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Inhibition of the hepatic vitamin B12-dependent methionine-salvage pathway by trichloroethylene metabolites accounts for the formic aciduria in the rat

ABSTRACT: The industrial solvent trichloroethylene (TCE) produces a marked formic aciduria in male and female F344 rats and in male C57Bl mice following single or multiple dosing. The two major metabolites of TCE formed by cytochromes P450 metabolism also produce formic aciduria. The quantity of formic acid excreted was about 2-fold higher following trichloroacetic acid (TCA) compared to trichloroethanol (TCE-OH) or TCE, at similar doses of 16mg/kg/day for 3 days. Prior treatment of male F344 rats with 1-aminobenzotriazole a cytochrome P450 inhibitor, followed by TCE, completely prevented the formic aciduria but had no effect on formic acid excretion produced by TCA, suggesting TCA is the proximate metabolite producing this response. Metabolism of formic acid is largely controlled by the vitamin B12 –dependent methionine salvage pathway. Transcriptomic analysis on the liver of rats dosed with 16mg/kg/day TCE for three days when compared to control liver showed nine differentially expressed genes, of particular interest was the down regulation of LMBRD1 involved in the conversion of vitamin B12 into one of two molecules, methylcobalamin (CH3Cbl) or S-adenosylcobalamin (AdoCbl). Administration of CH3Cbl or hydroxocobalamin for 3 days to rats given a single dose of TCE, lead to a reduction in formic acid in their urine. Similarly, rats given TCE followed by L-methionine for 3 days excreted less formic acid in their urine. These findings suggest an effect on the vitamin B12 –dependent methionine salvage pathway. This was supported by the finding that hepatic methionine synthase, which converts homocysteine to methionine, was inhibited following three large daily dose of TCE. We propose that TCE metabolites interact with the vitamin B12 -dependent methionine salvage pathway leading to tetrahydrofolate deficiency and increased excretion of formic acid in rat urine.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE122664 | GEO | 2020/11/20

REPOSITORIES: GEO

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Project description:Folate, and its synthetic form folic acid, function as donor of one-carbon units and have been, together with other B-vitamins, implicated in programming of epigenetic processes such as DNA methylation during early development. To what extent regulation of DNA methylation can be altered via B-vitamins later in life, and how this relates to health and disease, is not exactly known. The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B12 on genome-wide DNA methylation in elderly subjects. This project was part of a randomized, placebo-controlled trial on effects of supplemental intake of folic acid and vitamin B12 on bone fracture incidence (B-PROOF study). Participants with mildly elevated homocysteine levels, aged 65-75 years, were randomly assigned to take 400 µg folic acid and 500 µg vitamin B12 per day or a placebo during an intervention period of two years. DNA was isolated from buffy coats, collected before and after intervention, and genome-wide DNA methylation was determined in 87 participants (n=44 folic acid/vitamin B12, n=43 placebo) using the Infinium HumanMethylation450 BeadChip. After intervention with folic acid and vitamin B12, 162 (versus 14 in the placebo group) of the 431,312 positions were differentially methylated as compared to baseline. Comparisons of the DNA methylation changes in the participants receiving folic acid and vitamin B12 versus placebo, revealed one single differentially methylated position (cg19380919) with a borderline statistical significance. However, based on the analyses of differentially methylated regions (DMRs) consisting of multiple positions, we identified 6 regions that differed statistically significantly between the intervention and placebo group. Pronounced changes were found for regions in the DIRAS3, ARMC8 and NODAL genes, implicated in carcinogenesis and early embryonic development. Furthermore, serum levels of folate and vitamin B12 or plasma homocysteine were related to DNA methylation of 173, 425 and 11 regions, respectively. Interestingly, for several members of the developmental HOX genes, DNA methylation was related to serum levels of folate. Long-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, among which genes implicated in developmental processes.

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Inhibition of the hepatic vitamin B12-dependent methionine-salvage pathway by trichloroethylene metabolites accounts for the formic aciduria in the rat

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