Lee Donna W, Gelein Robert M, Opanashuk Lisa A
Department of Environmental Medicine, University of Rochester of School of Medicine and Dentistry, Rochester, New York 14642, USA.
Toxicol Sci. 2006 Mar;90(1):159-67. doi: 10.1093/toxsci/kfj052. Epub 2005 Nov 30.
Dopaminergic (DAergic) systems have been identified as putative targets for polycholorinated biphenyl (PCB) actions. However, the precise mechanisms leading to neurotoxicity are unresolved. Reactive oxygen species (ROS) were recently shown to mediate injury in DAergic MN9D cells following exposure to Aroclor 1254 (A1254), a commercial PCB mixture. The oxidative stress response in DAergic cells included a persistent expression of heme oxygenase-1 (HO-1). This study tested the hypothesis that a sustained PCB-induced HO-1 response leads to abnormally high Fe levels, which generates ROS production and mediates death in the MN9D DAergic cell model. Accordingly, results indicated that A1254 augmented intracellular Fe levels in MN9D cells after 24 h. Fe chelation by desferoxamine or pharmacologic inhibition of HO activity with tin-protoporphyrin reduced Fe accumulation, ROS production, and cytotoxicity following A1254 exposure. HO-1 over-expression predisposed MN9D DAergic cells to enhanced ROS production and cell death in response to PCBs. Conversely, antisense inhibition of HO-1 expression prevented PCB-induced ROS production and cell death. These observations suggest that enhanced HO-1 catalytic activity and subsequent liberation of Fe participate in neurotoxic DAergic cell injury caused by A1254 exposure in vitro.
多巴胺能（DAergic）系统已被确定为多氯联苯（PCB）作用的假定靶点。然而，导致神经毒性的确切机制尚未明确。最近研究表明，活性氧（ROS）介导了暴露于商业PCB混合物Aroclor 1254（A1254）后的DAergic MN9D细胞损伤。DAergic细胞中的氧化应激反应包括血红素加氧酶-1（HO-1）的持续表达。本研究验证了以下假设：PCB诱导的HO-1反应持续导致铁水平异常升高，从而产生活性氧并介导MN9D DAergic细胞模型中的细胞死亡。相应地，结果表明，A1254在24小时后增加了MN9D细胞内的铁水平。去铁胺螯合铁或用锡原卟啉对HO活性进行药理抑制可降低A1254暴露后的铁积累、活性氧产生和细胞毒性。HO-1过表达使MN9D DAergic细胞在接触PCB时更容易产生活性氧和细胞死亡。相反，HO-1表达的反义抑制可防止PCB诱导的活性氧产生和细胞死亡。这些观察结果表明，增强的HO-1催化活性和随后铁的释放参与了体外A1254暴露引起的神经毒性DAergic细胞损伤。
