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.

每年合成约 60 亿磅双酚 A (BPA)，使其成为合成量最高的双酚 A 之一 全球生产大量化学品。 BPA 最大的应用是作为原材料 聚碳酸酯塑料的制造以及作为饮料和食品罐内衬树脂的成分。 BPA 也是聚碳酸酯以外的塑料的成分，包括聚氯乙烯和聚乙烯 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。 人类通过多种途径接触 BPA，即食用受污染的食物 产品是最重要的。 BPA 暴露几乎无处不在，在 95% 的尿液样本在美国进行检测。人类母乳、羊水中也检测到了 BPA 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），并已被证明可以在细胞水平诱导非基因组事件 通过 GPR30，人们担心接触这种化合物会改变或干扰内分泌 信号通路，即使是低剂量，包括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 BPA 对免疫能力的影响。 具体来说，我们将检验以下假设：从子宫内开始长期接触低剂量 BPA，会导致 成人免疫发育和免疫能力的改变，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）或白细胞的 GPR30 表达。这 将使用四个特定目标（SA）来检验假设。 SA1 用于确定慢性 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。 SA2 是 通过免疫定量来表征长期 BPA 治疗对白细胞功能的影响 对指定刺激的反应。 SAS旨在确定慢性BPA暴露对雌激素受体的影响 白细胞亚群中的（ERa 和 ERp）、雌激素相关受体（ERRy）和 GPR30 水平。 SA4将 是为了定义慢性 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。上述具体目标的顺利完成将提供 关于 BPA 长期刺激雌激素受体对免疫的推定作用的关键信息 发展和能力。