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Transgenic rodent (TGR) models use bacterial reporter genes to quantify in vivo mutagenesis. Pairing TGR assays with next-generation sequencing (NGS) enables comprehensive mutation pattern analysis to inform mutational mechanisms. We used this approach to identify 2751 independent  lacZ  mutations in the bone marrow of MutaMouse animals exposed to four chemical mutagens: benzo[a]pyrene,  N -ethyl- N -nitrosourea, procarbazine, and triethylenemelamine. We also collected published data for 706  lacZ  mutations from eight additional environmental mutagens. We report that  lacZ  gene sequencing generates chemical-specific mutation signatures observed in human cancers with established environmental causes. For example, the mutation signature of benzo[a]pyrene, a carcinogen present in tobacco smoke, matched the signature associated with tobacco-induced lung cancers. Our results suggest that the analysis of chemically induced mutations in the  lacZ  gene shortly after exposure provides an effective approach to characterize human-relevant mechanisms of carcinogenesis and propose novel environmental causes of mutation signatures observed in human cancers.

Chemically induced mutations in a MutaMouse reporter gene inform mechanisms underlying human cancer mutational signatures