Gender Effects on PCB-Induced Dopamine Neurotoxicity

多氯联苯会降低基底节多巴胺(DA)的功能，包括 AS黑质DA含量及酪氨酸羟化酶阳性神经元数目 以及抑制单胺转运体。然而，这些数据只在男性和 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超高水平的 多氯联苯显示由于帕金森氏病而死亡的风险增加，与 血清多氯联苯浓度和DA终末密度仅在女性中。因为这些流行病 我们假设卵巢激素，包括由多氯联苯引起的减少或随后的 更年期或卵巢切除(OVX)，已知减少基底节单胺类转运体和 TH+神经元的数量，将与类似的多氯联苯引起的基底节改变相互作用并加剧 DA功能，导致荷尔蒙枯竭的女性比无与伦比的- 裸露的男性。这些假设将在一系列实验中得到验证，这些实验将表征这些效应 雄性和雌性大鼠暴露于多氯联苯以及多氯联苯引起的动情期变化的后果 周期性、OVX和卵巢激素替代对DA功能的影响，包括单胺的抑制 转运体、胞内和神经元外DA及其代谢物的变化、TH+SN数量 神经元，以及氧化应激和线粒体功能的测量。我们还将检测血清和 大脑中多氯联苯的浓度，以确定性别在改变多氯联苯身体负担中的作用。这个 拟议的实验将提供关于接触多氯联苯对女性DA功能的影响的信息， 在神经毒理学研究中被很大程度上忽视的人群，将决定 卵巢激素，包括其撤除，影响多氯联苯的后果和机制- 诱导DA功能、氧化应激和线粒体功能的改变。这些实验将设定 进一步研究性别和卵巢激素改变其他激素毒性的作用的阶段 环境和职业性多巴胺神经毒物。

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.