Altered generation pattern of reactive oxygen species triggering DNA and plasma membrane damages to human liver cells treated with arsenite

Human exposure to arsenic via drinking water is one of globally concerned health issues. Oxidative stress is regarded as the denominator of arsenic-inducing toxicities. Therefore, to identify intracellular sources of reactive oxygen species (ROS) could be essential for addressing the detrimental effects of arsenite (iAsIII). In this study, the contributions of different pathways to ROS formation in iAsIII-treated human normal liver (L-02) cells were quantitatively assessed, and then concomitant oxidative impairs were evaluated using metabolomics and lip-idomics approaches. Following iAsIII treatment, NADPH oxidase (NOX) activity and expression levels of p47phox and p67phox were upregulated, and NOX-derived ROS contributed to almost 60.0 % of the total ROS. Moreover, iAsIII also induced mitochondrial superoxide anion and impaired mitochondrial respiratory function of L-02 cells with a decreasing ATP production. The inhibition of NOX activity significantly rescued mitochondrial membrane potential in iAsIII-treated L-02 cells. Purine and glycerophospholipids metabolisms in L-02 cells were disrupted by iAsIII, which might be used to represent DNA and plasma membrane damages, respectively. Our study supported that NOX could be the primary pathway of ROS overproduction and revealed the potential mechanisms of iAsIII toxicity related to oxidative stress.

Automated summary

Human exposure to arsenic in drinking water is a global health concern. This study investigated the intracellular sources of reactive oxygen species (ROS) and the oxidative impairments caused by arsenite (iAsIII) toxicity. NADPH oxidase (NOX) was found to be the primary pathway of ROS overproduction, accounting for nearly 60.0% of total ROS. iAsIII also induced mitochondrial superoxide anion, impairing mitochondrial respiratory function and decreasing ATP production. The inhibition of NOX activity rescued mitochondrial membrane potential. Purine and glycerophospholipids metabolisms were disrupted by iAsIII, indicating DNA and plasma membrane damages. This study provides insights into the mechanisms of iAsIII toxicity related to oxidative stress.