Project Summary (2022-2027)

Exposure of people to single chemicals or mixtures at Superfund sites has unquestionably occurred. The unanswered question addressed in this project is whether those exposures can be associated with measurable risks to genome integrity or expression, which would provide biological plausibility to the argument that the chemicals in the environment have affected human health and welfare. The compounds chosen for investigation were inspired by engagement efforts with a local community containing a Superfund site and with tribal groups in Maine. Carcinogenic N-nitrosamines (e.g., N-nitrosodimethylamine or NDMA) as well as other toxicants are abundant in both of the project’s catchment areas. These agents have not been studied as mutagens or proteome disruptors at the level of detail proposed here, and they certainly have not been subjected to the combined multi-omic scrutiny of this project taken together with the Assessment of the Health Effects of N-Nitrosamines and Development of Disease Mitigation Strategies project.

The technology of this project has five components: (a) Employs a genetically engineered panel of mice (the Assessment of the Health Effects of N-Nitrosamines project) that responds to environmental toxicants in a manner that reveals underlying mechanisms that confer susceptibility to a toxicant. The pathway to toxicity involves disease initiation, concomitant complications such as tissue-destructive inflammation, through end stage pathologies such as cancers. (b) Utilizes a newly developed high-fidelity DNA sequencing procedure that provides unprecedentedly high-resolution mutational spectra (HRMS); HRMS can be used to identify chemical-specific mutational patterns resulting from environmental exposures. (c) Uses a unique proteomic platform that sensitively senses disruptions in thousands of nodes in signaling networks. (d) Applies a novel computational module via the Data Management and Analysis Core that quantitatively compares HRMS and proteomic patterns from their models with the rapidly expanding human data sets of The Cancer Genome Atlas Project (TCGA), other tumor sequencing efforts, and the growing body of knowledge of proteomic patterns. (e) Lastly, they introduce mouse embryo fibroblast (MEF) lines isogenic with mouse models that can be used as high-throughput screening tools to help find genotoxic fractions in complex mixtures.

The project’s multi-omic approach centers on animal and cellular models, but also looks ahead to application of these novel tools for molecular epidemiology and for disease prevention. Regarding the latter possibility, the proteomic and mutagenic biomarkers already seen in the work can immediately be used to assess the efficacy of probiotic mitigation of disease, via interactions with the Assessment of the Health Effects of N-Nitrosamines and the Development of Disease Mitigation Strategies project. Regarding contributions to epidemiology, the distinctive mutational spectra, the researchers have already observed that following NDMA exposure to animals and cells could eventually become valuable early-onset biomarkers that portend later life diseases. Taken together, this project leverages basic studies on genomics, adductomics, gene expression, and systems toxicology to provide practical tools that can help detect and mitigate human diseases caused by specific environmental chemicals that both MIT SRP community partners and regulators have defined as agents of concern.