Gender Effects on PCB-Induced Dopamine Neurotoxicity

多氯联苯（PCBs）降低基底神经节多巴胺（DA）功能，包括减少 黑质（SN）内DA含量和酪氨酸羟化酶阳性（TH+）神经元数 以及抑制单胺转运蛋白。然而，这些数据仅在男性中收集， 因此，多氯联苯对女性DA功能的影响在很大程度上是未知的。对这些数据的需求 变得更加相关，因为前电容器工人暴露在非常高的水平， 多氯联苯显示帕金森病死亡风险增加， 血清PCB浓度和DA末端密度仅在女性。由于这些流行病学 研究结果我们假设卵巢激素，包括多氯联苯诱导的减少， 绝经或卵巢切除术（OVX），已知可减少基底神经节单胺转运蛋白的事件， TH+神经元的数量，将相互作用，并加剧，在基底神经节类似的PCB诱导的变化 DA功能，导致更大的DA功能障碍，在脑功能衰竭的女性比无与伦比的- 暴露的男性这些假设将在一系列的实验中进行测试，这些实验将描述这些影响。 多氯联苯暴露在雄性和雌性大鼠中的影响以及多氯联苯引起的发情期变化的后果 周期性，OVX和卵巢激素替代对DA功能的影响，包括单胺抑制 转运蛋白，胞质和神经元外DA及其代谢产物的改变，TH+ SN的数量 神经元，氧化应激和线粒体功能的措施。我们还将测量血清， 大脑中多氯联苯的浓度，以确定性别在改变多氯联苯的身体负担的作用。的 拟议的实验将提供有关PCB暴露对女性DA功能影响的信息， 这一人群在神经毒理学研究中基本上被忽视了， 卵巢激素的后果和机制，包括它们的退出，影响PCB- 引起DA功能、氧化应激和线粒体功能的变化。这些实验将使 进一步研究性别和卵巢激素改变其他药物毒性的作用的阶段 环境和职业多巴胺神经毒物。

Polychlorinated biphenyls (PCBs) decrease basal ganglia dopamine (DA) function, including reductions in DA content and the number of tyrosine hydroxylase positive (TH+) neurons in the substantia nigra (SN) as well as inhibiting monoamine transporters. These data, however, have been gathered only in males and hence the effects of PCBs on DA function in the female are largely unknown. The need for these data become even more relevant because former capacitor workers exposed to extraordinarily high levels of PCBs show increased risk for mortality due to Parkinson's disease and a negative relationship between serum PCB concentrations and DA terminal densities only in women. Because of these epidemiological findings we hypothesize that ovarian hormones, including reductions induced by PCBs or following either menopause or ovariectomy (OVX), events known to reduce basal ganglia monoamine transporters and the number of TH+ neurons, will interact with, and exacerbate, similar PCB-induced changes in basal ganglia DA function, resulting in greater DA dysfunctions in hormonally-depleted females than incomparably- exposed males. These hypotheses will be tested in a series of experiments that will characterize the effects of PCB exposure in male and female rats and the consequences of PCB-induced changes in estrus cyclicity, OVX and ovarian hormone replacement on DA function, including inhibition of monoamine transporters, alterations in cytosolic and extra-neuronal DA and its metabolites, the number of TH+ SN neurons, and measures of oxidative stress and mitochondrial function. We will also measure serum and brain concentrations of PCBs to determine the role of gender in modifying PCB body burdens. The proposed experiments will provide information on the effects of PCB exposure on DA function in the female, a population that has been largely ignored in neurotoxicologicalstudies and will determine the consequences and mechanisms by which ovarian hormones, including their withdrawal, influence PCB- induced changes in DA function, oxidative stress and mitochondrial function. These experiments will set the stage for further study of the role of gender and ovarian hormones modifying the toxicity of other environmental and occupational dopamine neurotoxicants.