AH RECEPTOR INDEPENDENT CNS/REPRODUCTIVE EFFECTS OF PCBS

环境中暴露于多氯联苯(多氯联苯)的证据 对人类健康有害的混合物足以令人信服， 目前正在进行流行病学研究。多氯联苯的毒性 混合物一般归因于它们的共面和单邻位. 与2，3，7，8-受体结合的氯化同系物- 四氯二苯并对二恶英(TCDD)，接触多氯联苯的风险是 当前以存在多少“TCDD等效物”来衡量 混合物。然而，大多数多氯联苯的同系物并不与ah受体结合； 多氯联苯混合物引起许多非结合介导的生物反应 而有效的阿受体激动剂只构成了一个很小的 在环境样品中占所有多氯联苯的百分比。有没有可能 围产期接触多氯联苯混合物会对成年后的健康造成不利影响 通过Ah受体非依赖的机制基本上是未知的。我们的 假设多氯联苯混合物对男性发育有不利影响 生殖系统、女性生殖系统和中枢神经系统 至少有三个ah受体无关的机制，而多氯联苯混合物做到了 因此，如果不是在与环境相关的职业暴露水平上，也是如此。至 验证这一假设，怀孕/哺乳期的大鼠每天都会接受 原型同系物是人类多氯联苯主体的主要成分 负荷：2，2‘，4，4’，5，5‘-六氯联苯(PCB153)，诱导剂 苯巴比妥反应、药物和类固醇代谢酶； 2，2‘，5，5’-四氯联苯(PCB52)，其主要代谢物 是雌激素；以及2，3，3‘，4，4’-五氯联苯(PCB105)，一种同系物 其代谢产物与甲状腺激素结合蛋白结合强烈。一个 第四个同系物，AH受体激动剂3，3‘，4，4’，5-五氯联苯 (PCB126)，将作为阳性对照。这些同系物对人的影响 男性生殖器，女性生殖器，和中央 经过处理的水坝的后代的神经系统将被确定。多重 将对每个器官系统内的终点进行评估。对于男性来说，这些 包括雄激素状况的指标，定量分析 精子发生、生育能力测试和男性性行为的观察 表现女性性行为的行为和潜力。对于雌性来说， 包括血浆17β-雌二醇浓度，发情周期， 生育测试，以及对女性性行为的观察。电浆 T4、T3和TSH浓度将在性别间进行测量 新生儿期中央性分化的关键时期 神经系统的发生，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将 下定决心。对于每个对一个或多个器官产生不利影响的同系物 系统，将进行剂量反应实验，以确定如何 敏感的大鼠在子宫和哺乳期暴露于这种类型的 同类人。这样的结果将极大地促进健康能力的提高 官员们将在知情的情况下就“TCDD是否等同于”做出决定 多氯联苯风险评估方法足以保护公众健康或 PCB族混合物的一个或多个ah受体非依赖的作用是否必须 也要考虑。这一结果也将有助于今后的研究 多氯联苯导致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在 复杂的混合物会引起各种毒性反应。

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.