Gender Effects on PCB-Induced Dopamine Neurotoxicity

性别对 PCB 引起的多巴胺神经毒性的影响

• 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
• 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

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 PCB 引起的基底神经节 DA 功能的类似变化相互作用并加剧，从而导致更大的 DA 功能障碍。 与激素水平相当的男性相比，荷尔蒙缺乏的女性更容易受到影响。这些假设将在一系列实验中得到检验，这些实验将表征雄性和雌性大鼠中 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，包括单胺转运蛋白的抑制、细胞质和神经元外 DA 及其代谢物的变化、TH+ SN 神经元的数量以及测量 氧化应激和线粒体功能。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（包括其撤除）影响 PCB 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奠定基础。