Project 1: Assessment of the Health Effects of N-Nitrosamines and Development of Disease Mitigation Strategies

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PROJECT SUMMARY/ABSTRACT – PROJECT 1 N-Nitrosamines include some of the most mutagenic chemicals known to humankind, and they are present at and near Superfund Sites, in drinking water, in food and in drugs. Given their ubiquitous presence and potent mutagenicity, research focused on N-nitrosamines is critical. What is needed are better ways to predict N- nitrosamine-induced disease so that intervention strategies can be developed. A key barrier has been the difficulty of studying long-term low-dose conditions. To overcome this challenge, Project 1 will create ‘canary in a coal mine’ genetically engineered model (C-GEM) mice. The C-GEM mice will harbor genetic mutations in the alkyladenine DNA glycosylase (Aag) and the O6-methylguanine methyltransferase (Mgmt), two of the most important repair activities for NMDA-induced DNA damage. They will also harbor two transgenes for detecting mutations (to be analyzed in collaboration with Project 2). C-GEM mice will be exposed to environmentally relevant levels of NDMA, to be determined by Projects 3 and 4, and systems-level data (to be collected with Project 2) will be merged by the Data Management and Analysis Core (DMAC) to create predictive biomarkers and to better understand mechanisms of disease. Project 1 will also study a probiotic organism shown to suppress NDMA-induced cancer. Finally, Project 1 will also create “Chem-Sense Cells,” a novel cell array-based platform for screening environmentally relevant N-nitrosamines (to be identified by Projects 3 and 4) for their DNA damaging potential. Specific Aim 1 is to leverage the C-GEM mice at a sensitive window of susceptibility to reveal the long-term low-dose impact of NDMA administered under environmentally relevant conditions. Specific Aim 2 is to use chemical-genetics to create Chem-Sense Cells as a novel biosensor for DNA damage induced by N-nitrosamines present at Superfund Sites. Specific Aim 3 is to leverage the C-GEM mice to reveal the biological mechanisms by which probiotics modulate mutation susceptibility via studies of systems-level responses. Trainees will drive the research and will be supported by the Research Experience and Training Coordination Core to ensure optimal professional development. With support from the Community Engagement Core, Project 1 Leaders and trainees will also listen to and work with community members and tribes to develop novel hands-on teaching curricula that explain key concepts in biology that underlie their research activities. Importantly, Project 1 is part of a greater Systems Approach for the entire MIT SRP, for which interactions and interdependencies (supported by the Administrative Core) give rise to impact that is not otherwise possible. This includes using machine learning (in collaboration with the DMAC) to merge research results from this Project with that of other Projects to gain a better understanding of risk. The Administrative Core also promotes the dissemination of this Project’s innovative mouse and cell technologies, and it supports bringing research results to the EPA and other stakeholders in order to maximize impact on public health.