Project 2: Oxidative Stress and PCB Exposure in Mammalian Cells

我们小组和其他人最近的证据表明，接触多氯联苯 多氯联苯（PCB）可在哺乳动物细胞中引起代谢性氧化应激，从而导致细胞损伤和生物毒性。 PCBs的影响。慢性代谢性氧化应激也与退行性变密切相关。 与基因组不稳定性、致癌作用和衰老有关的疾病。 与前列腺癌和乳腺癌的风险增加有关。项目2将调查 代谢氧化应激在损伤和生长障碍机制中的作用， 乳腺上皮细胞在PCB暴露。初步结果显示，前列腺上皮细胞的暴露 细胞（PrECB）和乳腺上皮细胞（MCF10A）对PCB和PCB代谢物的敏感性增加 超氧化物生成和谷胱甘肽代谢的破坏与代谢诱导一致 氧化应激以及细胞生长中的扰动。具体而言，目前的提案将测试 线粒体假说!产生活性氧物质（ROS;即，超氧化物和氢 过氧化物）在PCB暴露期间引起氧化应激，这种增加的ROS产生有助于 多氯联苯对前列腺和乳腺上皮细胞生长的生物学影响。目标1将确定是否 暴露于PCB或PCB代谢物会诱导前列腺和乳腺上皮细胞的氧化应激， 有助于PCB诱导的细胞增殖和细胞毒性的改变。目标2将决定 特异性ROS（即，超氧化物、过氧化氢和有机过氧化氢）和生产地点 导致前列腺和乳腺的氧化应激和多氯联苯诱导的生长紊乱和细胞毒性 上皮细胞目标#3将确定细胞内硫醇或硒补充的操作是否可以 修改多氯联苯诱导的氧化应激和人类前列腺和乳腺上皮细胞的生长障碍。 这些研究的长期目标是提供一个严格的机制的理解， 代谢氧化应激在多氯联苯诱导的前列腺和乳腺上皮细胞生长的影响， 有助于致癌作用，并确定抗氧化机制的操作，可以保护人类 前列腺和乳腺上皮细胞受到多氯联苯的影响。

Recent evidence from our group and others has suggested that exposure to polychlorinated biphenyls (PCBs) can cause metabolic oxidative stress in mammalian cells contributing to cell injury and the biological effects of PCBs. Chronic metabolic oxidative stress has also been strongly implicated in degenerative diseases associated with genomic instability, carcinogenesis, and aging.PCB exposure has also been implicated in increased the risk of prostate and breast cancer. Project 2 will investigate the involvement of metabolic oxidative stress in mechanisms of injury and growth disturbances seen in human prostate and breast epithelial cells during PCB exposure. Preliminary results show that exposure of prostate epithelial cells (PrECB) and breast epithelial cells (MCF10A) to PCBs and PCB metabolites cause increased superoxide production and disruptions in glutathione metabolism consistent with induction of metabolic oxidative stress as well as perturbations in cell growth. Specifically the current proposal will test the hypothesis that mitochondria! production of reactive oxygen species (ROS; i.e., superoxide and hydrogen peroxide) causes oxidative stress during PCB exposure and this increased production of ROS contributes to the biological effects of PCBs on cell growth in prostate and breast epithelial cells. Aim#1 will determine if exposure to PCBs or PCB metabolites induces oxidative stress in prostate and breast epithelial cells that contributes to PCB-induced alterations in cell proliferation and cytotoxicity. Aim#2 will determine which specific ROS (i.e., superoxide, hydrogen peroxide, and organic hydroperoxides) and sites of production contribute to oxidative stress and PCB-induced growth disturbances and cytotoxicity in prostate and breast epithelial cells. Aim#3 will determine if manipulation of intracellular thiols or selenium supplementation can modify PCB-induced oxidative stress and growth disturbances in human prostate and breast epithelial cells. The long-term goal of these studies is to provide a rigorous mechanistic understanding of the involvement of metabolic oxidative stress in PCB-induced effects on prostate and breast epithelial cell growth that may contribute carcinogenesis and identify manipulations of antioxidant mechanisms that can protect human prostate and breast epithelial cells from PCB exposure.