AH RECEPTOR INDEPENDENT CNS/REPRODUCTIVE EFFECTS OF PCBS

多氯联苯（PCB）环境暴露的证据 混合物对人类健康的不利影响是令人信服的， 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邻位， 与2，3，7，8-四氯乙烷结合相同受体的氯化同系物 四氯二苯并对二恶英（TCDD），接触多氯联苯的风险是 目前衡量的是有多少“TCDD当量”存在于 的混合物。然而，大多数多氯联苯同系物不与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Ah受体激动剂只构成了一个微小的 环境样本中所有多氯联苯的百分比。的可能性 围产期接触多氯联苯混合物对成年期健康产生不利影响 通过AH受体独立机制基本上尚未探索。我们 假设多氯联苯混合物对雄性的发育有不利影响 生殖系统、女性生殖系统和中枢神经系统 至少有三种Ah受体独立机制，PCB混合物 因此，即使不是环境相关的接触水平，也是职业相关的。到 为了验证这一假设，妊娠/哺乳期大鼠将每天接受以下给药： 人体多氯联苯主要成分的原型同系物 2，2 '，4，4'，5，5 '-六氯联苯（PCB 153），一种 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），一种其主要代谢物 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质强烈结合。一 第四种同系物，Ah受体激动剂3，3 '，4，4'，5-五氯联苯 (PCB 126）将作为阳性对照。这些同系物对 雄性生殖系统、雌性生殖系统和中枢神经系统的发育 将测定处理母鼠后代的神经系统。多 将评价每个器官系统内的终点。对于男性来说，这些 包括雄激素状态指数、 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17 β-雌二醇浓度，发情周期， 生育测试和女性性行为观察。血浆 在研究期间，将测量两种性别的T4、T3和TSH浓度。 关键的新生儿时期，当中央性别分化 神经系统发生，芳香化酶活性的区域分布， 大脑中的雌激素受体和雄激素受体也会 测定对一个或多个器官产生不利影响的每种同系物 系统，剂量反应实验将进行，以确定如何 敏感的大鼠是在子宫内和哺乳期暴露于这种类型的 同类物。这样的结果将大大促进健康的能力 官员作出知情的决定，是否“TCDD当量” 多氯联苯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 也要考虑。这些结果也将有助于未来的研究， 多氯联苯造成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.