Arsenic exposure at environmentally relevant levels induced metabolic toxicity in development mice: Mechanistic insights from integrated transcriptome and metabolome

• Published in: Environment international 2024-08, Vol.190, p.108819, Article 108819
• Main Authors: Liu, Qianying, Li, Peiwen, Ma, Jinglan, Zhang, Jiazhen, Li, Weiya, Liu, Yuenan, Liu, Lu, Liang, Sen, He, Meian
• Format: Article
• Language: English
• Subjects: Animals; Arsenic; Arsenic - toxicity; Drinking water; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Metabolome - drug effects; Metabolomics; Mice; Non-alcoholic Fatty Liver Disease - chemically induced; Non-alcoholic Fatty Liver Disease - metabolism; Oxidative Stress - drug effects; Transcriptome; Transcriptome - drug effects
• ISSN: 0160-4120; 1873-6750; 1873-6750
• DOI: 10.1016/j.envint.2024.108819

[Display omitted] •The first transcriptome and metabolome network was established in arsenic-exposed mice.•Developmental arsenic disrupted mitochondrial fatty acid β-oxidation in mice.•Arsenic accumulation and pathological changes were found in liver and intestine.•Disrupted human serum metabolites linked with metabolic toxicity in mice.•L-palmitoylcarnitine was critical player in metabolic toxicity and late-life NAFLD development. Emerging evidence has linked arsenic exposure and metabolic homeostasis, but the mechanism is incompletely understood, especially at relatively low concentrations. In this study, we used a mouse model to evaluate the health impacts and metabolic toxicity of arsenic exposure in drinking water at environmentally relevant levels (0.25 and 1.0 ppm). Our results indicated that arsenic damaged intestinal barrier and induced arsenic accumulation, oxidative stress, and pathological changes in the liver and illum. Interestingly, arsenic increased the hepatic triglyceride (TG) and total cholesterol (TC), while reduced serum TG and TC levels. The liver transcriptome found that arsenic exposure caused transcriptome perturbation and promoted hepatic lipid accumulation by regulating the exogenous fatty acids degradation and apolipoproteins related genes. The serum metabolomics identified 74 and 88 differential metabolites in 0.25 and 1.0 ppm, respectively. The KEGG disease and subcellular location analysis indicated that arsenic induced liver and intestinal diseases, and the mitochondrion might be the target organelle for arsenic-induced toxicity. Co-enrichment of transcriptome and metabolome identified 24 metabolites and 9 genes as metabolic toxicity biomarkers. Moreover, 40 male (20 nonalcoholic fatty liver disease (NAFLD) cases and 20 healthy controls) was further selected to validate our findings. Importantly, the significantly changed L-palmitoylcarnitine, 3-hydroxybutyric acid, 2-hydroxycaproic acid and 6 genes of Hadha, Acadl, Aldh3a2, Cpt1a, Cpt2, and Acox1 were found in the NAFLD cases. The results from integrated multi-omics and chemical-protein network analysis indicated that L-palmitoylcarnitine played a critical role in metabolic toxicity by regulating mitochondrial fatty acids β-oxidation genes (Cpt1a, Cpt2). In conclusion, these findings provided new clues for the metabolic toxicity of arsenic exposure at environmentally relevant levels, which involved in the late-life NAFLD development. Our results also contribute to understan