Superfund Research Program
Systems Toxicology of Environmental Contaminants
Project Summary (2017-2022)
Polycyclic aromatic hydrocarbons (PAHs) and N-nitrosodimethylamine (NDMA) are common environmental pollutants that are known to be carcinogenic and are found in high quantities at superfund sites, including the Mystic River Watershed and the former Loring Air Force Base in Maine. Potential adverse health effects of these compounds are concerning to the people in these communities, as NDMA has been detected in well water in Wilmington MA, and the Maine Department of Human Services established a fish advisory stating that weekly consumption of fish from water contaminated by the Loring Air Force Base will lead to an increased risk of cancer.
Unfortunately, beyond genotoxicity, the mechanisms underlying potential adverse health effects associated with either acute exposure or chronic, low-dose exposures to these compounds are poorly characterized; yet it is known that PAHs, for instance, have widespread effects on a variety of different cell types and tissues.
To determine the systemic, molecular network and cellular effects of exposure to these compounds, the researchers are utilizing a systems toxicology approach comprising cutting-edge mass spectrometry for protein phosphorylation profiling, next-generation sequencing for transcript expression profiling, and computational modeling to integrate molecular network data with cell phenotypic data. In collaboration with other projects and as part of the Massachusetts Institute of Technology Superfund Research Program (MIT SRP) Center, the research team is assessing the effects of exposures to liver, connecting molecular network effects with DNA mutation signatures and downstream biological effects while assessing genetic susceptibility. As other projects define the concentrations and compositions of NDMA and PAHs at these Superfund sites, the researchers are performing in vitro and in vivo studies to assess the combined effects arising from these real-world mixtures, assessing the additivity and synergy of these mixtures compared to the individual compounds.
This innovative, integrative strategy provides new information regarding the health risks and mechanisms underlying exposure to the chemical contaminants present at these sites. Moreover, integrating this information into a predictive quantitative computational model that couples exposure to network response and resulting phenotype is defining biomarker signatures of exposure that can be used as an initial starting point for an eventual blood test for exposure signatures, and defining network nodes governing sensitivity to exposure and therefore potential therapeutic intervention points to abrogate adverse health responses to exposure. Together, the results of this MIT SRP project not only help to define the health risks for communities at risk, but may also provide potential therapeutic strategies to minimize adverse outcomes from exposures at these sites. These deliverables have direct relevance to SRP stakeholders, including the Environmental Protection Agency and the Massachusetts Department of Public Health.