Gender Effects on PCB-Induced Dopamine Neurotoxicity

描述（由申请人提供）：多氯联苯（PCBs）降低基底神经节多巴胺（DA）功能，包括减少DA含量和黑质（SN）中酪氨酸羟化酶阳性（TH+）神经元的数量，以及抑制单胺转运体。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。由于暴露于异常高水平多氯联苯的前电容器工人显示出因帕金森病而死亡的风险增加，并且仅在女性中血清多氯联苯浓度与DA末端密度之间存在负相关关系，因此对这些数据的需求变得更加重要。由于这些流行病学发现，我们假设卵巢激素，包括多氯联苯引起的减少，或绝经或卵巢切除术（OVX）后，已知的减少基底节区单胺转运蛋白和TH+神经元数量的事件，将与类似的多氯联苯引起的基底节区DA功能的变化相互作用，并加剧，导致激素枯竭的女性DA功能障碍比同等暴露的男性更严重。这些假设将在一系列实验中得到验证，这些实验将表征多氯联苯暴露对雄性和雌性大鼠的影响，以及多氯联苯诱导的发情周期、OVX和卵巢激素替代对DA功能的影响，包括单胺转运蛋白的抑制、胞质和神经元外DA及其代谢物的改变、TH+ SN神经元的数量、氧化应激和线粒体功能的测量。我们还将测量多氯联苯的血清和脑浓度，以确定性别在改变多氯联苯身体负担中的作用。拟议的实验将提供多氯联苯暴露对女性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，并将确定卵巢激素（包括其戒断）影响多氯联苯诱导的DA功能、氧化应激和线粒体功能变化的后果和机制。这些实验将为进一步研究性别和卵巢激素改变其他环境和职业多巴胺神经毒物的毒性的作用奠定基础。

DESCRIPTION (provided by applicant): 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. This data, however, has been gathered only in males and hence the effects of PCBs on DA function in the female are largely unknown. The need for this data becomes 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 in comparably-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 neurotoxicological studies 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.