AH RECEPTOR INDEPENDENT CNS/REPRODUCTIVE EFFECTS OF PCBS

PCBS 对 AH 受体的独立 CNS/生殖影响

• 批准号: 2684430
• 负责人: RICHARD Eugene PETERSON
• 金额: $ 20.07万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2684430
• 关键词: androgen receptor; aromatase; aromatic hydrocarbon receptor; autoradiography; behavioral /social science research tag; central nervous system disorders; developmental neurobiology; environmental toxicology; enzyme activity; estrogen receptors; female reproductive system disorder; gender difference; halobiphenyl /halotriphenyl compound; laboratory rat; male reproductive system disorder; neurotoxins; radioimmunoassay; receptor binding; reproductive development; sex behavior; statistics /biometry; thyroid hormones; toxicant interaction

Evidence that environmental exposure to polychlorinated biphenyl (PCB) mixtures adversely affects human health is compelling enough that eight epidemiological studies are currently being conducted. Toxicity of PCB mixtures is generally attributed to their coplanar and mono-ortho- chlorinated congeners that bind to the same (Ah) receptor as does 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), and risk of exposure to PCBs is currently measured in terms of how many "TCDD equivalents" are present in the mixtures. However, most PCB congeners do not bind to the Ah receptor; PCB mixtures cause numerous biological responses not mediated by binding to the Ah receptor; and potent Ah receptor agonists constitute only a tiny percentage of all PCBs in environmental samples. The possibility that perinatal exposure to PCB mixtures adversely affects health in adulthood via Ah receptor-independent mechanisms is essentially unexplored. Our hypothesis is that PCB mixtures adversely affect development of the male reproductive, female reproductive, and central nervous systems via at least three Ah receptor-independent mechanisms, and that PCB mixtures do so at occupationally if not environmentally relevant exposure levels. To test this hypothesis, pregnant/lactating rats will be treated daily with prototype congeners that are major constituents of the human PCB body burden: 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), an inducer of phenobarbital-responsive, drug and steroid metabolizing enzymes; 2,2',5,5'-tetrachlorobiphenyl (PCB 52), a congener whose major metabolite is estrogenic; and 2,3,3',4,4'-pentachlorobiphenyl (PCB 105), a congener whose metabolites bind strongly to thyroid hormone-binding proteins. A fourth congener, the Ah receptor agonist 3,3',4,4',5-pentachlorobiphenyl (PCB 126), will serve as a positive control. Effects of these congeners on development of the male reproductive,, female reproductive, and central nervous systems of offspring of treated dams will be determined. Multiple endpoints within each organ system will be evaluated. For males, these include indices of androgenic status, quantitative analysis of spermatogenesis, fertility testing, and observations of masculine sexual behaviors and potential to display feminine sexual behavior. For females, these include plasma l7beta-estradiol concentrations, estrus cycling, fertility testing, and observations of feminine sexual behaviors. Plasma T4, T3, and TSH concentrations will be measured in both sexes during the critical neonatal period when sexual differentiation of the central nervous system occurs, and regional distribution of aromatase activity, estrogen receptors, and androgen receptors in the brain will also be determined. For each congener that adversely affects one or more organ systems, a dose-response experiment will be conducted to determine how sensitive rats are to in utero and lactational exposure to this type of congener. Such results will greatly facilitate the ability of health officials to make informed decisions about whether the "TCDD equivalents" approach to PCB risk assessment is sufficient to protect public health or whether one or more Ah receptor-independent actions of PCB mixtures must also be considered. The results will also facilitate future research on mechanisms by which PCBs cause developmental and reproductive toxicity, currently handicapped by lack of knowledge as to which congener types in complex mixtures cause the various toxic responses.

环境暴露于多氯联苯 (PCB) 的证据 混合物对人类健康的不利影响足以令人信服，以至于八 目前正在进行流行病学研究。 PCB的毒性 混合物通常归因于它们的共面和单正交 与 2,3,7,8- 结合相同 (Ah) 受体的氯化同系物 四氯二苯并二恶英 (TCDD)，接触 PCB 的风险为 目前以有多少“TCDD 等价物”来衡量 混合物。然而，大多数 PCB 同源物不与 Ah 受体结合； PCB 混合物会引起许多非结合介导的生物反应 Ah 受体；和有效的Ah受体激动剂仅构成很小的一部分 环境样本中所有 PCB 的百分比。的可能性是 围产期接触 PCB 混合物会对成年后的健康产生不利影响 通过Ah受体独立的机制基本上尚未被探索。我们的 假设 PCB 混合物对雄性的发育产生不利影响 生殖、女性生殖和中枢神经系统 至少有三种与 Ah 受体无关的机制，而 PCB 混合物确实如此 因此，即使不是与环境相关的暴露水平，也是职业暴露水平。到 为了检验这一假设，怀孕/哺乳期大鼠将每天接受 作为人体 PCB 体主要成分的原型同系物 负荷：2,2',4,4',5,5'-六氯联苯 (PCB 153)，一种诱导剂 苯巴比妥反应性药物和类固醇代谢酶； 2,2',5,5'-四氯联苯 (PCB 52)，一种同系物，其主要代谢物 具有雌激素作用；和 2,3,3',4,4'-五氯联苯 (PCB 105)，一种同系物 其代谢物与甲状腺激素结合蛋白强烈结合。一个 第四个同源物，Ah 受体激动剂 3,3',4,4',5-五氯联苯 (PCB 126)，将作为阳性对照。这些同系物的影响 男性生殖器官、女性生殖器官和中枢生殖器官的发育 将确定经过处理的母鼠后代的神经系统。多种的 将评估每个器官系统内的终点。对于男性来说，这些 包括雄激素状态指标、定量分析 精子发生、生育力测试和男性性行为观察 表现出女性性行为的行为和潜力。对于女性来说， 这些包括血浆l7β-雌二醇浓度、发情周期、 生育力测试以及女性性行为的观察。等离子体 在测试期间，将测量两性的 T4、T3 和 TSH 浓度。 新生儿关键时期，是中枢性别分化的关键时期 神经系统发生，以及芳香酶活性的区域分布， 大脑中的雌激素受体和雄激素受体也会 决定。对于对一个或多个器官产生不利影响的每种同系物 系统，将进行剂量反应实验以确定如何 敏感大鼠在子宫内和哺乳期接触此类 同类。这样的结果将极大地促进健康能力 官员就是否“TCDD 等同物”做出明智的决定 PCB 风险评估方法足以保护公众健康或 PCB混合物的一种或多种Ah受体独立作用是否必须 也可以考虑。该结果也将有助于未来的研究 PCB 引起发育和生殖毒性的机制， 目前由于缺乏关于哪些同系物类型的知识而受到限制 复杂的混合物会引起各种毒性反应。

项目成果

Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate.

子宫内和哺乳期接触抗雄激素增塑剂邻苯二甲酸二（2-乙基己基）酯的雄性大鼠性发育异常。

• DOI: 10.1289/ehp.01109229
• 发表时间: 2001-03
• 期刊: Environmental Health Perspectives
• 影响因子: 10.4
• 作者: Moore RW;Rudy TA;Lin TM;Ko K;Peterson RE
• 通讯作者: Peterson RE