Folate metabolism modifies chromosomal damage induced by 1,3-butadiene: results from a match-up study in China and in vitro experiments

Abstract

Objectives To explore the role of folate metabolism in 1,3-Butadiene (BD)'s genotoxicity, we conducted a match-up study in BD-exposed workers in China to analyze the associations between the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and the chromosomal damage induced by BD exposure, and culture-based experiments in TK-6 cells to examine the global DNA methylation levels and chromosomal damage when exposed both to BD’s genotoxic metabolite, 1,2:3,4-diepoxybutane (DEB), and MTHFR’s direct catalytic product, 5-methyltetrahydrofolate (5-MTHF). Methods Cytokinesis block micronucleus assay (CBMN) was used to examine the chromosomal damage induced by BD or DEB. Poisson regression models were produced to quantify the relationship of chromosomal damage and genetic polymorphisms in the BD-exposed workers. Global DNA methylation levels in TK6 cells were examined using DNA Methylation Quantification Kit. Results We found that BD-exposed workers carrying MTHFR C677T CC (2.00 ± 2.00‰) (FR = 0.36, 95%CI: 0.20–0.67, P < 0.01) or MTHFR C677T CT (2.87 ± 1.98‰) (FR = 0.49, 95%CI: 0.32–0.77, P < 0.01) genotypes had significantly lower nuclear bud (NBUD) frequencies than those carrying genotype MTHFR 677 TT (5.33 ± 2.60‰), respectively. The results in TK6 cells showed that there was a significant increment in frequencies of micronucleus (MN), nucleoplasmic bridge (NPB) and nuclear bud (NBUD) with exposure to DEB at each 5-MTHF dose (ANOVA, P < 0.01). Additionally, there was a significant decrease in frequencies of MN, NPB and NBUD in DEB-exposed cultures with increasing concentration of 5-MTHF (ANOVA, P < 0.05). The levels of global DNA methylation were significantly decreased by DEB treatment in a dose-dependent manner within each 5-MTHF concentration in TK-6 cells (ANOVA, P < 0.01), and were significantly increased by 5-MTHF supplementation within each DEB concentration (ANOVA, P < 0.01). Conclusion We reported that folate metabolism could modify the association between BD exposure and chromosomal damage, and such effect may be partially mediated by DNA hypomethylation, and 5-MTHF supplementation could rescue it.

Drug substitution and adjuvant therapy in patients with genetics related infertility: A review

“…In the metabolism of folic acid, methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme. Homocysteine (Hcy) accumulation (21) and DNA hypomethylation (22) are caused by incorrect catalytic steps of gene-related enzymes and low folic acid levels caused by the MTHFR gene mutation. Hcy results in poor villui vascularization and hypercoagulability by destroying vascular endothelial cells.…”

1,3-Butadiene: a ubiquitous environmental mutagen and its associations with diseases

“…The other group of Chinese researchers, the Cao and Ao group in the Department of Hygiene Toxicology of the Third Military Medical University, Chongqing, China, conducted a 1:1 matched pair study in a population of workers in a large petrochemical facility in Nanjing, China [ 165 – 167 ]. The workers were exposed to significantly higher levels of BD than did the control (5.02 vs. 1.86 mg/m 3 , p < 0.01), and exhibited elevated frequency of MN and nucleoplasmic bridge (NPB) (both p < 0.01) but lower nuclear division index ( p < 0.01) in comparison to the control [ 165 ].…”

“…The workers were exposed to significantly higher levels of BD than did the control (5.02 vs. 1.86 mg/m 3 , p < 0.01), and exhibited elevated frequency of MN and nucleoplasmic bridge (NPB) (both p < 0.01) but lower nuclear division index ( p < 0.01) in comparison to the control [ 165 ]. The polymorphisms of some metabolism- and DNA repair-related genes, and a folate metabolism-related gene were observed to affect the NPB and nuclear bud frequency [ 165 – 167 ].…”