Caudle W Michael, Richardson Jason R, Delea Kristin C, Guillot Thomas S, Wang Minzheng, Pennell Kurt D, Miller Gary W
Department of Environmental and Occupational Health, Rollins School of Public Health and Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, Georgia 30322-3090, USA.
Toxicol Sci. 2006 Aug;92(2):490-9. doi: 10.1093/toxsci/kfl018. Epub 2006 May 15.
Epidemiological and laboratory studies have suggested that exposure to polychlorinated biphenyls (PCBs) may be a risk factor for Parkinson's disease. The purpose of this study was to examine the potential mechanisms by which PCBs may disrupt normal functioning of the nigrostriatal dopamine (DA) system. We utilized an environmentally relevant exposure of PCBs (7.5 or 15 mg/kg/day Aroclor 1,254:1,260 for 30 days by oral gavage) to identify early signs of damage to the DA system. This dosing regimen, which resulted in PCB levels similar to those found in human brain samples, did not cause overt degeneration to the DA system as shown by a lack of change in striatal DA levels or tyrosine hydroxylase levels. However, we did observe a dramatic dose-dependent decrease in striatal dopamine transporter (DAT) levels. The observed reductions appear to be specific to the DAT populations located in the striatum, as no change was observed in other dopaminergic brain regions or to other neurotransmitter transporters present in the striatum. These data demonstrate that PCB tissue concentrations similar to those found in postmortem human brain specifically disrupt DA transport, which acts as a precursor to subsequent damage to the DA system. Furthermore, DAT imaging may be useful in evaluating alterations in brain function in human populations exposed to PCBs.
流行病学和实验室研究表明，接触多氯联苯（PCBs）可能是帕金森病的一个风险因素。本研究的目的是探讨多氯联苯可能破坏黑质纹状体多巴胺（DA）系统正常功能的潜在机制。我们采用与环境相关的多氯联苯暴露（通过口服灌胃给予7.5或15 mg/kg/天的Aroclor 1,254:1,260，持续30天）来确定多巴胺系统损伤的早期迹象。这种给药方案导致的多氯联苯水平与在人脑样本中发现的水平相似，如纹状体多巴胺水平或酪氨酸羟化酶水平没有变化所示，并未导致多巴胺系统明显退化。然而，我们确实观察到纹状体多巴胺转运体（DAT）水平出现显著的剂量依赖性下降。观察到的降低似乎特定于纹状体中的DAT群体，因为在其他多巴胺能脑区或纹状体中存在的其他神经递质转运体中未观察到变化。这些数据表明，与死后人类大脑中发现的多氯联苯组织浓度相似，会特异性地破坏多巴胺转运，而多巴胺转运是随后多巴胺系统损伤的前兆。此外，DAT成像可能有助于评估接触多氯联苯的人群的脑功能改变。
