Immunotoxicology of Chronic Exposure to Estrogenic Bisphenol-A

长期接触雌激素双酚 A 的免疫毒理学

• 批准号: 8477192
• 负责人: Norbert E Kaminski
• 金额: $ 19.01万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8477192
• 关键词: Acute; Adult; Affect; Amniotic Fluid; B-Lymphocytes; Beverages; Binding; Biological; Biological Assay; Canned Foods; Cell Culture Techniques; Cells; Chemicals; Chloride Ion; Chlorides; Chronic; Competence; Complex; Consumption; Coupled; Detection; Development; Dose; Endocrine; Estrogen Receptors; Estrogens; Evaluation; Event; Exposure to; Flow Cytometry; Food; Future; Genes; Goals; Health; Human; Human Milk; Immune; Immune response; Immune system; Immunologics; Immunotoxicology; In Vitro; Instruction; Investigation; Lead; Leukocytes; Long-Term Effects; Lymphoid Tissue; Mediating; Modeling; Molecular; Molecular Profiling; Mononuclear; Plant Resins; Plastics; Polyethylene Terephthalates; Population; RNA; Rattus; Regulation; Relative (related person); Research; Role; Sampling; Signal Pathway; Signal Transduction; Source; Spleen; Splenocyte; Stimulus; Systems Development; T-Lymphocyte; Testing; Toxic effect; Toxicology; Umbilical Cord Blood; Urine; base; bisphenol A; density; design; estrogen-related receptor; estrogenic activity; exposed human population; immune function; immunoregulation; in utero; in vivo; insight; non-genomic; polycarbonate; polycarbonate plastic; receptor; receptor expression

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.

每年合成大约60亿磅的双酚A（BPA），使其成为最高 批量化学品在全球生产。 BPA最大的应用是作为起始材料 生产聚碳酸酯塑料，并作为生产线条饮料和食品罐的树脂中的组成部分。 BPA也是塑料以外的塑料组成部分，包括聚氯化物和聚乙烯 邻苯二甲酸酯，也广泛使用。现在已经很好地确定BPA可以从聚碳酸酯中浸出。 人类暴露于BPA是通过各种污染食品的来源发生的 产品是最重要的。 BPA暴露实际上无处不在 95％在美国测试的尿液样品。在人类母乳，羊水中也发现了BPA 和脐带血。因为BPA通过与雌激素受体（ER）结合而具有雌激素活性，所以 与雌激素相关的受体（ERR），已显示出在细胞水平上诱导非基因组事件 通过GPR30，人们担心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，包括影响免疫系统开发和功能的信号通路。 这项四年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，我们将检验假设：从子宫开始的慢性低剂量BPA暴露导致 成年人的免疫发育和免疫能力改变了，部分是通过 白细胞组成，功能和通过雌激素受体（ER）的变化，雌激素相关的变化 受体（ERR）和/或雌激素相关受体（ERR）或白细胞表达GPR30。这 假设将使用四个特定目标（SA）进行检验。 SA1是确定慢性BPA的影响 脾脏中白细胞亚群的相对数量和比例。 SA2是 通过定量免疫来表征慢性BPA治疗对白细胞功能的影响 对定义刺激的反应。 SAS是确定慢性BPA暴露对雌激素受体的影响 （ERA和ERP），白细胞亚群中的雌激素相关受体（ERRY）和GPR30水平。 SA4 Will 要定义慢性BPA暴露对所选雌激素敏感基因套件的影响 参与白细胞功能。上述特定目标的成功完成将提供 关于BPA对雌激素受体长期刺激的假定作用的关键信息 发展和能力。