Department of Occupational and Environmental Health and The Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
Department of Laboratory, Xijing Hospital, Fourth Military Medical University, Xi'an China.
Toxicol Lett. 2014 Feb 10;225(1):110-8. doi: 10.1016/j.toxlet.2013.11.034. Epub 2013 Dec 6.
The blood-cerebrospinal fluid barrier (BCB) plays a key role in maintaining copper (Cu) homeostasis in the brain. Cumulative evidences indicate that lead (Pb) exposure alters cerebral Cu homeostasis, which may underlie the development of neurodegenerative diseases. This study investigated the roles of Cu transporter 1 (CTR1) and ATP7A, two Cu transporters, in Pb-induced Cu accumulation in the choroidal epithelial cells. Pb exposure resulted in increased intracellular (64)Cu retention, accompanying with up-regulated CTR1 level. Knockdown of CTR1 using siRNA before Pb exposure diminished the Pb-induced increase of (64)Cu uptake. The expression level of ATP7A was down-regulated following the Pb exposure. ATP7A siRNA knockdown, or PCMB treatment, inhibited the (64)Cu efflux from the cells, while the following additional incubation with Pb failed to further increase the intracellular (64)Cu retention. Cu exposure, or intracellular Cu accumulation following the tetracycline (Tet)-induced overexpression of CTR1, did not result in significant change in ATP7A expression. Taken together, these data indicate that CTR1 and ATP7A play important roles in Cu transport in choroidal epithelial cells, and the Pb-induced intracellular Cu accumulation appears to be mediated, at least in part, via the alteration of CTR1 and ATP7A expression levels following Pb exposure.
血脑屏障（BCB）在维持大脑内铜（Cu）稳态方面发挥着关键作用。越来越多的证据表明，铅（Pb）暴露会改变大脑内的 Cu 稳态，这可能是神经退行性疾病发展的基础。本研究探讨了铜转运蛋白 1（CTR1）和 ATP7A 这两种 Cu 转运蛋白在 Pb 诱导的脉络膜上皮细胞 Cu 积累中的作用。Pb 暴露导致细胞内（64）Cu 保留增加，同时 CTR1 水平上调。在 Pb 暴露前使用 siRNA 敲低 CTR1 可减少 Pb 诱导的（64）Cu 摄取增加。Pb 暴露后 ATP7A 的表达水平下调。ATP7A siRNA 敲低或 PCMB 处理抑制了细胞内（64）Cu 的外排，而随后与 Pb 的孵育未能进一步增加细胞内（64）Cu 的保留。Cu 暴露或 Tet 诱导的 CTR1 过表达导致的细胞内 Cu 积累并未导致 ATP7A 表达发生显著变化。综上所述，这些数据表明 CTR1 和 ATP7A 在脉络膜上皮细胞的 Cu 转运中发挥重要作用，Pb 诱导的细胞内 Cu 积累似乎至少部分是通过 Pb 暴露后 CTR1 和 ATP7A 表达水平的改变介导的。
