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: 8230321
• 负责人: Norbert E Kaminski
• 金额: $ 20.19万
• 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/8230321
• 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; Research Personnel; 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

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.

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原材料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，包括也广泛使用的聚氯乙烯和聚对苯二甲酸乙二醇酯。现在已经确定 BPA 可以从聚碳酸酯中浸出。 人类接触 BPA 的途径有多种，其中最重要的是食用受污染的食品。 BPA 暴露几乎无处不在，美国 95% 的尿液样本中都检测到了 BPA。人类母乳、羊水和脐带血中也检测到了 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，并且已被证明可通过 GPR30 在细胞水平诱导非基因组事件，因此人们担心接触该化合物可能会改变或干扰与内分泌信号通路有关，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。 具体而言，研究人员将检验以下假设：从子宫内开始长期接触低剂量 BPA，会导致成人的免疫发育和免疫能力发生改变，这在一定程度上是通过白细胞组成、功能的变化以及雌激素受体的变化来介导的。白细胞表达ER)、雌激素相关受体(ERR)和/或雌激素相关受体(ERR)或GPR30。该假设将使用四个特定目标（SA）进行检验。 SA1 用于确定慢性 BPA 暴露对脾脏中白细胞亚群的相对数量和比例的影响。 SA2 通过量化对特定刺激的免疫反应来表征长期 BPA 治疗对白细胞功能的影响。 SA3旨在确定长期接触BPA对白细胞亚群中雌激素受体（ER？和ER？）、雌激素相关受体（ERRy）和GPR30水平的影响。 SA4 将定义慢性 BPA 暴露对已知参与白细胞功能的一组选定的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重要信息。