1,4-Dioxane exposure induces kidney damage in mice by perturbing specific renal metabolic pathways: An integrated omics insight into the underlying mechanisms.


Key Laboratory of Pathogen Biology of Jiangsu Province, Department of Pathogen Biology, Nanjing Medical University, Nanjing, 211166, China. Electronic address: [Email]


1,4-Dioxane (dioxane), an industrial solvent widely detected in environmental and biological matrices, has potential nephrotoxicity. However, the underlying mechanism by which dioxane induces kidney damage remains unclear. In this study, we used an integrated approach, combining kidney transcriptomics and urine metabolomics, to explore the mechanism for the toxic effects of dioxane on the mouse kidney. Transcriptomics profiling showed that exposure to 0.5 mg/L dioxane induced perturbations of multiple signaling pathways in kidneys, such as MAPK and Wnt, although no changes in oxidative stress indicators or anatomical pathology were observed. Exposure to 500 mg/L dioxane significantly disrupted various metabolic pathways, concomitantly with observed renal tissue damage and stimulated oxidant defense system. Urine metabolomic analysis using NMR indicated that exposure to dioxane gradually altered the metabolic profile of urine. Within the full range of altered metabolites, the metabolic pathway containing glycine, serine and threonine was the most significantly altered pathway at the early stage of exposure (3 weeks) in both 0.5 and 500 mg/L dioxane-treated groups. However, with prolonged exposure (9 and 12 weeks), the level of taurine significantly decreased after treatment of 0.5 mg/L dioxane, while exposure to 500 mg/L dioxane significantly increased glutathione levels in urine and decreased arginine metabolism. Furthermore, integrated omics analysis showed that 500 mg/L dioxane exposure induced arginine deficiency by perturbing several genes involved in renal arginine metabolism. Shortage of arginine coupled with increased oxidative stress could lead to renal dysfunction. These findings offer novel insights into the toxicity of dioxane.


1,4-Dioxane,Arginine metabolism,Kidney damage,Metabolome,Transcriptome,