Paternal exposure to benzo(a)pyrene induces genome-wide mutations in mouse offspring

Abstract

Understanding the effects of environmental exposures on germline mutation rates has been a decades-long pursuit in genetics. We used next-generation sequencing and comparative genomic hybridization arrays to investigate genome-wide mutations in the offspring of male mice exposed to benzo(a)pyrene (BaP), a common environmental pollutant. We demonstrate that offspring developing from sperm exposed during the mitotic or post-mitotic phases of spermatogenesis have significantly more de novo single nucleotide variants (1.8-fold; P < 0.01) than controls. Both phases of spermatogenesis are susceptible to the induction of heritable mutations, although mutations arising from post-fertilization events are more common after post-mitotic exposure. In addition, the mutation spectra in sperm and offspring of BaP-exposed males are consistent. Finally, we report a significant increase in transmitted copy number duplications ( P = 0.001) in BaP-exposed sires. Our study demonstrates that germ cell mutagen exposures induce genome-wide mutations in the offspring that may be associated with adverse health outcomes.

DNA Copy Number Variations as Markers of Mutagenic Impact

“…Germ cells mutations may occur as a result of errors in DNA replication during gametogenesis, inefficient repair of DNA damages or exposure to mutagens during lifetime [61]. Yet we still know little about the role of environmental agents in the etiology of heritable mutations because germ cell mutations are rare (10 −8 per nucleotide) and difficult to detect because of technological limitations [60]. Many rodent germ cell mutagens have been identified; however, there are no accepted human germ cell mutagens [62].…”

“…The consequences of paternal exposure to benzo(a)pyrene (BaP), a ubiquitous environmental pollutant, on the mouse germline was studied using NGS and aCGH [60]. Paternal exposure to BaP induces single-nucleotide variants, indels and CNV in the offspring.…”

Heritable hazards of smoking: Applying the “clean sheet” framework to further science and policy

“…An additional human study byLaubenthal et al (2012) found that paternal preconception smoking was positively associated with single-and double-strand DNA breaks in the cord blood of their offspring. These human findings are complemented by a recent mouse study byBeal et al (2019) showing that paternal exposure to B[a]P significantly increased copy number duplications and de novo mutations in the offspring. Thus, there is growing evidence that paternal tobacco smoking and exposure to the components of tobacco smoke lead to an increase in the number of mutations that offspring inherit.…”

“…These human findings are complemented by a recent mouse study by Beal et al . (2019) showing that paternal exposure to B[ a ]P significantly increased copy number duplications and de novo mutations in the offspring. Thus, there is growing evidence that paternal tobacco smoking and exposure to the components of tobacco smoke lead to an increase in the number of mutations that offspring inherit.…”

Mutation Induction in Humans and Mice: Where Are We Now?

“…Their elevated frequency among the offspring of irradiated males can be attributed to the delayed or compromised repair of radiation-induced clustered damaged sites [43]. The results of a recent study also show significant genome-wide changes in the spectrum of mutations in the germline of male mice exposed to chemical mutagen benzo(a)pyrene [44].…”