Yu Libing, Lin Zhaozhu, Cheng Xuedan, Chu Jian, Li Xijian, Chen Chun, Zhu Tinghua, Li Wenjing, Lin Wei, Tang Wei
Institute of Materials, China Academy of Engineering Physics, Mianyang 621907, China.
Department of Pathogen Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
J Hazard Mater. 2022 Feb 15;424(Pt B):127546. doi: 10.1016/j.jhazmat.2021.127546. Epub 2021 Oct 20.
Thorium is a radioactive heavy metal and an emerging environmental pollutant. Ecological and human health risks from thorium exposure are growing with the excavation of rare earth metals and implementation of thorium-based nuclear reactors. Thorium poisoning is associated with carcinogenesis, liver impairments, and congenital anomalies. To date, the biomolecular targets that underlie thorium-induced toxicity remain unknown. Here, we used in vitro enzymatic activity assays to comprehensively evaluate the effects of thorium on the mitochondrial respiration process. Thorium was found to inhibit respiratory chain complex IV (cytochrome c oxidase) at sub-micromolar concentrations (IC ~ 0.4 μM, 90 μg/L). This is lower than the thorium level limit (246 μg/L) in drinking water specified by the World Health Organization. The inhibitory effects were further verified in mitochondria from human bone and liver cells (thorium mainly deposits in these organs). The inhibition of cytochrome c oxidase can readily rationalize well-documented cellular toxicities of thorium, such as alteration of mitochondrial membrane potential and production of reactive oxygen species. Therefore, cytochrome c oxidase is potentially a key molecular target underlying thorium-induced toxicological effect.
钍是一种放射性重金属，也是一种新出现的环境污染物。随着稀土金属的开采以及钍基核反应堆的应用，钍暴露带来的生态和人类健康风险正在增加。钍中毒与致癌、肝脏损伤和先天性异常有关。迄今为止，钍诱导毒性的生物分子靶点仍不清楚。在此，我们使用体外酶活性测定法全面评估钍对线粒体呼吸过程的影响。发现钍在亚微摩尔浓度（IC~0.4μM，90μg/L）下抑制呼吸链复合物IV（细胞色素c氧化酶）。这低于世界卫生组织规定的饮用水中钍含量限值（246μg/L）。在人骨和肝细胞的线粒体中进一步验证了这种抑制作用（钍主要沉积在这些器官中）。细胞色素c氧化酶的抑制作用能够很好地解释钍已被充分证明的细胞毒性，如线粒体膜电位的改变和活性氧的产生。因此，细胞色素c氧化酶可能是钍诱导毒理学效应的关键分子靶点。
