Prenatal exposure to N-nitrosodimethylamine (NDMA) has been linked to childhood cancer, according to a long-term study published March 24 by the Massachusetts Department of Public Health (DPH). In 2003, in response to residents’ concerns about possible NDMA contamination, DPH determined that the public water supply in Wilmington, Massachusetts, had been contaminated by NDMA from a chemical manufacturer. The area is now listed by the United States Environmental Protection Agency (EPA) as a Superfund site.
Engelwards’ research focuses on developing technology for quantifying DNA damage and repair and revealing factors that affect genome stability. (Photo courtesy of Bevin Engelward)
Separately, NIEHS beneficiaries from the Massachusetts Institute of Technology (MIT) published a study on March 16 in the journal Cell Reports that revealed molecular details about how NDMA causes disease in mice. The work was primarily done by Jenny Kay, Ph.D., with support from Josh Corrigan. Both work in the lab led by senior author Bevin Engelward, Sc.D.
The study was funded in part by a grant from the NIEHS Superfund Research Program (SRP). “From a scientific standpoint, I think this is an interesting example of how basic science can provide mechanistic insight into association studies,” said Michelle Heacock, Ph.D., a NIEHS health scientist who oversees SRP fellowships.
“The MIT researchers did not contribute directly to the Massachusetts DPH study, but their work with the Wilmington community drove them to investigate how NDMA might cause health effects,” Heacock noted. “The demonstrated link between NDMA and childhood cancer underscores the importance of the work the MIT team is doing.”
The Massachusetts investigation began after concerned residents and the local health board contacted DPH about a childhood cancer cluster that residents discovered in 1999. The investigation, which began that year, focused on a chemical manufacturing facility operated by a series of companies from 1953 until it closed in 1986. Olin Chemical Corp. bought the 53-acre site in 1980.
Before joining NIEHS in 2007, Heacock studied DNA repair proteins in Sam Wilson, Ph.D.’s NIEHS lab, and at Texas A&M University, where she also studied telomeres. (Photo courtesy of Steve McCaw / NIEHS)
Only two childhood cancers were diagnosed in Wilmington between 1982 and 1989. But between 1990 and 2000, 22 Wilmington children were diagnosed with leukemia, lymphoma and other cancers. Since 2001, the cancer rate in children has returned to near the baseline, about one case per year.
“It’s really remarkable that a link was found by the Massachusetts DPH,” said Engelward, a professor of biological engineering. “In general, these types of studies are inconclusive, and it is very difficult to determine the cause of a cancer cluster. Unfortunately, the fact that the situation was so serious may have been the reason that a link could be made. Importantly, the Massachusetts DPH study does not prove cause and effect, so more research is needed. “
On April 1, the EPA approved a $ 48 million plan to partially clean the Olin Chemical Superfund site. According to the Massachusetts DPH, Wilmington’s public drinking water, which now comes from other sources, does not pose a known risk to public health. Nevertheless, townspeople want a more comprehensive clean-up and a return of their previously pristine spring water, Engelward explained.
Turning the balance
In the new study, Engelward and her team found that a molecule in mice called alkyladenine DNA glycosylase (AAG) affects their susceptibility to diseases caused by NDMA. “We found that AAG has a huge impact on whether cells will survive DNA damage and whether they will eventually develop mutations and cancer,” explains Engelward.
In humans, AAG activity can vary as much as 20 times. As a result, there may be low and high risk populations with different expected health outcomes from NDMA exposure.
“The results of this work have broad public health relevance,” Engelward said. “NDMA is still being formed in the environment. This isn’t just a legacy contamination; it is also a contemporary problem. We are working hard to find ways to translate MIT research into impact on public health. ”
Kay JE, Corrigan JJ, Armijo AL, Nazari IS, Kohale IN, Torous DK, Avlasevich SL, Croy RG, Wadduwage DN, Carrasco SE, Dertinger SD, White FM, Essigmann JM, Samson LD, Engelward BP. 2021. Excision of mutagenic replication-blocking lesions suppresses cancer, but promotes cytotoxicity and lethality in nitrosamine-exposed mice. Cell Rep 34 (11): 108864.
(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)