The toxic chemicals all around us
As part of the MIT Superfund Research Program, Nicolette Bugher is working to expose the poisons lurking in our environment and discover what they mean for human health.
MIT J-WAFS announces 2022 seed grant recipients
Ariel Furst’s 2022 J-WFS seed grant hopes to clean water and other environmental areas from persistent pollutants.
Read the article at MIT News
MIT SRP Labs Collaborate on Study of NDMA Susceptibility
Congratulations to Amanda L. Armijo, Pennapa Thongararm, Bogdan I. Fedeles, Judy Yau, Jennifer E. Kay, Joshua J. Corrigan, Marisa Chancharoen, Supawadee Chawanthayatham, Leona D. Samson, Sebastian E. Carrasco, Bevin P. Engelward, James G. Fox, Robert G. Croy and John M. Essigmann on their recent publication in NAR Cancer in 2023! In this work, the authors show that there is a distinct mutation pattern when mice are exposed to N-nitrosodimethylamine, a DNA methylating agent. This pattern is strikingly similar to the pattern of mutations in tumors from patients treated with a related DNA methylating agent, temozolomide. The pattern appears to be driven largely by O6-methylguanine, a damaged base that readily mispairs with thymine to induce GC to AT mutations.
Trainee Spotlight | Jessica Beard
Congratulations to SRP trainee, Jessica Beard, and faculty member, Timothy Swager, for their publication in the Journal of Organic Chemistry! This is a pivotal paper for the MIT Superfund Research Program, both because it is tour de force in terms of the chemistry that is described, and also because it helps to inform cleanup. Importantly, it was written in response to members of the Wilmington Community who wanted to understand better whether or not N-nitrosamines are continuing to be formed at the Olin Chemical Superfund Site (located in Wilmington, MA). Being responsive to the community is key to the mission of the MIT SRP.
Jessica was also interviewed for a podcast by the Boston Museum of Science. Jessica shares her thoughts about her favorite molecule, her career aspirations, and her appreciation of the MIT Superfund Research Program. Listen to the podcast on the museum’s website website.
High Throughput Toxicity Assay
Cell survival assays are routine in many life science laboratories, yet direct measurements of cell growth are rarely performed due to the fact that the gold standard colony forming assay is slow and laborious. A novel adaptation to the traditional colony forming assay was developed by Postdoc Lizzie Ngo of the Engelward and Samson laboratories. Whereas the typical colony forming assay requires many large cell culture dishes, Dr. Ngo’s rapid assay fits into a 96-well plate format, enabling higher throughput direct testing of the ability of cells to divide. This technology was highlighted in the AAAS EurekAlert, MIT News, and as an NIEHS Environmental Factor Paper of the Month. In addition, Dr. Ngo’s excellent work was highlighted in a Trainee Spotlight in the April edition of SRP e-Posted Notes.
Outreach Publication in Scientia
Program Director Prof. Bevin Engelward and RTC leader Dr. Jenny Kay collaborated with editors of the science outreach journal Scientia to produce an article about the MIT SRP and its biological research projects. The article describes the NIEHS Superfund Research Program and MIT SRP’s chemicals of interest, N-nitrosamines, probable human carcinogens that contaminate the groundwater of Wilmington, MA. Drs. Engelward and Kay provided an overview of NDMA-induced DNA damage and repair and the team’s approach to evaluating how varied DNA repair activity may impact susceptibility to adverse health outcomes following exposure. They also described several technologies developed in the Engelward laboratory for detecting DNA damage, toxicity, and mutations. This publication enabled dissemination of advancements at the MIT SRP to a broad audience.
Study Links Childhood Cancer to NDMA Exposure
The Olin Chemical Superfund Site in Wilmington, MA, contains high levels of NDMA, a probable human carcinogen that traveled nearly a mile underground, contaminating town wells that had been used by thousands of people. After the discovery of a childhood cancer cluster, the Massachusetts Department of Public Health did an epidemiological study, and the results show an association between exposure to NDMA in utero and cancer in children. The MIT Superfund Research Program is actively engaged in being responsive to the affected community by performing relevant research and developing technologies to help address the public health impacts of NDMA. Recent research performed by the MIT team points to the possibility that the AAG DNA repair enzyme is a susceptibility factor for NDMA-induced cancer.
Leventhal City Prize for Equitable Resilience
A team led by CEC Director Dr. Kathy Vandiver won the Norman B. Leventhal City Prize, a $100,000 award offered by MIT’s Leventhal Center. The objective of the ‘Malden River Works for Waterfront Equity and Resilience’ project is to create a public open space to improve opportunities for community recreation and health. It is envisioned the river will become a place where people can gather or walk, and also enjoy being out in nature where the surroundings are healthy for both the mind and body. The project work involves redesigning a city-owned parcel which is the home of the Dept. of Public Works (DPW). The most ambitious goal, however, is a social capacity-building one, with the aim of broadening civic participation for communities of color. For this purpose, a Steering Committee for the project has been created with representative leaders from Malden’s diverse immigrant groups, including people of color who are currently underrepresented in the city government. This project was featured in an MIT News article and video and in the NIEHS PEPH Newsletter.
HepaCometChip Enables SRP Research and Chemical Safety Testing
A blind spot for high throughput genotoxicity assays is the inability to detect bulky lesions on DNA that have the potential to be carcinogenic. To overcome this limitation, Drs. Lizzie Ngo and Norah Owiti from the Engelward laboratory developed new methodologies for the CometChip, a high throughput comet assay developed at MIT. By incorporating hepatocytes, the platform can detect bulky lesions that are formed as a consequence of metabolic activation. Another challenge is that bulky lesions are not easily detected using the traditional comet assay, which reveals the presence of strand breaks but not bulky lesions. By incorporating inhibitors of DNA synthesis, the new assay traps repair intermediates, effectively enabling the cell to convert undetectable bulky lesions into detectable strand breaks. The assay is currently being used for a collaboration between an environmental science and engineering project and a biomedical project, where the goal is to identify novel PAH breakdown products and to test their biological impact. The new platform can also be used to screen for chemical safety and is described in a manuscript published in Nucleic Acids Research (DOI: 10.1093/nar/gkz1077). This work was featured in Technology Networks, Science Daily, the MIT News, and as an NIEHS Paper of the Month.
Trainee Spotlight | Dr. Amanda Armijo
Amanda Armijo, a postdoctoral fellow at MIT Professor John Essigmann’s group in the Department of Biological Engineering and Dr. James Fox’s group in the Division of Comparative Medicine, is studying the genotoxic signatures caused by environmental contaminants and how these mutations result in development of liver cancer. Specifically, her research focuses on the mutational patterns induced by the probable human carcinogen, N-nitrosodimethylamine (NDMA). NDMA is key contaminant of the Superfund site in Wilmington, MA, which for many years has contaminated the drinking water from several municipal wells. As part of the MIT Superfund Research Program, Amanda is utilizing a high-fidelity duplex consensus sequencing (DS) method to reveal early onset genetic signatures of environmental toxicant-driven human diseases that occur later in life. Identifying these mutational processes can inform strategies for Superfund site remediation as well as clinical genetic disease early-detection, intervention and prevention.
These experiments are being performed in transgenic C57Bl/6 mice that contain a reporter gene to enable a mutational assessment and high-fidelity sequencing of the changes in the DNA triplets in the reporter gene region. To accomplish this, the transgenic mice are treated with a carcinogenic regimen of NDMA and then liver DNA is analyzed 10 weeks post-exposure (prior to development of cancerous lesions) with DS to produce high resolution mutational spectra (HRMS). DS is a highly accurate method to identify rare, unique mutations present in a heterogenous genetic milieu. Mutational spectra patterns will also be identified in lesions that have fully developed into pathological cancer induced by NDMA. Gene-environment interactions that define inter-individual variations in sensitivity to NDMA will be identified using mutational patterns.
Amanda received her Bachelor’s degree in Microbiology, Immunology, and Molecular Genetics from UCLA. After working as a laboratory technician, she entered graduate school at UCLA in the department of Molecular and Medical Pharmacology where her work focused on the link between nucleotide metabolism and DNA replication stress responses. Her graduate work subsequently led to the preclinical development of a panel of small molecule inhibitors of deoxycytidine kinase as an anti-cancer therapeutic. Amanda successfully defended her dissertation and next attended Cornell University’s College of Veterinary Medicine, receiving a Doctor of Veterinary Medicine degree. Following completion of her DVM, Amanda completed an internship in Laboratory Animal Surgery and Medicine at Tufts University. She is happy to have found a program at MIT that combines her interests in both caring for laboratory animals and in performing important research that can positively impact human health. In her spare time, she enjoys sports, volunteering for spay/neuter clinics, cooking, and spending time with her family.
