Next generation sequencing of benzo(a)pyrene-induced lacZ mutants identifies a germ cell-specific mutation spectrum

O’Brien, Jason M.; Beal, Marc A.; Yauk, Carole L.; Marchetti, Francesco

doi:10.1038/srep36743

Cited by 13 publications

(17 citation statements)

References 53 publications

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“…Compared with exposure in adults (data from Beal et al. 2015 and O’Brien et al. 2016b), in utero exposure results in a higher degree of clonal expansion.…”

Section: Resultsmentioning

confidence: 99%

In Utero Exposure to Benzo[ a ]Pyrene Increases Mutation Burden in the Soma and Sperm of Adult Mice

Meier

O’Brien

Beal

et al. 2017

Environ Health Perspect

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Background:Mosaicism, the presence of genetically distinct cell populations within an organism, has emerged as an important contributor to disease. Mutational events occurring during embryonic development can cause mosaicism in any tissue, but the influence of environmental factors on levels of mosaicism is unclear.Objectives:We investigated whether in utero exposure to the widespread environmental mutagen benzo[a]pyrene (BaP) has an impact on the burden and distribution of mutations in adult mice.Methods:We used the Muta™Mouse transgenic rodent model to quantify and characterize mutations in the offspring of pregnant mice exposed to BaP during postconception days 7 through 16, covering the major period of organogenesis in mice. Next-generation DNA sequencing was then used to determine the spectrum of mutations induced in adult mice that were exposed to BaP during fetal development.Results:Mutation frequency was significantly increased in the bone marrow, liver, brain, and sperm of first filial generation (F1) males. Developing embryos accumulated more mutations and exhibited higher proportions of mosaicism than exposed adults, particularly in the brain. Decreased sperm count and motility revealed additional negative impacts on the reproductive function of F1 males.Conclusion:In utero exposure to environmental mutagens contributes to somatic and germline mosaicism, permanently affecting both the genetic health of the F1 and the population gene pool.Citation:Meier MJ, O’Brien JM, Beal MA, Allan B, Yauk CL, Marchetti F. 2017. In utero exposure to benzo[a]pyrene increases mutation burden in the soma and sperm of adult mice. Environ Health Perspect 125:82–88; http://dx.doi.org/10.1289/EHP211

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“…Compared with exposure in adults (data from Beal et al. 2015 and O’Brien et al. 2016b), in utero exposure results in a higher degree of clonal expansion.…”

Section: Resultsmentioning

confidence: 99%

In Utero Exposure to Benzo[ a ]Pyrene Increases Mutation Burden in the Soma and Sperm of Adult Mice

Meier

O’Brien

Beal

et al. 2017

Environ Health Perspect

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“…In BP-or AA-treated animals, mutations within G:C base pairs were frequently observed in the CpG context, but were not clearly observed in MNU, ENU, and DEN-treated samples, suggesting that this phenomenon is specific only to certain mutagens. Mutagens such as BP and aflatoxin B1 (AFB1) could reportedly preferentially form adducts with G bases in the methylated CpG context (Chen et al 1998;Weisenberger and Romano 1999;Beal et al 2015;O'Brien et al 2016). Therefore, it can be hypothesized that these kinds of mutagens could possibly influence epigenetic regulation, by introducing mutations into the methylated genomic region.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the G:C mutations observed in samples exposed to BP or AA were apparently more frequently observed in the CpG context. This might be attributable to the previously reported tendency of mutagens to bind to methylated CpG during in vitro and in vivo analysis in mice (Chen et al 1998;Weisenberger and Romano 1999;Beal et al 2015;O'Brien et al 2016).…”

Section: Analysis Of Trinucleotide Mutational Signatures In Gpt Deltamentioning

confidence: 91%

Genome-wide somatic mutation analysis via Hawk-Seq™ reveals mutation profiles associated with chemical mutagens

et al. 2019

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It is difficult to identify mutagen-induced genome-wide somatic mutations using next generation sequencing; hence, mutagenic features of each mutagen and their roles in cancer development require further elucidation. We described Hawk-Seq™, a highly accurate genome sequencing method and the optimal conditions, for using it to construct libraries that would enable the accurate (c.a. 1 error/10 7-10 8 bp) and efficient survey of genome-wide mutations. Genomic mutations in gpt delta mice or Salmonella typhimurium TA100 exposed to methylnitrosourea (MNU), ethylnitrosourea (ENU), diethylnitrosamine (DEN), benzo[a]pyrene (BP), and aristolochic acid (AA) were profiled using Hawk-Seq™ to analyse positions, substitution patterns, or frequencies. The resultant vast mutation data provided high-resolution mutational signatures, including for minor mutational fractions (e.g. G:C>A:T by AA), which enabled the clarification of the mutagenic features of all mutagens. The 96-type mutational signatures of MNU, AA, and BP indicate their partial similarity to signature 11, 22, and 4 or 29, respectively. Meanwhile, signatures attributable to ENU and DEN were highly similar to each other, but not to signature 11, suggesting that the mechanisms of these agents differed from those of typical alkylating agents. Thus, Hawk-Seq™ can clarify genome-wide chemical mutagenicity profiles at extraordinary resolutions, thereby providing insight into mutagen mechanisms and their roles in cancer development.

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“…This is followed by a long, 35‐day period during which sperm mature. Our study design was based on a similar study using the direct‐DNA damaging agent benzo[a]pyrene (BaP) (O'Brien et al, ). BaP is a direct‐acting mutagen requiring only a single “hit” and a short exposure.…”

Section: Discussionmentioning

confidence: 99%

Effects of hydroxyurea on CNV induction in the mouse germline

Arlt

Rajendran

Holmes

et al. 2018

Environ and Mol Mutagen

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Copy number variants (CNVs) are important in genome variation and genetic disease, with new mutations arising frequently in the germline and somatic cells. Replication stress caused by aphidicolin and hydroxyurea (HU) is a potent inducer of de novo CNVs in cultured mammalian cells. HU is used extensively for long-term management of sickle cell disease. Here, we examined the effects of HU treatment on germline CNVs in vivo in male mice to explore whether replication stress can act as a CNV mutagen in germline mitotic divisions as in cultured cells and whether this would support a concern for increased CNV mutations in offspring of men treated with HU. Several trials of HU administration were performed by oral gavage and subcutaneous pump, with CNVs characterized in C57BL/6 x C3H/HeJ hybrid mouse offspring by microarray and mate-pair sequencing. HU had a short half-life of ~14 min and a narrow dose window over which studies could be performed while maintaining fertility. Tissue histopathology and reticulocyte micronucleus assays verified that doses had a substantial tissue and genetic toxicity. CNVs were readily detected in offspring that originated in both paternal and maternal mouse strains, as de novo and inherited events. However, HU did not increase CNV formation above baseline levels. These results reveal a high rate of CNV mutagenesis in the mouse germline but do not support the hypothesis that HU would increase CNV formation during mammalian spermatogenesis, perhaps due to highly toxic effects on sperm development or experimental variables related to HU pharmacology in mice. Environ. Mol. Mutagen. 59:698-714, 2018. © 2018 Wiley Periodicals, Inc.

show abstract

Next generation sequencing of benzo(a)pyrene-induced lacZ mutants identifies a germ cell-specific mutation spectrum

Cited by 13 publications

References 53 publications

In Utero Exposure to Benzo[ a ]Pyrene Increases Mutation Burden in the Soma and Sperm of Adult Mice

In Utero Exposure to Benzo[ a ]Pyrene Increases Mutation Burden in the Soma and Sperm of Adult Mice

Genome-wide somatic mutation analysis via Hawk-Seq™ reveals mutation profiles associated with chemical mutagens

Effects of hydroxyurea on CNV induction in the mouse germline

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