Integration of transcriptomics and metabolomics analysis for unveiling the toxicological profile in the liver of mice exposed to uranium in drinking water.

Uranium is a contaminate in the underground water in many regions of the world, which poses health risks to the local populations through drinking water. Although the health hazards of natural uranium have been concerned for decades, the controversies about its detrimental effects continue at present since it is still unclear how uranium interacts with molecular regulatory networks to generate toxicity. Here, we integrate transcriptomic and metabolomic methods to unveil the molecular mechanism of lipid metabolism disorder induced by uranium. Following exposure to uranium in drinking water for twenty-eight days, aberrant lipid metabolism and lipogenesis were found in the liver, accompanied with aggravated lipid peroxidation and an increase in dead cells. Multi-omics analysis reveals that uranium can promote the biosynthesis of unsaturated fatty acids through dysregulating the metabolism of arachidonic acid (AA), linoleic acid, and glycerophospholipid. Most notably, the disordered metabolism of polyunsaturated fatty acids (PUFAs) like AA may contribute to lipid peroxidation induced by uranium, which in turn triggers ferroptosis in hepatocytes. Our findings highlight disorder of lipid metabolism as an essential toxicological mechanism of uranium in the liver, offering insight into the health risks of uranium in drinking water.

Roles of glutathione peroxidase 4 on the mercury-triggered ferroptosis in renal cells: implications for the antagonism between selenium and mercury.

Understanding of how mercury species cause cellular impairments at the molecular level is critical for explaining the detrimental effects of mercury exposure on the human body. Previous studies have reported that inorganic and organic mercury compounds can induce apoptosis and necrosis in a variety of cell types, but more recent advances reveal that mercuric mercury (Hg2+) and methylmercury (CH3Hg+) may result in ferroptosis, a distinct form of programmed cell death. However, it is still unclear which protein targets are responsible for ferroptosis induced by Hg2+ and CH3Hg+. In this study, human embryonic kidney 293T cells were used to investigate how Hg2+ and CH3Hg+ trigger ferroptosis, given their nephrotoxicity. Our results demonstrate that glutathione peroxidase 4 (GPx4) plays a key role in lipid peroxidation and ferroptosis in renal cells induced by Hg2+ and CH3Hg+. The expression of GPx4, the only lipid repair enzyme in mammal cells, was downregulated in response to Hg2+ and CH3Hg+ stress. More importantly, the activity of GPx4 could be markedly inhibited by CH3Hg+, owing to the direct binding of the selenol group (-SeH) in GPx4 to CH3Hg+. Selenite supplementation was demonstrated to enhance the expression and activity of GPx4 in renal cells, and consequently relieve the cytotoxicity of CH3Hg+, suggesting that GPx4 is a crucial modulator implicated in the Hg-Se antagonism. These findings highlight the importance of GPx4 in mercury-induced ferroptosis, and provide an alternative explanation for how Hg2+ and CH3Hg+ induce cell death.

Emerging health risks and underlying toxicological mechanisms of uranium contamination: Lessons from the past two decades.

Uranium contamination is a global health concern. Regarding natural or anthropogenic uranium contamination, the major sources of concern are groundwater, mining, phosphate fertilizers, nuclear facilities, and military activities. Many epidemiological and laboratory studies have demonstrated that environmental and occupational uranium exposure can induce multifarious health problems. Uranium exposure may cause health risks because of its chemotoxicity and radiotoxicity in natural or anthropogenic scenarios: the former is generally thought to play a more significant role with regard to the natural uranium exposure, and the latter is more relevant to enriched uranium exposure. The understanding of the health risks and underlying toxicological mechanisms of uranium remains at a preliminary stage, and many controversial findings require further research. In order to present state-of-the-art status in this field, this review will primarily focus on the chemotoxicity of uranium, rather than its radiotoxicity, as well as the involved toxicological mechanisms. First, the natural or anthropogenic uranium contamination scenarios will be briefly summarized. Second, the health risks upon natural uranium exposure, for example, nephrotoxicity, bone toxicity, reproductive toxicity, hepatotoxicity, neurotoxicity, and pulmonary toxicity, will be discussed based on the reported epidemiological cases and laboratory studies. Third, the recent advances regarding the toxicological mechanisms of uranium-induced chemotoxicity will be highlighted, including oxidative stress, genetic damage, protein impairment, inflammation, and metabolic disorder. Finally, the gaps and challenges in the knowledge of uranium-induced chemotoxicity and underlying mechanisms will be discussed.