Superfund Research Program
NDMA and DNA Alkylation Repair in the Liver: Impact of Gene-Environment Interactions on Cellular Responses, Mutations and Cancer
Project Summary (2017-2022)
Residents who live near the Olin Superfund site (within the Mystic River Watershed) are worried because there was a cancer cluster in their community and their water contains N-nitrosodimethylamine (NDMA), a potent carcinogen in animal models. Policy decisions depend not only on knowing if NDMA can cause cancer, but also knowing how gene-environment interactions impact disease risk. NDMA is known to be potently carcinogenic in animal models, but little is known about how genetic factors modulate NDMA's effects on DNA damage, mutations, and cancer. In this project, as part of the Massachusetts Institute of Technology Superfund Research Program (MIT SRP) Center, the researchers focus on Aag and Mgmt, the two genes that together are responsible for repairing more than 80% of the NDMA-induced DNA lesions. The researchers are exploiting innovative mouse models with varied DNA repair capacity to learn how Aag and Mgmt impact susceptibility to NDMA-induced mutations and tumors.
The researchers are working to reveal the impact of Aag and Mgmt in modulating the risk of NDMA-induced short-term physiological responses and systems level network responses. They are also working to reveal the impact of Aag and Mgmt on high-resolution point mutation spectra, homologous recombination, and tumors. They are using RaDR mice for fluorescence detection of large-scale sequence rearrangements mediated by homologous recombination (an important class of mutations). They are also quantifying tumor burden so that they can relate early responses to downstream consequences. As resources permit, the researchers will also measure the impact of PAH exposure on mutations, recombination, tumors, and systems level responses.
Taken together, in collaboration with the other Center projects, this MIT SRP project plays the exciting role of unifying key cancer related endpoints into an integrated whole that promises to yield insights into genetic risk factors (impacting risk assessment), to give rise to deeper understanding of the mechanisms of disease progression (which can ultimately open doors to new opportunities for prevention and mitigation), to improve the understanding of the impact of NDMA on a potentially vulnerable window of susceptibility, to yield mutational and proteomic biomarkers that predict disease susceptibility, and to reveal the real-world impact of NDMA on health under conditions that reflect those that are present in the Mystic River Watershed.