Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location

Abstract

Particulate air pollution is widespread, yet we have little understanding of the long-term health implications associated with exposure. We investigated DNA damage, mutation, and methylation in gametes of male mice exposed to particulate air pollution in an industrial/ urban environment. C57BL/CBA mice were exposed in situ to ambient air near two integrated steel mills and a major highway, alongside control mice breathing high-efficiency air particulate (HEPA) filtered ambient air. PCR analysis of an expanded simple tandem repeat (ESTR) locus revealed a 1.6-fold increase in sperm mutation frequency in mice exposed to ambient air for 10 wks, followed by a 6-wk break, compared with HEPA-filtered air, indicating that mutations were induced in spermatogonial stem cells. DNA collected after 3 or 10 wks of exposure did not exhibit increased mutation frequency. Bulky DNA adducts were below the detection threshold in testes samples, suggesting that DNA reactive chemicals do not reach the germ line and cause ESTR mutation. In contrast, DNA strand breaks were elevated at 3 and 10 wks, possibly resulting from oxidative stress arising from exposure to particles and associated airborne pollutants. Sperm DNA was hypermethylated in mice breathing ambient relative to HEPAfiltered air and this change persisted following removal from the environmental exposure. Increased germ-line DNA mutation frequencies may cause population-level changes in genetic composition and disease. Changes in methylation can have widespread repercussions for chromatin structure, gene expression and genome stability. Potential health effects warrant extensive further investigation.DNA adducts ͉ DNA strand breaks ͉ tandem repeat mutation C ombustion of fossil fuels results in the production of complex mixtures of chemicals that are released into the environment and potentially affect millions of people globally. Previous work demonstrated that the offspring of wild birds breeding near integrated steel mills on the North American Great Lakes inherited increased numbers of tandem repeat DNA sequence mutations compared with those from areas without steel mills (1, 2). Subsequent studies investigated expanded simple tandem repeat (ESTR) mutation in outbred laboratory mice caged near two integrated steel mills and a major highway in Hamilton, Ontario, Canada, and at a rural reference site (3, 4). Using a pedigree approach (5), a significant increase in germ-line mutation rate was found in mice housed in the industrial environment compared with the reference site. The majority of mutations were transmitted through the paternal germ line. High-efficiency particulate-air (HEPA) filtration of the ambient air resulted in a significant reduction in mutation frequency, down to levels measured at the reference location (4). Therefore, the particulate fraction of air in this industrial location was largely responsible for the mutagenic hazard.These findings show that chemical pollutants may cause heritable mutation. Further research is required to confirm these results...

DNA adduct kinetics in reproductive tissues of DNA repair proficient and deficient male mice after oral exposure to benzo(a)pyrene

“…The difference between the adduct levels in testes and lung tissue was found previously [Yauk et al, 2008]. It is possible that B[a]P does not reach the testes as well as lung tissue after exposure by oral gavage, and/or that testes may contain lower concentrations of enzymes converting B[a]P into DNA binding derivatives.…”

Global and gene‐specific promoter methylation changes are related to anti‐B[a]PDE‐DNA adduct levels and influence micronuclei levels in polycyclic aromatic hydrocarbon‐exposed individuals

“…39 These and our findings are in line with the global hypermethylation found in the sperm of mice exposed for 3 weeks to particulate air pollution of urban/ industrial source, in which PAH exposure was confirmed by the presence of elevated PAH-DNA adduct levels in the mice lungs. 15 Moreover, following in vitro chronic exposure to B[a]P, global DNA hypermethylation was associated to DNMT1 overexpression in mouse embryonic fibroblasts. 14 DNMTs (chiefly DNMT1) were found upregulated during DNA damage and bind with high affinity to DNA lesions.…”

“…13 Global DNA hypermethylation following in vitro chronic exposure to B[a]P was recently revealed in mouse embryonic fibroblasts and was associated to mutation as a consequence of genetic instability. 14,15 PBLs, although not considered target cells for PAH(B[a]P)-induced lung tumorigenesis, can be easily obtained from human subjects and their genetic (PAH(B[a]P)-DNA adducts) and epigenetic alterations (methylation) are correlated with levels in target tissues (e.g., lung). [16][17][18] Moreover, high levels of adduct and micronuclei (as markers of chromosome instability 19 ) and p53 hypomethylation in PBLs are predictive of lung cancer risk.…”

Low dose effects of dichlorodiphenyltrichloroethane (DDT) on gene transcription and DNA methylation in the hypothalamus of young male rats: implication of hormesis-like effects

“…Consequently, the two main roles of DNA methylation are thought to be maintenance of genome stability (Eden et al, 2003) and control of gene transcription (Bird, 2002). In higher organisms, which have functionally different cell types, DNA methylation is thought to be important in the control of gene expression, and changes in DNA methylation can dramatically affect chromatin structure and genome stability (Yauk et al, 2008). Franco et al (2008) indicated that reactive oxygen spemultistage process of carcinogenesis by both genetic and epigenetic mechanisms.…”