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Combined transcriptomics and proteomics analysis unveiled the impact of vitamin C in modulating specific mitochondrial protein abundance in the mouse liver

ABSTRACT: : In the present study, we used the Gulo-/- female and male mice model which depends entirely on ascorbate derived from the diet. We tested different concentrations of ascorbate ranging from 0 to 0.4% (w/v) ascorbate, added into drinking water, until the age of four months. Importantly, the levels of ascorbate found in the liver of Gulo-/- mice reflect the amounts of ascorbate provided in drinking water. We performed label-free Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) global quantitative proteomic profiling to identify and quantify proteins in whole liver extracts from our different ascorbate treated cohorts of Gulo-/- females and males. We compared the proteomic profiles to the transcriptomic profiles of the same treated animals. Although several proteins of the mitochondrial complex III significantly correlated with vitamin C concentrations, their corresponding transcripts did not correlate with vitamin C in both females and males. Such observations were confirmed by western blot and quantitative RT-PCR analyses, respectively. Our findings suggest that transcriptome profiling alone provides an incomplete picture of molecular changes associated with vitamin C deficiency in the liver of mice and examination of changes in protein abundances is essential to unveil variations that are not transcriptionally regulated.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Michel Lebel

PROVIDER: MSV000092040 | MassIVE | Fri May 26 08:28:00 BST 2023

SECONDARY ACCESSION(S): PXD042513

REPOSITORIES: MassIVE

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Project description:1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States (US). While it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, we performed chronic and short-term dosing studies in female BDF-1 mice to explore the toxic effects of 1,4-DX. Histopathology studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Mice were exposed to various concentrations of 1,4-DX (0, 50, 500 and 5,000 mg/L) in their drinking water for one or four weeks. Immunohistochemical analysis of the liver revealed an increase in the number of H2AXγ-positive hepatocytes (a marker of DNA double strand breaks) in mice exposed to 5,000 mg/L 1,4-DX for one and four weeks. In addition, an expansion of precholangiocytes was observed after four weeks of 5,000 mg/L 1,4-DX exposure, as reflected by CK-7 immunostaining. An increase in these markers reflect both DNA damage and repair mechanisms. Liver transcriptomics profiling showed that exposure to 5,000 mg/L 1,4-DX for four weeks resulted in the differential expression of 65 genes compared to controls. Pathway analysis of the transcriptomic data revealed 1,4-DX-induced perturbations in multiple signaling pathways in the liver, including those involved in xenobiotic metabolism, nicotine degradation and glutathione-mediated detoxification. Changes to these pathways as a result of 1,4-DX exposure reflect would be predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, stool and urine metabolomics profiling revealed no effect of 5,000 mg/L 1,4-DX exposure for one or four weeks on metabolites. We speculate that this may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death, but have activated the repair systems in response to 1,4-DX exposure

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Combined transcriptomics and proteomics analysis unveiled the impact of vitamin C in modulating specific mitochondrial protein abundance in the mouse liver

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