The MIT SRP Center with its diverse expertise (from engineers, to chemists, to biologists and to biological engineers) has the tools, the commitment, and the willingness to collaborate, making it possible to take on these serious environmental health challenges. All research is aimed at revealing the impact of alkylating agents in the environment, with a specific emphasis on N-nitrosodimethylamine and polycyclic aromatic hydrocarbons (NDMA and PAHs, respectively). Specifically, the MIT SRP Center focuses on:
- Predicting the fate and transport of carcinogenic alkylating agents in the environment.
- Identifying novel PAH breakdown products.
- Developing novel sensor technologies.
- Using high fidelity duplex consensus sequencing to reveal patterns of mutations that can be traced to specific contaminants.
- Revealing how gene-environment interactions impact susceptibility to genomic instability and cancer.
- Using phosphoproteomics and transcriptomics to uncover systems-level molecular responses that shed light on underlying mechanisms of disease and give rise to novel biomarkers of disease risk. Results from these studies will help to mitigate and treat cancer.
This research informs policy, enables risk estimates, and guides remediation. The bi-directional program is based on established relationships with stakeholders who live near the Olin Industriplex, Wells G&H and the Loring Airforce Base Superfund Sites.
NDMA is a carcinogenic alkylating agent that is has been shown to be present in well water in Wilmington at the Olin Industriplex Superfund Site. It creates DNA damage that can be repaired. Since people are variable in their DNA repair capacity, genes that code for DNA repair enzymes are predicted to be important susceptibility factors.
PAHs are composed primarily of carbon rings. They are highly variable with regard to exocyclic functional groups, making some more carcinogenic than others. They are created by combustion and they contaminate the air, soil and water at the Olin Industriplex, Wells G&H and Loring Airforce Base Superfund Sites.
Project 1: Development of sensors for carcinogenic alkylating agents and predicting their spatiotemporal dynamics in water near Superfund Sites. Project Leaders: Harry Hemond and Tim Swager. This project develops microsensor-based low cost methods for measuring NDMA and PAHs in water, to develop time-resolved spectrofluorimetry for mapping contaminants, and to quantify chemical fluxes from contaminated sediments. Results from Project 1 will significantly improve toxicant mapping, which is key to remediation. Project 1 informs Projects 3, 4 and 5.
Project 2: Development of novel carbon nanotube sensors for carcinogenic PAHs and analysis of PAH chemical evolution in the air near Superfund Sites. Project Leaders: Noelle Selin, Jesse Kroll, and Tim Swager. This project develops novel chemiresistive carbon nanotube sensors for PAHs and PAH breakdown products, estimates the role of atmospheric transformation for multigenerational contaminants, models the fate of pollutants in air, and develops spatiotemporal pollutant tracking devices. These inexpensive sensors will be readable via direct electrical connections or wireless communication between a passive RFID card and a smartphone, and can be designed to give quantitative results. Projects 1 and 2 interact in the development of nanotube sensors. Project 2 identifies PAHs for study by Projects 3 and 5.
Project 3: Leveraging high resolution mutation spectra to deduce prior exposure to environmental mutagens, with a focus on benzo[a]pyrene and N-nitrosodimethylamine (NDMA). Project Leaders: John Essigmann and Bob Croy. This project learns from Projects 1 and 2 about PAHs and N-nitrosamines of concern in the environment. Project 3 examines the ability of these agents to cause mutations in animal models of human disease. It reveals the high-resolution mutational spectra specific to NDMA and its sister N-nitrosamines and PAHs using the new tool of high fidelity duplex consensus sequencing. Project 3 will also work with Project 4 to reveal genetic factors with the potential to impact inter-individual variation in mutation susceptibility.
Project 4: Revealing the impact of genetic susceptibility factors for carcinogenic alkylating agents in the environment, with a focus on benzo[a]pyrene and N-nitrosodimethylamine. Project Leaders: Bevin Engelward and Leona Samson. This project defines the impact of genetic factors predicted to modulate the impact of NDMA on tumor-promoting mutations. Project 4 collaborates with Project 3 to study genetic modulation of mutation spectra, and Project 5, to learn about systems level responses that correlate with risk of disease.
Project 5: Leveraging systems biology to reveal biomarkers and cellular responses to carcinogens. This project will lead to novel strategies for disease mitigation and treatment. Project Leaders: Forest White and Doug Lauffenburger. Studies thousands of signal transduction cascades in parallel via analysis of the phosphoproteome and the transcriptome enable biomarker development and mechanistic analysis of disease. Project 5 will reveal molecular responses responsible for disease mechanisms, as well as identifying valuable biomarkers. Developing tools to deconvolute complex mixtures remains a longstanding goal for modern toxicology.