# Project 4: NDMA and DNA Alkylation Repair in the Lung: Impact of Gene-Environment Interactions on Cellular Responses, Mutations and Cancer

> **NIH NIH P42** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $162,799

## Abstract

Project 4: Project Summary/Abstract
Residents who live near the Olin Superfund site (within the Mystic River Watershed) are worried because there
was a cancer cluster in their community and their water contains N-nitrosodimethylamine (NDMA), a potent
carcinogen in animal models. Policy decisions depend not only on knowing if NDMA can cause cancer, but we
also need to know about how gene-environment interactions impact disease risk. NDMA is known to be
potently carcinogenic in animal models, but little is known about how genetic factors modulate NDMA's effects
on DNA damage, mutations and cancer. Here, we focus on Aag and Mgmt, the two genes that together are
responsible for repairing more than 80% of the NDMA-induced DNA lesions. Here, we propose to exploit
innovative mouse models with varied DNA repair capacity to learn how Aag and Mgmt impact susceptibility to
NDMA-induced mutations and tumors. Specific Aim 1 is to reveal the impact of Aag and Mgmt on NDMA-
induced tissue damage. Project 5 we will reveal systems level early after exposure. Among other endpoints,
we will use our recently developed CometChip to measure DNA damage. For Specific Aim 2, we will
collaborate with Project 3 to study mutations and we will use our RaDR mice for fluorescence detection of
large-scale sequence rearrangements mediated by homologous recombination (an important class of
mutations). We will also quantify tumor burden so that we can relate early responses to downstream
consequences. For Specific Aim 3, we will compare the susceptibility of juvenile versus adult animals to
NDMA-induced genomic instability and cancer. For Specific Aim 4, we will study long-term low-dose
exposure to NDMA in water, and we will include NDMA levels that reflect environmental levels based on the
findings of Project 1 and Project 2. Project 4 will be supported by Core A and Core D for support of
personnel in terms of enrichment activities and professional development. Project 4 will also be supported by
Core B to communicate results to Stakeholders, including a visit to the EPA and meetings with representatives
from the Massachusetts Department of Public Health. Project 4 will also work closely with Core C to help
develop materials for communicating to the local community as well as State and Federal Stakeholders.
Taken together, in collaboration with Projects 1, 2, 3, and 5, Project 4 plays the exciting role of unifying key
cancer related endpoints into an integrated whole that promises to yield insights into genetic risk factors
(impacting risk assessment), to give rise to deeper understanding of the mechanisms of disease progression
(which can ultimately open doors to new opportunities for prevention and mitigation), to improve our
understanding of the impact of NDMA on a potentially vulnerable window of susceptibility, to yield mutational
and proteomic biomarkers that predict disease susceptibility, and to reveal the real-world impact of
NDMA on health under conditions that reflect ...

## Key facts

- **NIH application ID:** 10145685
- **Project number:** 5P42ES027707-05
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Bevin P. Engelward
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $162,799
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145685

## Citation

> US National Institutes of Health, RePORTER application 10145685, Project 4: NDMA and DNA Alkylation Repair in the Lung: Impact of Gene-Environment Interactions on Cellular Responses, Mutations and Cancer (5P42ES027707-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145685. Licensed CC0.

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