Effects on the ApoE-/- mouse lung epigenome of exposure to a candidate modified risk tobacco product, THS 2.2, compared with conventional cigarettes


Abstract

Smoking cigarettes is a major risk factor in the development and progression of cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD). Candidate modified risk tobacco products (MRTPs) are being developed to reduce smoking-related health risks. The goal of this study was to investigate over an 8-month period the effects of exposure to conventional cigarette smoke (CS) or to the aerosol of a candidate MRTP, Tobacco Heating System (THS) 2.2, on DNA methylation in the lung of apolipoprotein E-deficient mice. In addition to chronic exposure, cessation or switching to THS 2.2 after 2 months of CS exposure were also assessed. High-throughput sequencing of bisulfite treated DNA revealed a gradual increase in the number of hypermethylated CpG loci in DNA extracted from lungs of mice exposed to CS. The number of hypermethylated CpG loci after 2 month exposure to THS 2.2 aerosol (nicotine concentration matched to CS, 29.9 mg/m3) also increased, however, hypermethylation was limited from 3 month on. Cessation or switching to THS 2.2 both resulted in a decrease in the number of hypermethylated CpG loci. In conclusion, this mouse model indicated that initial exposure to CS or THS 2.2 resulted in hypermethylation of CpG loci in lung, and that continuous exposure to CS further increased the number of hypermethylated CpG loci while continuous exposure to THS 2.2 reverted the CpG methylation level to the level observed in the lung of mice exposed to fresh air. Likewise, cessation or switching to THS 2.2 reverted the hypermethylation of CpG loci.