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.