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.

每年约有60亿磅的双酚A(BPA)被合成，使其成为世界上合成双酚A最多的 世界范围内大量生产的化学品。双酚A最大的应用是作为一种起始材料 制造聚碳酸酯塑料，并作为饮料和食品罐头衬里树脂的一种成分。 双酚A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，这也是广泛使用的。现在已经很好地证实，双酚A可以从聚碳酸酯中浸出。 人类通过食用受污染食物的各种来源接触双酚A。 产品是最重要的。双酚A接触几乎无处不在，从其在 95%的尿样在美国进行了检测。在人类母乳、羊水中也检测到了双酚A。 和脐带血。由于双酚A通过与雌激素受体(ER)结合而具有雌激素样活性， 雌激素相关受体(ERR)，并已被证明在细胞水平上诱导非基因组事件 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，即使在低剂量下，包括那些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双酚A对免疫能力的影响。 具体地说，我们将检验这一假设：从子宫开始，慢性低剂量双酚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、功能的变化及其通过雌激素受体(ER)的变化，雌激素相关 白细胞表达ERR和/或雌激素相关受体(ERR)或GPR30。这 假设将使用四个特定目标(SA)进行检验。SA1是为了确定慢性双酚A的影响 暴露对脾中白细胞亚群的相对数量和比例的影响。SA2是TO 用免疫定量表征慢性双酚A治疗对白细胞功能的影响 对特定刺激的反应。SAS是为了确定慢性BPA暴露对雌激素受体的影响 白细胞亚群中雌激素相关受体(ERRY)和GPR30水平。SA4将 确定长期接触双酚A对一组已知的雌激素敏感基因的影响 与白细胞功能有关。上述具体目标的成功完成将提供 双酚A长期刺激雌激素受体对免疫作用的关键信息 发展和能力。