（BPA）被合成，使其成为世界上最高的双酚A之一。 全球生产的化学品。BPA最大的应用是作为原料， 制造聚碳酸酯塑料，并作为饮料和食品罐内衬树脂的成分。 BPA也是除聚碳酸酯（包括聚氯化物和聚乙烯）以外的塑料的成分 对苯二甲酸酯，也被广泛使用。现在已经确定BPA可以从聚碳酸酯中浸出。 人类通过食用受污染的食物，通过各种途径接触BPA 产品是最重要的。BPA暴露几乎是无处不在的，这一点可以从以下几个方面得到证明： 95%的尿液样本在美国进行检测。BPA还在人类母乳、羊水中被检测到 和脐带血由于BPA通过与雌激素受体（ER）结合而具有雌激素活性， 雌激素相关受体（ERR），并已显示在细胞水平诱导非基因组事件 通过GPR 30，人们担心接触这种化合物会改变或干扰内分泌系统， 即使在低剂量下，也会影响免疫系统的信号通路，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。 具体来说，我们将检验这一假设：从子宫内开始的慢性低剂量BPA暴露， 改变成人的免疫发育和免疫能力，这部分是通过 白细胞组成、功能的变化以及通过雌激素受体（ER）的变化，雌激素相关 受体（ERR）和/或雌激素相关受体（ERR）或GPR 30的表达。这 假设将使用四个特定目标（SA）进行测试。SA 1是为了确定慢性BPA的影响， 暴露对脾脏中白细胞亚群的相对数量和比例的影响。SA 2为 通过免疫细胞化学定量来表征慢性BPA治疗对白细胞功能的影响， 对特定刺激的反应。SAS旨在确定慢性BPA暴露对雌激素受体的影响 (ERa和ER β）、雌激素相关受体（ERR γ）和GPR 30水平。SA 4将 确定慢性BPA暴露对已知的一组选定的雌激素敏感基因的影响， 参与白细胞功能。上述具体目标的成功实现将为 关于BPA对雌激素受体的长期刺激对免疫系统的作用的重要信息 发展和能力。

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 subpopulafions 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 subpopulafions. 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.