Whole DNA methylome profiling in mice exposed to secondhand smoke

Abstract

Aberration of DNA methylation is a prime epigenetic mechanism of carcinogenesis. Aberrant DNA methylation occurs frequently in lung cancer, with exposure to secondhand smoke (SHS) being an established risk factor. The causal role of SHS in the genesis of lung cancer, however, remains elusive. To investigate whether SHS can cause aberrant DNA methylation in vivo, we have constructed the whole DNA methylome in mice exposed to SHS for a duration of 4 mo, both after the termination of exposure and at ensuing intervals post-exposure (up to 10 mo). Our genome-wide and gene-specific profiling of DNA methylation in the lung of SHS-exposed mice revealed that all groups of SHS-exposed mice and controls share a similar pattern of DNA methylation. Furthermore, the methylation status of major repetitive DNA elements, including long-interspersed nuclear elements (LINE L1), intracisternal A particle long-terminal repeat retrotransposons (IAP-LTR), and short-interspersed nuclear elements (SINE B1), in the lung of all groups of SHS-exposed mice and controls remains comparable. The absence of locus-specific gain of DNA methylation and global loss of DNA methylation in the lung of SHS-exposed mice within a timeframe that precedes neoplastic-lesion formation underscore the challenges of lung cancer biomarker development. Identifying the initiating events that cause aberrant DNA methylation in lung carcinogenesis may help improve future strategies for prevention, early detection and treatment of this highly lethal disease.

Exposure of mice to secondhand smoke elicits both transient and long‐lasting transcriptional changes in cancer‐related functional networks

“…We have also verified that male C57BL/6 mice are sufficiently sensitive to the genotoxic and epigenetic effects of chemical carcinogens . Our genome‐wide and epigenome‐wide studies in these mice have also shown that five animals per experimental/control groups are sufficient to yield statistically significant results . In our preliminary studies, we have also confirmed that short‐term and long‐term effects of SHS can be established in this mouse model 1 month and 7 months, respectively, post‐treatment.…”

“…Work in our laboratory has shown that SHS is a comparatively weak mutagen and carcinogen, whose biological effects can be established in the C57BL/6 mice with high specificity . We have also verified that male C57BL/6 mice are sufficiently sensitive to the genotoxic and epigenetic effects of chemical carcinogens . Our genome‐wide and epigenome‐wide studies in these mice have also shown that five animals per experimental/control groups are sufficient to yield statistically significant results .…”

“…We note that although C57BL/6 mice are less sensitive to pulmonary carcinogens as compared to other strains, such as A/J mice, the latter mice, however, develop spontaneously lung tumors, e.g ., adenomas, at high frequencies . Work in our laboratory has shown that SHS is a comparatively weak mutagen and carcinogen, whose biological effects can be established in the C57BL/6 mice with high specificity . We have also verified that male C57BL/6 mice are sufficiently sensitive to the genotoxic and epigenetic effects of chemical carcinogens .…”

“…Research in our laboratory and others' (reviewed in Refs. ]) has shown that tobacco smoke or its constituents cause genetic and epigenetic alterations that may lead to transcriptional changes in cancer‐related genes.…”

World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung

“…Evidence suggests that inflammatory gene expression is regulated, in part, by global and gene-specific DNA methylation and histone modifications (Adcock and Lee, 2006; Tommasi et al, 2012). Alu repetitive elements (B1 element in mouse) and Line-1 element have been used as surrogate markers for estimating global DNA methylation levels (Yang et al, 2004; Weisenberger et al, 2005).…”