Title: Sex-specific differences in genotoxic and epigenetic effects of 1,3-butadiene among mouse tissues.
Authors: Lewis, Lauren; Chappell, Grace A; Kobets, Tetyana; O'Brian, Bridget E; Sangaraju, Dewakar; Kosyk, Oksana; Bodnar, Wanda; Tretyakova, Natalia Y; Pogribny, Igor P; Rusyn, Ivan
Published In Arch Toxicol, (2019 03)
Abstract: Exposure to environmental chemicals has been shown to have an impact on the epigenome. One example is a known human carcinogen 1,3-butadiene which acts primarily by a genotoxic mechanism, but also disrupts the chromatin structure by altering patterns of cytosine DNA methylation and histone modifications. Sex-specific differences in 1,3-butadiene-induced genotoxicity and carcinogenicity are well established; however, it remains unknown whether 1,3-butadiene-associated epigenetic alterations are also sex dependent. Therefore, we tested the hypothesis that inhalational exposure to 1,3-butadiene will result in sex-specific epigenetic alterations. DNA damage and epigenetic effects of 1,3-butadiene were evaluated in liver, lung, and kidney tissues of male and female mice of two inbred strains (C57BL/6J and CAST/EiJ). Mice were exposed to 0 or 425 ppm of 1,3-butadiene by inhalation (6 h/day, 5 days/week) for 2 weeks. Strain- and tissue-specific differences in 1,3-butadiene-induced DNA adducts and crosslinks were detected in the liver, lung and kidney; however, significant sex-specific differences in DNA damage were observed in the lung of C57BL/6J mice only. In addition, we assessed expression of the DNA repair genes and observed a marked upregulation of Mgmt in the kidney in female C57BL/6J mice. Sex-specific epigenetic effects of 1,3-butadiene exposure were evident in alterations of cytosine DNA methylation and histone modifications in the liver and lung in both strains. Specifically, we observed a loss of cytosine DNA methylation in the liver and lung of male and female 1,3-butadiene-exposed C57BL/6J mice, whereas hypermethylation was found in the liver and lung in 1,3-butadiene-exposed female CAST/EiJ mice. Our findings suggest that strain- and sex-specific effects of 1,3-butadiene on the epigenome may contribute to the known differences in cancer susceptibility.
PubMed ID: 30552462
MeSH Terms: Animals; Butadienes/metabolism; Butadienes/toxicity*; DNA; DNA Adducts/metabolism; DNA Damage; DNA Methylation; Epigenesis, Genetic*; Female; Inhalation Exposure; Kidney; Liver; Lung; Male; Mice; Mice, Inbred C57BL; Mutagens/metabolism; Mutagens/toxicity*; Sex Characteristics; Toxicity Tests