Epigenetic Events Determine Tissue-Specific Toxicity of Inhalational Exposure to the Genotoxic Chemical 1,3-Butadiene in Male C57BL/6J Mice

Abstract

1,3-Butadiene (BD), a widely used industrial chemical and a ubiquitous environmental pollutant, is a known human carcinogen. Although genotoxicity is an established mechanism of the tumorigenicity of BD, epigenetic effects have also been observed in livers of mice exposed to the chemical. To better characterize the diverse molecular mechanisms of BD tumorigenicity, we evaluated genotoxic and epigenotoxic effects of BD exposure in mouse tissues that are target (lung and liver) and non-target (kidney) for BD-induced tumors. We hypothesized that epigenetic alterations may explain, at least in part, the tissue-specific differences in BD tumorigenicity in mice. We evaluated the level of N-7-(2,3,4-trihydroxybut-1-yl)guanine adducts and 1,4-bis-(guan-7-yl)-2,3-butanediol crosslinks, DNA methylation, and histone modifications in male C57BL/6 mice exposed to filtered air or 425 ppm of BD by inhalation (6 h/day, 5 days/week) for 2 weeks. Although DNA damage was observed in all three tissues of BD-exposed mice, variation in epigenetic effects clearly existed between the kidneys, liver, and lungs. Epigenetic alterations indicative of genomic instability, including demethylation of repetitive DNA sequences and alterations in histone-lysine acetylation, were evident in the liver and lung tissues of BD-exposed mice. Changes in DNA methylation were insignificant in the kidneys of treated mice, whereas marks of condensed heterochromatin and transcriptional silencing (histone-lysine trimethylation) were increased. These modifications may represent a potential mechanistic explanation for the lack of tumorigenesis in the kidney. Our results indicate that differential tissue susceptibility to chemical-induced tumorigenesis may be attributed to tissue-specific epigenetic alterations.

Application of epigenetic data in human health risk assessment

“…• Significant variability in tissues and experimental paradigms can exist, so confidence in data interpretation from non-target tissue, in vitro cell lines or, to a lesser extent, from primary cell cultures will be increased by coherence with other evidence streams [38];…”

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

“…The extent of global DNA hypomethylation was strain-specific and also varied across target and non-target tissues of 1,3-butadiene-induced carcinogenesis [161, 162]. For example, a loss of methylation within repetitive DNA elements was observed in the lung and liver (target tissues of carcinogenesis), but not in the kidney (non-target tissue of carcinogenesis) in C57BL/6J mice.…”

“…Loss of these histone modifications is known to impair the maintenance of proper chromatin structure, diminish cellular maintenance and regulation of the cell cycle, disrupt the balance between cell proliferation and differentiation, and severely reduce cell viability [163, 164]. These histone modifications in the liver have also been shown to vary across several inbred mouse strains, as well as in target and non-target tissues of carcinogenesis [161, 162]. Interestingly, an increase in the repressive histone marks H3K9me3, H3K27me3, and H4K20me3 was observed in the kidney, a non-target tissue of carcinogenesis, in C57BL/6J mice that were subjected to short-term exposure to 1,3-butadiene.…”

Response of transposable elements to environmental stressors

“…Importantly, this study demonstrated the dose-dependent response, where exposure to higher concentrations of 1.3-butadiene was associated with the more pronounced loss of methylation within the TEs. Subsequent studies have shown that these effects were strain- [161] and tissue- [162] specific. Furthermore, 1,3-butadiene-induced hypomethylation of TEs was associated with their subsequent reactivation [160].…”