Chemically induced mutations in a MutaMouse reporter gene inform mechanisms underlying human cancer mutational signatures
- DOI
- Language of the publication
- English
- Date
- 2020-08-14
- Type
- Article
- Author(s)
- Beal, Marc A.
- Meier, Matthew J.
- LeBlanc, Danielle P.
- Maurice, Clotilde
- O’Brien, Jason M.
- Yauk, Carole L.
- Marchetti, Francesco
- Publisher
- Nature Research
Abstract
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.
Plain language summary
Health Canada is responsible for evaluating new and existing chemicals for the ability to induce mutations (changes in the sequence of DNA). As mutations are required to induce cancer and other types of disease, obtaining information on the potential ability of a chemical to induce mutations is a key aspect of assessing the health risk hazard posed by chemicals present in the environment. Mutagenicity (the ability of inducing mutations) is normally evaluated using test guidelines endorsed by the Organization for the Economic Development and Co-Operation (OECD). One of these OECD test guidelines uses special mice or rats, called Transgenic rodent models (TGR), that allow the detection of mutations in any tissue in the body. These models are very effective in identifying chemicals that induce mutations, however, they do not generate information on the mechanisms by which the mutations are induced. In this study, Health Canada scientists have used a sequencing approach that allows the precise characterization of which changes are induced in the sequence of the DNA. Using this approach, they were able to demonstrate that each chemical has a unique pattern of mutations (called signature) and that this signature is similar to the pattern of mutations that are observed in human cancers that are associated with exposure to those chemicals. These results show that mutations detected using TGR models provide valuable information on mechanisms that are operating during the process of cancer development and represent a new avenue for identifying novel environmental causes of mutations found in human cancers. The conclusions contained in this study will be of interest to regulatory agencies to make a more informed decision on the health risk posed by chemicals with mutagenic properties.
Subject
- Health,
- Health and safety