Gender Effects on PCB-Induced Dopamine Neurotoxicity

性别对 PCB 引起的多巴胺神经毒性的影响

基本信息

批准号：
7199495
负责人：
Richard Field Seegal
金额：
$ 32.67万
依托单位：
WADSWORTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7199495
关键词：
Address Adult Affect Age Basal Ganglia Body Burden Brain Cessation of life Complex Consumption Corpus striatum structure Data Disruption Dopamine End Point Epidemiologic Studies Estrus Event Exposure to Female Fishes Functional disorder Gender Gender Role Hormonal Human Inclusion Bodies Investigation Laboratory Study Light Measures Menopause Menstrual cycle Mitochondria Neurons Neurotoxins Numbers Occupational Oils Ovarian hormone Ovariectomy Oxidative Stress Oxidative Stress Induction Parkinson Disease Periodicity Play Polychlorinated Biphenyls Population Postmenopause Predisposition Proteins Rattus Reporting Research Personnel Rice Risk Rodent Role Series Serum Staging Substantia nigra structure Supplementation Testing Toxic effect Tyrosine 3-Monooxygenase Withdrawal Woman alpha synuclein base density dibenzofuran dopamine transporter male men mitochondrial dysfunction monoamine mortality neurochemistry neurotoxicity nonhuman primate parkin gene/protein programs research study uptake vesicular monoamine transporter

项目摘要

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.

描述（由申请人提供）：多氯联苯 (PCB) 会降低基底神经节多巴胺 (DA) 功能，包括降低 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蛋白。然而，该数据仅在男性中收集，因此多氯联苯对女性 DA 功能的影响很大程度上未知。对这些数据的需求变得更加重要，因为暴露于极高水平 PCB 的前电容器工人显示出帕金森病导致的死亡风险增加，并且仅在女性中血清 PCB 浓度与 DA 末端密度之间存在负相关关系。由于这些流行病学发现，我们假设卵巢激素，包括 PCB 引起的减少或绝经或卵巢切除 (OVX) 后已知会减少基底神经节单胺转运蛋白和 TH+ 神经元数量的事件，将与类似的 PCB 相互作用并加剧-引起基底神经节 DA 功能的变化，导致荷尔蒙耗尽的女性比同等暴露的女性更严重的 DA 功能障碍男性。这些假设将在一系列实验中得到检验，这些实验将描述雄性和雌性大鼠中 PCB 暴露的影响，以及 PCB 引起的发情周期变化、OVX 和卵巢激素替代对 DA 功能的影响，包括抑制单胺转运蛋白、细胞质和神经元外 DA 及其代谢物的变化、TH+ SN 神经元的数量以及氧化应激和线粒体功能的测量。我们还将测量血清和大脑中 PCB 的浓度，以确定性别在改变 PCB 身体负担中的作用。拟议的实验将提供有关 PCB 暴露对女性 DA 功能影响的信息，这一群体在神经毒理学研究中很大程度上被忽视，并将确定卵巢激素（包括其撤回）影响 PCB 引起的变化的后果和机制。 DA 功能、氧化应激和线粒体功能。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奠定基础。