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：
7744054
负责人：
Richard Field Seegal
金额：
$ 39.83万
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/7744054
关键词：
Address Adult Affect Age Basal Ganglia Body Burden Brain Cessation of life Complex Consumption Corpus striatum structure Data Dopamine Epidemiologic Studies Epidemiology 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 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

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.

多氯联苯 (PCB) 会降低基底神经节多巴胺 (DA) 功能，包括降低黑质（SN）中的DA含量和酪氨酸羟化酶阳性（TH+）神经元的数量为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，PCB 对女性 DA 功能的影响在很大程度上尚不清楚。需要这些数据变得更加重要，因为前电容器工人暴露于极高水平的 PCB 显示帕金森病导致的死亡风险增加，并且与以下因素呈负相关：仅女性血清 PCB 浓度和 DA 末端密度。由于这些流行病学我们假设卵巢激素（包括多氯联苯或以下任一因素引起的减少）更年期或卵巢切除术（OVX），已知会减少基底神经节单胺转运蛋白的事件和 TH+ 神经元的数量，将与基底神经节中 PCB 引起的类似变化相互作用并加剧 DA 功能，导致荷尔蒙耗尽的女性比其他女性更严重的 DA 功能障碍 - 暴露的男性。这些假设将在一系列实验中得到检验，这些实验将描述其影响雄性和雌性大鼠 PCB 暴露的影响以及 PCB 引起的发情变化的后果周期性、OVX 和卵巢激素替代对 DA 功能的影响，包括单胺的抑制转运蛋白、细胞质和神经元外 DA 及其代谢物的变化、TH+ SN 的数量神经元，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。这拟议的实验将提供有关 PCB 暴露对女性 DA 功能影响的信息，在神经毒理学研究中很大程度上被忽视的人群将决定卵巢激素（包括其戒断）影响 PCB- 的后果和机制诱导 DA 功能、氧化应激和线粒体功能的变化。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阶段环境和职业多巴胺神经毒物。