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Link to original content: http://pubmed.ncbi.nlm.nih.gov/21602187
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Comparative Study
. 2011 Aug;122(2):448-56.
doi: 10.1093/toxsci/kfr133. Epub 2011 May 20.

Epigenetic mechanisms of mouse interstrain variability in genotoxicity of the environmental toxicant 1,3-butadiene

Igor Koturbash  1 , Anne Scherhag, Jessica Sorrentino, Kenneth Sexton, Wanda Bodnar, James A Swenberg, Frederick A Beland, Fernando Pardo-Manuel Devillena, Ivan Rusyn, Igor P Pogribny
Affiliations
Comparative Study

Epigenetic mechanisms of mouse interstrain variability in genotoxicity of the environmental toxicant 1,3-butadiene

Igor Koturbash et al. Toxicol Sci. 2011 Aug.

Abstract

1,3-Butadiene (BD) is a common environmental contaminant classified as "carcinogenic to humans." Formation of BD-induced DNA adducts plays a major role in its carcinogenicity. BD is also an epigenotoxic agent (i.e., it affects DNA and histone methylation in the liver). We used a panel of genetically diverse inbred mice (NOD/LtJ, CAST/EiJ, A/J, WSB/EiJ, PWK/PhJ, C57BL/6J, and 129S1/SvImJ) to assess whether BD-induced genotoxic and epigenotoxic events may be subject to interstrain differences. Mice (male, 7 weeks) were exposed via inhalation to 0 or 625 ppm BD for 6 h/day and 5 days/week for 2 weeks and liver BD-DNA adducts, epigenetic alterations, and liver toxicity were assessed. N-7-(2,3,4-trihydroxybut-1-yl)-guanine adducts were detected in all strains after exposure, yet BD-induced DNA damage in CAST/EiJ mice was two to three times lower. Epigenetic effects of BD were most prominent in C57BL/6J mice where loss of global DNA methylation and loss of trimethylation of histone H3 lysine 9, histone H3 lysine 27, and histone H4 lysine 20, accompanied by dysregulation of liver gene expression indicative of hepatotoxicity, were found. Interestingly, we observed an increase in histone methylation in the absence of changes in gene expression and DNA methylation in CAST/EiJ strain. We hypothesized that mitigated genotoxicity of BD in CAST/EiJ mice may be due to chromatin condensation. Indeed, we show that in response to BD exposure, chromatin condensation occurs in CAST/EiJ, whereas the opposite effect is observed in C57BL/6J mice. These findings demonstrate that interstrain susceptibility to genotoxicity by a well-known environmental carcinogen may be due to strain-specific epigenetic events in response to the exposure.

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Figures

FIG. 1.
FIG. 1.
Amounts of THB-Gua-BD adducts in liver DNA from mice exposed to 0- or 625-ppm BD. Data are presented as mean ± SD (n = 5). Asterisk and ampersand (* and &) denote significant (p < 0.05) differences in the same DNA adduct as compared with the corresponding strain's control mice or as compared with BD-treated mice of other strains, respectively.
FIG. 2.
FIG. 2.
Effects of BD exposure on the extent of DNA methylation in mouse liver. (A) Loss of global DNA methylation in the livers of BD-exposed mice as measured by a cytosine extension ([3H]dCTP incorporation) DNA methylation assay. (B) Loss of LINE1 repetitive elements methylation in the livers of BD-exposed mice as measured by a methylation-sensitive McrBC-qPCR assay. Data are presented as fold change in BD (625 ppm)-exposed mice relative to the control mice in each strain, mean ± SD (n = 5). Asterisks (*) denote a significant (p < 0.05) difference from the corresponding strain's control group.
FIG. 3.
FIG. 3.
Effects of BD exposure on histone lysine trimethylation in mouse liver. Histone H3K4me3 (A), histone H3K9me3 (B), histone H3K27me3 (C), and histone H4K20me3 (D) levels were assessed by immunostaining using specific antibodies against trimethylated histones. Equal sample loading was confirmed by immunostaining against total histone H3 or H4 where appropriate (data not shown). Densitometry analysis of the immunostaining results is shown as change in methylation levels relative to control after correction for the total amount of each histone in the individual samples. Data are presented as mean ± SD (n = 5). Asterisks (*) denote a significant (p < 0.05) difference from the corresponding strain's control group.
FIG. 4.
FIG. 4.
Heatmap of differentially expressed hepatotoxicity biomarker genes in the livers of control and BD-exposed C57BL/6J, A/J, and CAST/EiJ mice. Gene expression was determined in total liver RNA from control and BD-exposed mice (n = 3 from each group). A heatmap (average of fold change between control and exposed groups within each strain) of genes identified as significant (p < 0.05) and changing in expression by at least 1.5-fold is shown. The color bar identifies up and downregulated genes as indicated. See Supplementary table 1 for a list of genes and gene expression values.
FIG. 5.
FIG. 5.
Analysis of chromatin structure in the livers of control and BD-exposed C57BL/6J, A/J, and CAST/EiJ mice. (A) Chromatin structure in the livers of control and BD-exposed C57BL/6J, A/J, and CAST/EiJ mice was determined by analyzing the accessibility of CCGG sites within nucleosomal DNA to methylation. The extent of [3H]dCTP incorporation into DNA is directly proportional to changes in chromatin condensation. (B) Total liver RNA from control mice (white bars) and mice exposed to 625-ppm BD (black bars) was used to evaluate transcript abundance of Ezh2. Data are presented as mean ± SD (n = 5). Asterisks (*) denote a significant (p < 0.05) difference from the corresponding strain's control group.
FIG. 6.
FIG. 6.
Expression of LINE1 and major and minor satellites in the livers of control and BD-exposed CAST/EiJ, A/J, and C57BL/6J mice. Total liver RNA from control mice (white bars) and mice exposed to 625-ppm BD (black bars) was used to evaluate transcript abundance of LINE1, as well as major and minor satellites. Data are presented as mean ± SD (n = 5). Asterisks (*) denote a significant (p < 0.05) difference from the corresponding strain's control group.
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