Sex-specific differences in genotoxic and epigenetic effects of 1,3-butadiene among mouse tissues

Lewis, Lauren; Chappell, Grace A.; Kobets, Tetyana; O’Brian, Bridget E.; Sangaraju, Dewakar; Kosyk, Oksana; Bodnar, Wanda M.; Tretyakova, Natalia; Pogribny, Igor P.; Rusyn, Ivan

doi:10.1007/s00204-018-2374-x

Cited by 14 publications

(16 citation statements)

References 49 publications

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“…Figure A shows the global correlation matrix that includes phenotypes for all strains and tissues. This analysis shows that tissue-specific responses to 1,3-butadiene exposure are most evident and in agreement with previous observations. , As noted previously, levels of THB-Gua were most similar in the lung and kidney and significantly correlated in all three organs. Among the epigenetic alterations evaluated, the effect of 1,3-butadiene on cytosine DNA methylation and histone modifications was most prominent and concordant among the strains in the lung and liver, target organs for 1,3-butadiene carcinogenicity (Figure B,C).…”

Section: Resultssupporting

confidence: 92%

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Population-Based Analysis of DNA Damage and Epigenetic Effects of 1,3-Butadiene in the Mouse

Lewis

Borowa-Mazgaj

Conti

et al. 2019

Chem. Res. Toxicol.

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Metabolism of 1,3-butadiene, a known human and rodent carcinogen, results in formation of reactive epoxides, a key event in its carcinogenicity. Although mice exposed to 1,3-butadiene present DNA adducts in all tested tissues, carcinogenicity is limited to liver, lung, and lymphoid tissues. Previous studies demonstrated that strain-and tissue-specific epigenetic effects in response to 1,3-butadiene exposure may influence susceptibly to DNA damage and serve as a potential mechanism of tissue-specific carcinogenicity. This study aimed to investigate interindividual variability in the effects of 1,3-butadiene using a population-based mouse model. Male mice from 20 Collaborative Cross strains were exposed to 0 or 635 ppm 1,3-butadiene by inhalation (6 h/day, 5 days/week) for 2 weeks. We evaluated DNA damage and epigenetic effects in target (lung and liver) and nontarget (kidney) tissues of 1,3-butadiene-induced carcinogenesis. DNA damage was assessed by measuring N-7-(2,3,4-trihydroxybut-1-yl)-guanine (THB-Gua) adducts. To investigate global histone modification alterations, we evaluated the trimethylation and acetylation of histones H3 and H4 across tissues. Changes in global cytosine DNA methylation were evaluated from the levels of methylation of LINE-1 and SINE B1 retrotransposons. We quantified the degree of variation across strains, deriving a chemical-specific human variability factor to address population variability in carcinogenic risk, which is largely ignored in current cancer risk assessment practice. Quantitative trait locus mapping identified four candidate genes related to chromatin remodeling whose variation was associated with interstrain susceptibility. Overall, this study uses 1,3-butadiene to demonstrate how the Collaborative Cross mouse population can be used to identify the mechanisms for and quantify the degree of interindividual variability in tissue-specific effects that are relevant to chemically induced carcinogenesis.

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Section: Resultssupporting

confidence: 92%

“…In previous studies, strain- and tissue-specific effects have also been identified. C57BL/6J mice demonstrated loss of methylation of SINE B1 in the liver, whereas CAST/EiJ mice showed loss of methylation in the lung …”

Section: Resultsmentioning

confidence: 99%

Population-Based Analysis of DNA Damage and Epigenetic Effects of 1,3-Butadiene in the Mouse

Lewis

Borowa-Mazgaj

Conti

et al. 2019

Chem. Res. Toxicol.

Self Cite

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“…Our finding that the female bias in Trim24 expression is lost in CAST mouse liver, where Trim24 shows high expression in males (S2 Fig), suggests sex differences in hepatic tumorigenesis may be reduced in CAST mice. B6 and CAST mice differ in their sensitivity to genotoxic damage induced by 1,3-butadiene, which induces strain-dependent epigenetic and transcriptomic changes in liver, lung and kidney [90,91]; however, differences in hepatocellular carcinoma between mouse strains [92,93] have not been determined for B6 vs CAST mice.…”

Section: Plos Geneticsmentioning

confidence: 99%

Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model

2021

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Sex differences in gene expression are widespread in the liver, where many autosomal factors act in tandem with growth hormone signaling to regulate individual variability of sex differences in liver metabolism and disease. Here, we compare hepatic transcriptomic and epigenetic profiles of mouse strains C57BL/6J and CAST/EiJ, representing two subspecies separated by 0.5–1 million years of evolution, to elucidate the actions of genetic factors regulating liver sex differences. We identify 144 protein coding genes and 78 lncRNAs showing strain-conserved sex bias; many have gene ontologies relevant to liver function, are more highly liver-specific and show greater sex bias, and are more proximally regulated than genes whose sex bias is strain-dependent. The strain-conserved genes include key growth hormone-dependent transcriptional regulators of liver sex bias; however, three other transcription factors, Trim24, Tox, and Zfp809, lose their sex-biased expression in CAST/EiJ mouse liver. To elucidate the observed strain specificities in expression, we characterized the strain-dependence of sex-biased chromatin opening and enhancer marks at cis regulatory elements (CREs) within expression quantitative trait loci (eQTL) regulating liver sex-biased genes. Strikingly, 208 of 286 eQTLs with strain-specific, sex-differential effects on expression were associated with a complete gain, loss, or reversal of the sex differences in expression between strains. Moreover, 166 of the 286 eQTLs were linked to the strain-dependent gain or loss of localized sex-biased CREs. Remarkably, a subset of these CREs apparently lacked strain-specific genetic variants yet showed coordinated, strain-dependent sex-biased epigenetic regulation. Thus, we directly link hundreds of strain-specific genetic variants to the high variability in CRE activity and expression of sex-biased genes and uncover underlying genetically-determined epigenetic states controlling liver sex bias in genetically diverse mouse populations.

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“…S2), suggests sex differences in hepatic tumorigenesis may be reduced in CAST mice. B6 and CAST mice differ in their sensitivity to genotoxic damage induced by 1,3-butadiene, which induces strain-dependent epigenetic and transcriptomic changes in liver, lung and kidney [89,90]; however, differences in hepatocellular carcinoma between mouse strains [91,92] have not been determined for B6 vs CAST mice.…”

Section: Discussionmentioning

confidence: 99%

Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model

Matthews

Waxman

2021

Preprint

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Sex differences in gene expression are widespread in the liver, where a large number of autosomal factors act in tandem with growth hormone signaling to regulate individual variability of sex differences in liver metabolism and disease. Here, we compare hepatic transcriptomic and epigenetic profiles of mouse strains C57Bl/6J and CAST/EiJ, representing two subspecies separated by 0.5-1 million years of evolution, to elucidate the actions of genetic factors regulating liver sex differences. We identify 144 protein coding genes and 78 lncRNAs showing strain-conserved sex bias; many have gene ontologies relevant to liver function, are more highly liver-specific and show greater sex bias, and are more proximally regulated than genes whose sex bias is strain-dependent. The strain-conserved genes include key growth hormone-dependent transcriptional regulators of liver sex bias; however, three other transcription factors, Trim24 , Tox , and Zfp809, lose sex-biased expression in CAST/EiJ mouse liver. To elucidate these strain specificities in expression, we characterized the strain-dependence of sex-biased chromatin opening and enhancer marks at cis regulatory elements (CREs) within expression quantitative trait loci (eQTL) regulating liver sex-biased genes. Strikingly, 208 of 286 eQTLs with strain-specific, sex-differential effects on expression were associated with a complete gain, loss, or reversal of expression sex differences between strains. Moreover, 166 of the 286 eQTLs were linked to the strain-specific gain or loss of localized sex-biased CREs. Remarkably, a subset of these CREs lacked strain-specific genetic variants yet showed coordinated, strain-dependent sex-biased epigenetic regulation. Thus, we directly link hundreds of strain-specific genetic variants to the high variability in CRE activity and expression of sex-biased genes, and uncover underlying genetically-determined epigenetic states controlling liver sex bias in genetically diverse mouse populations.

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Sex-specific differences in genotoxic and epigenetic effects of 1,3-butadiene among mouse tissues

Cited by 14 publications

References 49 publications

Population-Based Analysis of DNA Damage and Epigenetic Effects of 1,3-Butadiene in the Mouse

Population-Based Analysis of DNA Damage and Epigenetic Effects of 1,3-Butadiene in the Mouse

Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model

Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model

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