PCB-Induced Inflammation and Nigral Dopamine Loss

PCB 引起的炎症和黑质多巴胺损失

• 批准号: 6915680
• 负责人: Richard Field Seegal
• 金额: $ 19.18万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6915680
• 关键词: SCID mouse; autoantibody; basal ganglia; confocal scanning microscopy; cytotoxicity; dopamine; embryo /fetus toxicology; free radical oxygen; genetically modified animals; halobiphenyl /halotriphenyl compound; high performance liquid chromatography; inflammation; interleukin 6; microglia; neural degeneration; neuroimmunomodulation; neurons; neurotoxicology; substantia nigra; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Exposure of adult non-human primates and rodents to polychlorinated biphenyls (PCBs) reduces the number of tyrosine hydroxylase positive (TH+) neurons in the substantia nigra pars compacta (SNpc). This neuronal loss may also occur following developmental exposure to PCBs since such exposures reduce basal ganglia dopamine (DA) concentrations that persist well into adulthood. These data suggest that PCBs may contribute to the etiology and/or pathogenesis of Parkinson's Disease (PD). However, the mechanisms responsible for these losses in both the adult and during development remain unclear. PCBs inhibit monoamine transporters thus contributing to neuronal dysfunction due to elevated cytosolic DA and formation of reactive DA metabolites and reactive oxygen species (ROS). Additionally, central inflammatory processes, induced both directly by PCBs and as a result of neuronal damage, including activation of central microglia, release of cytotoxic cytokines and formation of reactive auto-antibodies may contribute to this cell loss. The major hypotheses are that: (i) developmental exposure to PCBs reduce nigral DA neuronal viability; (ii) activation of nigral microglia and subsequent release of cytotoxic cytokines exacerbate the initial chemical insult,(iii) the loss of nigral DA viability will worsen as the animals age and (iv) auto-antibodies raised against surface antigens on compromised DA neurons exacerbate DA cell death. These hypotheses will be tested by using cytokine knockout and SCID mice exposed to PCB in utero and during lactation and measuring TH+ neurons in the SNpc, DA concentrations in the SNpc and striatum, nigral and striatal cytokine expression, formation of ROS in the basal ganglia and determining the presence and concentrations of auto-antibodies on nigral DA neurons. These proposed experiments will determine whether: (i) developmental exposure to PCBs leads to significant loss of nigral DA neurons and (ii) central inflammatory processes, including cytotoxic cytokines and reactive auto-bodies contribute to that loss.

描述（由申请人提供）：成年非人类灵长类动物和啮齿类动物接触多氯联苯 (PCB) 会​​减少黑质致密部 (SNpc) 中酪氨酸羟化酶阳性 (TH+) 神经元的数量。这种神经元损失也可能发生在发育过程中接触 PCB 后，因为这种接触会降低基底神经节多巴胺 (DA) 浓度，而这种浓度会持续到成年期。这些数据表明 PCB 可能与帕金森病 (PD) 的病因和/或发病机制有关。然而，在成人和发育过程中造成这些损失的机制仍不清楚。 PCB 会抑制单胺转运蛋白，从而因胞质 DA 升高以及反应性 DA 代谢物和活性氧 (ROS) 的形成而导致神经元功能障碍。此外，由 PCB 直接诱导的中枢炎症过程以及神经元损伤导致的中枢炎症过程，包括中枢小胶质细胞的激活、细胞毒性细胞因子的释放和反应性自身抗体的形成，可能导致这种细胞损失。主要假设是：(i) 发育过程中接触 PCB 会降低黑质 DA 神经元的活力； (ii) 黑质小胶质细胞的激活和随后释放的细胞毒性细胞因子加剧了最初的化学损伤，(iii) 随着动物年龄的增长，黑质 DA 活力的丧失将进一步恶化，(iv) 针对受损 DA 神经元表面抗原产生的自身抗体加剧了 DA 细胞死亡。这些假设将通过使用细胞因子敲除小鼠和在子宫内和哺乳期间暴露于 PCB 的 SCID 小鼠进行测试，并测量 SNpc 中的 TH+ 神经元、SNpc 和纹状体中的 DA 浓度、黑质和纹状体细胞因子的表达、基底神经节中 ROS 的形成，并确定黑质 DA 神经元上自身抗体的存在和浓度。这些拟议的实验将确定：(i) 发育过程中接触 PCB 是否会导致黑质 DA 神经元的显着损失，以及 (ii) 中枢炎症过程，包括细胞毒性细胞因子和反应性自身体，会导致这种损失。