PCB-Induced Inflammation and Nigral Dopamine Loss

描述（由申请人提供）：成年非人灵长类动物和啮齿动物暴露于多氯联苯（PCBs）中会减少黑质致密部（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多氯联苯的发育暴露之后，因为这种暴露会降低基底神经节多巴胺（DA）的浓度，并持续到成年。这些数据表明多氯联苯可能与帕金森病（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尚不清楚。多氯联苯抑制单胺转运体，从而由于胞质DA升高和活性DA代谢物和活性氧（ROS）的形成而导致神经元功能障碍。此外，多氯联苯直接诱导的中枢炎症过程和神经元损伤的结果，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，都可能导致这种细胞损失。主要的假设是：(i)发育暴露于多氯联苯会降低神经DA神经元的活力；（ii）黑质小胶质细胞的激活和随后细胞毒性细胞因子的释放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）受损DA神经元表面抗原引起的自身抗体加剧了DA细胞的死亡。这些假设将通过细胞因子敲除和SCID小鼠在子宫内和哺乳期暴露于多氯联苯，测量SNpc中的TH+神经元，SNpc和纹状体中的DA浓度，黑质和纹状体中的细胞因子表达，基底神经节中ROS的形成以及确定黑质DA神经元上自身抗体的存在和浓度来验证。这些拟议的实验将确定：(1)发育过程中暴露于多氯联苯是否会导致黑质DA神经元的显著丧失；(2)中枢炎症过程，包括细胞毒性细胞因子和反应性自身，是否会导致这种丧失。

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.