NDMA model 400black

Center Highlights | NDMA and Other N-Nitrosamines Impact on Diseases

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.

MIT facade

Awards and Honors

Dr. Amanda Armijo

  • 25th recipient of 2022 Karen Wetterhahn Memorial Award at NIEHS SRP Annual Meeting

Barathkumar Baskaran

  • One of four 2023 Travel Grant recipients, Abdul Latif Jameel Water & Food Systems Lab (J-WAFS), to attend the UNC Water & Health Conference

Nicolette Bugher

  • 2023 Poster Winner for the category of Environmental Science and Engineering at NIEHS SRP Annual Meeting

Dr. Bevin Engelward

  • 2023 Society of Toxicology Education Award
  • 2024 Alexander Hollaender Award, Environmental Mutagenesis and Genomic Society

Dr. Ariel Furst

  • 2023 NIH Director’s New Innovator Award
  • NSF Career Award
  • 2023 Camille Dreyfus Teacher-Scholar Award
  • 2023 Scialog Fellow for Negative Emissions Science
  • 2023 Scialog: Negative Emissions Science – Collective Innovation Award
  • 2023 American Institute of Chemical Engineers – Women in Chemical Engineering Rising Star Award

Dr. Jennifer Kay

  • 2024 Society of Toxicology, Women in Toxicology – Outstanding Young Investigator Award

Dr. Desirée Plata

  • Appointed Co-Director of MIT Climate and Sustainability Consortium, September 2023

Dr. Kathleen Vandiver

  • 2022 Massachusetts Association of Science Teacher Conference Recognized Presenter Award
  • Recognized at Leventhal Center 10th Anniversary Event (2023) for the Malden River Works Project

Dr. Lindsay Volk

  • 2023 Best Poster Award at the Environmental Mutagenesis and Genomics Society 54th Annual Meeting

Dr. Christa Wright

  • Outstanding Technical Contribution in Industry Award at the 2024 Black Engineer of the Year Aw
ELO Participants Group Photo

Environmental Justice Experiential Learning Opportunity Program – Summer 2023

The MIT SRP created and conducted an Environmental Justice Experiential Learning Opportunity (ELO) program from June 3rd to July 28th, 2023.  Supported in part by an MIT ELO award, this program offered eight MIT undergraduate students the ability to participate and experience on-hands laboratory activities in a range of ongoing SRP research.  In addition, there were seminars from the US EPA and Silent Spring Institute to underscore the need for public health work centered on environmental justice.  Furthermore, workshops such as strategies in reading manuscripts and research papers as well as career options gave the ELO students practical concepts as they continue their academic path.  To make the learning tangible, there a visit to Wilmington, MA where the Olin Chemical Superfund site is located.  This field trip allowed the students to see first-hand how environmental contamination has public health consequences, but more importantly, the discussions and interactions with Wilmington community members showed them on a personal level, the difficulties and the life changing aspects for those living near a Superfund site.

As part of the program, the students kept a journal, reflecting upon each experience, whether it was a workshop, research work, or a field trip.  These reflections were to describe not just what they learned academically, but also to ponder on and to examine societal behavior and moral struggles regarding public health and economics.  The feedback from the students expressed a new understanding and a greater appreciation of how research can advance public health and the benefits of community engagement.  They noted that this multi-faceted learning experience enriched their:

  • Understanding of environmental justice and its associated challenges
  • Research skills
  • Knowledge of public health organizations and their impact on problem-solving
  • Career development ideas
  • Wellness in balancing studies and personal happiness
  • Awareness of what community members experience when they are impacted by hazardous chemicals.

A critical aspect to the training program was to provide training to Postdocs and Graduate Students who served as mentors for the undergraduates. The mentoring experience both enhanced their leadership skills while also raising awareness to the public health challenge that are faced by millions of people living close to Superfund Sites. The importance of environmental justice was also a theme throughout the training experience.

 

Learn More

Nikki Bugher

MIT SRP in the News | Nicolette Bugher: The toxic chemicals all around us

Struck at a young age of how lake water quality can negatively impact fish population, that experience shaped Nicolette Bugher’s educational goals. As a Ph.D. candidate conducting research at the Plata Lab, Nicolette’s work is to find and identify harmful chemicals in the environment. Also, as a part of the MIT SRP, Nicolette is investigating potentially carcinogenic chemicals found at unregulated hazardous waste sites, known as Superfund sites. A particular chemical of concern in Nicolette’s research is N-nitrosodimethylamine (NDMA), a contaminant found in the groundwater at Wilmington, MA where the Olin Superfund site is also located. Working on this compound has significance for her and in her research, because this compound is a potential carcinogen at low levels according to the International Agency for Research on Cancer and the U.S. Environmental Protection Agency. Yet, typical analytical laboratory instruments cannot detect this chemical at these low exposure levels to be protective of public health.

“Cancer—it’s unplanned, it’s unexpected. You’re never prepared for it—you don’t know where it comes from,” Nicolette says. “The work that we do is really important, because we’re trying to help toxicologists figure out where cancer is coming from and how to solve it.” As such, the research and discoveries by Nicolette will have broader public health implications beyond Wilmington, MA. It can offer more insights to help other communities that are dealing with similar contamination problems.

Read the article at MIT Technology Review