Prenatal exposure to N-nitrosodimethylamine (NDMA) is linked to childhood cancer, according to a long-term study released March 24 by the Massachusetts Department of Public Health (DPH). In 2003, in response to residents’ concerns of possible NDMA contamination, DPH determined that the public water supply in Wilmington, Massachusetts, was contaminated by NDMA from a chemical manufacturer. The area is now listed by the U.S. Environmental Protection Agency (EPA) as a Superfund site.

Engelward’s research focuses on developing technology for quantifying DNA damage and repair and revealing factors that affect the stability of the genome. (Photo courtesy of Bevin Engelward)

Separately, on March 16, NIEHS grantees at the Massachusetts Institute of Technology (MIT) published a study in the journal Cell Reports that revealed molecular details about how NDMA causes disease in mice. The work was done primarily 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 partially funded by a grant from the NIEHS Superfund Research Program (SRP). “From a scientific point of view, I think this is an interesting example of how basic science can provide mechanistic insight into association studies,” said Michelle Heacock, Ph.D., an NIEHS health science administrator who oversees SRP grants.

“The MIT researchers did not directly contribute to the Massachusetts DPH study, but their work with the Wilmington community drove them to examine how NDMA might be eliciting health effects,” Heacock noted. “The demonstrated link between NDMA and childhood cancer underscores the significance of the work the MIT team is doing.”

Suspicious spike

The investigation in Massachusetts began after concerned residents and the local board of health contacted DPH about a childhood cancer cluster that residents discovered in 1999. The study, launched that year, focused on a chemical manufacturing facility operated by a series of companies from 1953 until it closed in 1986. Olin Chemical Corp. purchased the 53-acre site in 1980.

Prior to joining the NIEHS in 2007, Heacock studied DNA repair proteins in the NIEHS lab of Sam Wilson, Ph.D., and at Texas A&M University, where she also studied telomeres. (Photo courtesy of Steve McCaw / NIEHS)

Only two cases of childhood cancer 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 childhood cancer rate has returned to near-baseline, approximately one case per year.

“It is truly remarkable that a link was found by the Massachusetts DPH,” said Engelward, a professor of biological engineering. “Generally, these types of studies are inconclusive, and it is very difficult to identify the cause of a cancer cluster. The fact that the situation was so grave may have sadly been the reason that a connection could be drawn. Importantly, the Massachusetts DPH study does not prove cause and effect, so more research is needed.”

On April 1, EPA approved a $48 million plan to partially clean up the Olin Chemical Superfund Site. According to the Massachusetts DPH, Wilmington’s public drinking water, which now comes from other sources, poses no known risk to public health. Nevertheless, town members want more extensive cleanup and a return of their formerly pristine well water, Engelward explained.

Tipping 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 disease caused by NDMA. “We found that that AAG has an enormous impact on whether cells will survive DNA damage and whether they will eventually develop mutations and cancer,” Engelward explained.

In humans, AAG activity can vary by as much as 20-fold. As a result, there could be low- and high-risk populations with different expected health outcomes from exposure to NDMA.

“The results of this work have broad relevance to public health,” Engelward said. “NDMA continues to be formed in the environment. This is not only a legacy contaminant; it is also a contemporary problem. We are working hard to find avenues to translate the MIT research into impact on public health.”

Citation:
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.)