Study suggests link between NDMA-contaminated water and childhood cancer

A new study from MIT suggests that a carcinogen found in drinking water contaminated with drugs and chemical plants may have more serious effects on children than adults.

In a study of rats, researchers found that teenagers exposed to drinking water containing this compound, called NDMA, showed dramatically higher rates of DNA damage and cancer than adults.

The researchers say the findings may help explain an epidemiological link between childhood cancer and prenatal exposure to NDMA in people living near a contaminated site in Wilmington, Massachusetts. The study also shows that it is important to evaluate the effects of potential carcinogens on people of all ages.

“We really hope that the groups doing safety testing will change their paradigm and start looking at younger animals, so that we can catch potential carcinogens before people come in contact with them,” says Bevin Engelwardt, an MIT professor of biological engineering.

As a solution to cancer, cancer prevention is clearly much better than cancer treatment, so we hope we can identify dangerous chemicals before people come into contact with them, and thus prevent widespread cancer risk.”

Bevin Engelvard, Massachusetts Institute of Technology

MIT postdoc Lindsey Volk is the paper’s lead author. Engelwardt is the senior author of the study, which appears nature communication.

From DNA damage to cancer

NDMA (N-nitrosomethylamine) can be produced as a byproduct of many industrial chemical processes, and is also found in cigarette smoke and processed meat. In recent years, NDMA has been found in some formulations of the drugs valsartan, ranitidine, and metformin. It was also found in drinking water in Wilmington, Massachusetts as a result of contamination from the Olin Chemical site in the 1990s.

In 2021, a study by the Massachusetts Department of Health suggested a link between water pollution and an increased incidence of childhood cancer in Wilmington. Between 1990 and 2000, 22 Wilmington children were diagnosed with cancer. The contaminated wells were shut down in 2003.

Also in 2021, Engelvard and others at MIT published a study on the mechanism of how NDMA can cause cancer. in new nature communication Pepper, Engelwardt and their colleagues worked to see if they could determine why the compound affected children more than adults.

Most studies evaluating potential carcinogens are conducted on mice that are at least 4 to 6 weeks old, and often older. For this study, researchers studied two groups of mice – one 3 weeks old (adolescents), and one 6 months old (adults). Each group was given drinking water containing low levels of NDMA, about five parts per million, for two weeks.

Inside the body, NDMA is metabolized by a liver enzyme called CYP2E1. It produces toxic metabolites that can damage DNA by adding a small chemical group known as a methyl group to the DNA base, forming lesions known as adducts.

When researchers examined the livers of mice, they found that adolescents and adults had similar levels of DNA adducts. However, there were dramatic differences in what happened after that initial damage. In adolescent mice, DNA adducts led to a significant accumulation of double-stranded DNA breaks, which occur when cells try to repair the adducts. These breaks generate mutations that ultimately lead to the development of liver cancer.

In adult mice, researchers saw essentially no double-stranded breaks and significantly fewer mutations than in juveniles. Furthermore, the livers did not develop serious pathologies, including tumors, even though they experienced similar initial levels of DNA adducts.

“Early structural changes in DNA had very different consequences depending on age,” Engelwardt says. “Double-stranded breaks were seen especially in the young.”

Further experiments showed that these differences arise from differences in rates of cell proliferation. Cells in juvenile liver divide rapidly, giving them more opportunity to alter DNA attachments to mutations, whereas adult liver cells rarely divide.

“It really emphasizes the overall problem we’re trying to highlight in the paper,” says Volk. “In toxicological studies, a lot of times the standard is to use fully grown mice. At that time, they’re already slowing cell division, so if we’re testing the harmful effects of NDMA in adult mice, we’re completely missing how vulnerable particular groups are, such as young animals.”

While most of these effects were seen in the liver, because this is where NDMA is metabolized, some mice developed other types of cancer, including lung cancer and lymphoma.

Adult risk is not zero

For most of these studies, researchers used mice that had two DNA repair systems malfunctioned. This mutation speeds up the process, allowing researchers to more easily see the effects of NDMA exposure, without having to study a large population of mice.

However, a small study in mice with normal DNA repair showed that adolescents experienced NDMA-induced double-strand breaks, regenerative proliferation, and large-scale mutations that were completely absent in adults. This occurs because rapidly growing adolescents have a highly active DNA replication machinery that encounters DNA adducts before the cell has time to repair itself.

The researchers also found that if they treated adult mice with thyroid hormone, which stimulates the proliferation of liver cells, those cells began to accumulate mutations at the same rate as teenage liver cells. Previous work in the Engelwardt laboratory has shown that inflammation can also stimulate cell proliferation-driven vulnerability to DNA damage, so the findings from this study suggest that whatever causes liver inflammation may make the adult liver more sensitive to damage caused by agents like NDMA.

“We certainly don’t want to say that adults are completely resistant to NDMA,” says Volk. “Everything affects your susceptibility to carcinogens, whether it’s your genetics, your age, your diet, etc. In adults, if they have a viral infection, or a high-fat diet, or chronic excessive drinking, that can affect proliferation within the liver and potentially make them more sensitive to NDMA.”

Researchers are now investigating how a high-fat diet might affect cancer development in mice that are exposed to NDMA.

This collaborative effort across multiple MIT laboratories was funded by the National Institute of Environmental and Health Sciences (NIEHS) Superfund Research Program, an NIEHS Core Center Grant, a National Institutes of Health Training Grant, and the Anonymous Fund for Climate Action.