Epigenetic Alterations in Liver of C57BL/6J Mice after Short-Term Inhalational Exposure to 1,3-Butadiene

Background1,3-Butadiene (BD) is a high-volume industrial chemical and a known human carcinogen. The main mode of BD carcinogenicity is thought to involve formation of genotoxic epoxides.ObjectivesIn this study we tested the hypothesis that BD may be epigenotoxic (i.e., cause changes in DNA and histone methylation) and explored the possible molecular mechanisms for the epigenetic changes.Methods and ResultsWe administered BD (6.25 and 625 ppm) to C57BL/6J male mice by inhalation for 2 weeks (6 hr/day, 5 days a week) and then examined liver tissue from these mice for signs of toxicity using histopathology and gene expression analyses. We observed no changes in mice exposed to 6.25 ppm BD, but glycogen depletion and dysregulation of hepatotoxicity biomarker genes were observed in mice exposed to 625 ppm BD. We detected N-7-(2,3,4-trihydroxybut-1-yl)guanine (THB-Gua) adducts in liver DNA of exposed mice in a dose-responsive manner, and also observed extensive alterations in the cellular epigenome in the liver, including demethylation of global DNA and repetitive elements and a decrease in histone H3 and H4 lysine methylation. In addition, we observed down-regulation of DNA methyltransferase 1 (Dnmt1) and suppressor of variegation 3–9 homolog 1, a histone lysine methyltransferase (Suv39h1), and up-regulation of the histone demethylase Jumonji domain 2 (Jmjd2a), proteins responsible for the accurate maintenance of the epigenetic marks. Although the epigenetic effects were most pronounced in the 625-ppm exposure group, some effects were evident in mice exposed to 6.25 ppm BD.ConclusionsThis study demonstrates that exposure to BD leads to epigenetic alterations in the liver, which may be important contributors to the mode of BD carcinogenicity

Epigenetic Mechanisms of Mouse Interstrain Variability in Genotoxicity of the Environmental Toxicant 1,3-Butadiene

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

Antarctic ozone enhancement during the 2019 sudden stratospheric warming event

International audienceWe analyze the 2019 sudden stratospheric warming event that occurred in the Southern Hemisphere through its impact on the Antarctic ozone. Using temperature, ozone, and nitric acid data from the Infrared Atmospheric Sounding Interferometer (IASI), our results show that the average increase in stratospheric temperature reached a maximum of 34.4° on September 20th in the [60‐90]°S latitude range when compared to the past three years. Dynamical parameters suggest a locally‐reversed and weakened zonal winds and a shift in the location of the polar jet vortex. This led to air masses mixing, to a reduced polar stratospheric clouds formation detected at a ground station, and as such to lower ozone and nitric acid depletion. 2019 total ozone columns for the months of September, October, and November, were on average higher by 29%, 28%, and 26% respectively when compared to the 11‐year average of the same months