MIT SRP News

The team of Dr. Clara Chow (MIT SRP), Sarah Boyd (Academic Web Pages, Inc.), Dr. Moala Bannavti (MIT SRP), and Dr. Bevin Engelward (MIT SRP Director) created a new website for the MIT Superfund Research Program, with contributions from MIT faculty, Core Leaders, and SRP trainees.  To have the broadest beneficial impact, the goal of the new website was to be inclusive by serving as a resource for all stakeholders and communities.  To accomplish this, several unique website features now provide lessons learned and creative research translation for facilitating collaboration, community engagement, bidirectional discussions, and methods for finding environmental solutions.  One such website feature to promote collaboration is a dedicated page with links to all universities that have Superfund Research Programs.  Another website feature addresses the diverse interest and scientific backgrounds of the audience by describing the SRP projects in both technical and lay language.  Following that mission of serving multiple audiences, the website using creative research translation put forth a series of 3-minute videos with closed captions by our eight MIT SRP trainees.  The trainees describe their groundbreaking research in a storytelling fashion to show the tangible nature of their work in protecting public health to non-experts.  Ultimately, as a resource to share knowledge, the greatest effect is when SRPs partner with community organizations.  As such, an added and equally important feature of this website is a page specifically devoted to communities.  This interactive community informational section addresses the needs of the public and their communities that are facing environmental challenges by offering practical guidance from real-world experiences to help them tackle specific public health issues.  Taken together, the new MIT SRP website provides resources that are helpful to stakeholders from sister SRPs, government agencies, tribal nations, and communities.

NDMA, an unregulated environmental contaminant, has been found in water, air, and soil.  It has also been detected in some food and in several recalled drugs.  The chemical is recognized as a probable human carcinogen by International Agency for Research on Cancer (IARC), EPA, and NTP.  The MIT Superfund Projects 1 and 2 aim to learn more about how NDMA affects the body.  The goal is to examine the health impacts of NDMA by studying the pathways leading to cancer due to DNA damage and mutations.  Given the presence of NDMA found at Superfund sites, like the Olin Chemical Superfund site located in Wilmington, MA, the findings from Projects 1 and 2 will also reveal gene-environmental interactions affecting susceptibility.  The collective research findings from these projects to be accomplished in collaboration with ESE Project 3 and 4, can help in measuring and predicting exposure, leading to innovative disease prevention and mitigation strategies.

Dr. Bevin Engelward leads the Project 1 team by enabling her lab members to create and leverage “canary in a coal mine” genetically engineered model mice (C-GEM mice) in the research to discover short- and long-term health effects from acute and chronic NDMA exposure.  The C-GEM mice have a combination of DNA repair deficiencies, thereby making them sensitive to NDMA.  Moreover, by changing the genetic make-up of these mice, it would also enable mutation detection, which will be analyzed in this project as well as in Project 2.  The important outcome of this research is expected to reveal specific molecular mechanisms associated with impacts from low-level NDMA exposure.  This information will contribute to the development of predictive biomarkers which in turn will help elucidate the biological impacts of NDMA at environmentally relevant levels.

In collaboration with Project 1, Drs. John Essigmann, Robert Croy and Forest White of Project 2 and their team continue the investigation of NDMA exposures from both acute and more environmentally relevant lower-doses of the toxicant. Studies after acute doses of NDMA and chemical models of NDMA revealed a very distinctive mutational fingerprint.  In animals, this fingerprint emerged shortly after toxicant exposure and was persistent in the liver, a target organ for NDMA carcinogenicity.  Analysis of various features of the pattern showed that it is composed of three distinct classes of mutations, implicating three chemical lesions in the genetic effects of NDMA.  Each of the three mutation types occurs in a DNA sequence context-dependent manner, which allows the aggregate pattern to be used as a biomarker of past exposure to NDMA or similar chemicals.  Using the engineered mice from Project 1, they showed that the major mutation type was erased by the DNA repair protein, MGMT. A secondary mutation type was diminished by the repair enzyme AAG.  A third mutation type appears to be refractory to repair and may be environmentally relevant in situations where the primary repair factors are strongly expressed.

In addition to studies on acute exposure, Project 2 established the conditions for long-term lower dose-exposure to NDMA via drinking water.  These experiments were necessary for both Projects 1 and 2 to mimic better the route and level of exposure experienced by people in Wilmington.  Conditions were established that permitted the high-resolution mutational spectrum of NDMA from oral exposure to be correlated with the levels of specific methyl-DNA adducts formed by the toxicant.  Additionally, the cancer-prevention agent, sulforaphane, is being evaluated to determine if it can reduce biomarkers, such as the distinctive NDMA-induced mutational spectrum, that predict eventual cancers.  In parallel, Project 2 is working with Project 1 to apply the same analytical tools to determine if microbiome manipulation can mitigate the biological effects of NDMA.

Another part of Project 2 examines the cellular signaling consequences downstream of exposure of cells to NDMA-like chemicals.  This part of the project will use DNA adduct measurements to help establish the relationship between toxicant dose and biochemical effects on signaling pathways, such as those that are triggered in the wake of DNA damage.  To more fully capture the impact of NDMA-like chemical exposure, we have coupled our signaling network analyses to quantification of protein synthesis rates (e.g., the translatome) and to alterations in MHC Class I immunopeptides.  Together, these data highlight a systemic response to exposure including cell stress signaling, altered protein translation, and display of new peptide antigens on the cell surface to inform immune cells as to the level of exposure.

This project, like Project 1, will also leverage C-GEM cells but for a different purpose.  The aim is to use these cells to study mutation consequences of different kinds of N-nitrosamines found in the environment.

Dr. Jennifer Kay received a Bachelor of Science in Chemical Engineering from the University of Pittsburgh followed with a Ph.D. in Biological Engineering at MIT working in the Engelward and Samson Labs.  Following her postdoctoral fellowship with the MIT SRP, she is currently a Research Scientist at Silent Spring Institute.  During her tenure at MIT and with SRP, she conducted animal-based research to examine the key biological outcomes caused by exposure to N-nitrosodimethylamine (NDMA), an environmental contaminant.   In particular, she studied the impact of DNA repair capacity on responses to NDMA to identify genetic susceptibility factors.  Research in gene-environment interactions, as with Dr. Kay’s work, could offer insights into biological mechanisms of disease, which in turn could provide strategies in public health protection.  Also, as a critical member of the SRP team, Dr. Kay was the lead for the Research Translation Core, building communication bridges with internal and external stakeholders to advance a holistic approach with SRP projects.

At Silent Spring Institute, Dr. Kay and her colleagues focus on identifying chemicals that may promote breast cancer.  Globally, breast cancer has surpassed lung cancer to become the most common cancer diagnosis, predominantly impacting women.  The need for investigating environmental chemicals that increase breast cancer risk is even more pressing as cancer is affecting more young people (ages 15-39 according to National Cancer Institute data:  Abbott, Brianna. “Cancer is Hitting More Young People.” Wall Street Journal, 12 January 2024, pgs. A1 and A9).  The concern is heightened because screening for many types of cancer, including breast cancer, tends to start at a later age for most people.

Combing through multiple international and U.S. agency databases, the Silent Spring team aimed to identify chemicals that have experimental evidence suggesting they could increase breast cancer risk.  Specifically, they looked at chemicals that cause mammary tumors in animal studies, increase certain hormones (estrogen or progesterone), or activate the estrogen receptor, which is present in breast cells. They focused on chemicals that increase estrogen and progesterone signaling in particular because these hormones are well established to increase breast cancer risk.  After searching through many databases for these targeted biological endpoints, the study yielded 921 chemicals that have the potential of initiating the development of breast cancer.

Knowing that DNA damage can also promote cancer, the team scoured additional databases to identify the mammary carcinogens and endocrine disruptors that damage DNA, finding 420 chemicals on their list were also genotoxic.  They demonstrated that chemicals producing mammary tumors in laboratory animals also tend to display DNA damaging and hormone-disrupting traits, supporting the use of mechanistic data for endocrine activity and genotoxicity to flag breast cancer hazards.

The importance and relevance of this study goes beyond a better understanding of endocrine disruptors in relation to breast cancer risk.  This study also provides added insights for regulators to include biological mechanisms in assessing chemicals for a more comprehensive evaluation of exposure.  To that end, the work spearheaded by Dr. Kay can lead to better public health protection for women.

Read more of Dr. Kay’s work