A new MIT study shows that carcinogenic chemicals in drinking water contaminated by some pharmaceuticals and industrial activities may pose a far greater risk to children than adults.
In experiments with mice, researchers found that young animals exposed to water containing this compound, called NDMA, developed far more DNA damage and cancer than older mice exposed to the same amount.
These results may help clarify previous findings linking prenatal exposure to NDMA to increased rates of childhood cancer in people living near a contaminated site in Wilmington, Massachusetts. The study also highlights the importance of studying how potential carcinogens affect people at different stages of life.
“I really hope that the safety testing community changes the paradigm and starts looking at young animals so they can discover potential carcinogens before people are exposed,” said Bevin Engelward, a professor of bioengineering at the Massachusetts Institute of Technology (MIT). “It’s clear that as a solution to cancer, prevention is far better than cancer treatment, so we hope to find dangerous chemicals before people are exposed to them and prevent widespread cancer risk.”
MIT postdoc Lindsay Volk is the study’s lead author. nature communications. Engelward is senior author.
NDMA exposure from water, drugs, and food
NDMA (N-nitrosodimethylamine) is produced as a byproduct of various industrial processes. It is also found in tobacco smoke and processed meat. In recent years, it has been detected in certain types of drugs, including valsartan, ranitidine, and metformin. In the 1990s, NDMA was also detected in drinking water in Wilmington, Massachusetts, due to contamination from an Olin Chemical plant.
A 2021 report from the Massachusetts Department of Health suggests a link between that contamination and an increase in childhood cancer cases in the area. From 1990 to 2000, 22 children were diagnosed with cancer in Wilmington. The affected wells were shut down in 2003.
That same year, Engelward and colleagues published a study explaining how NDMA causes cancer at the molecular level. In this latest study, the team focused on understanding why young people appear to be more vulnerable than adults.
How NDMA damages DNA and causes cancer
Most studies on carcinogens are based on adult mice, usually at least 4 to 6 weeks old. In this study, the researchers compared two groups: 3-week-old infant mice and 6-month-old adult mice. Both groups drank water containing low levels of NDMA, around 5 ppm, for two weeks.
Once in the body, NDMA is processed by a liver enzyme called CYP2E1. This process produces harmful byproducts that attach small chemical units known as methyl groups to DNA. These changes form lesions called adductor bodies.
When scientists examined liver tissue, they found that these early DNA adducts occurred at similar levels in both young and adult mice. Differences appeared in the cells’ subsequent responses. In young mice, this damage causes an accumulation of double-stranded DNA breaks that occur as cells attempt to repair the adducts. These cuts introduce mutations that can ultimately lead to liver cancer.
In contrast, adult mice had fewer double-strand breaks and far fewer mutations. Their livers did not develop severe disease or tumors despite similar levels of initial DNA damage.
“The initial structural changes in DNA had very different consequences depending on age,” Engelward says. “Double-strand breaks were observed only in young individuals.”
Rapid cell growth increases risk in young people
Further analysis revealed that the key factor behind this difference was the rate of cell division. In young livers, cells are actively growing and dividing, making it more likely that DNA damage will turn into permanent mutations. Adult liver cells divide much less frequently, giving them more time to repair damage before it becomes harmful.
“This really highlights the overall issue that we’re trying to highlight in this paper,” Volk says. “In toxicological studies, it is often standard to use fully grown mice. At that point, the mice have already slowed cell division, so if you are testing the harmful effects of NDMA in adult mice, you completely miss how vulnerable certain groups, such as young animals, are.”
The liver was most affected, but a small number of mice also developed other cancers, such as lung cancer and lymphoma.
Risk for adults depends on health status and cellular activity
To facilitate observation of mutations, many experiments used mice lacking two important DNA repair systems. This approach accelerates mutation formation and reduces the number of animals needed for research.
However, even in mice with normal DNA repair, young mice still developed NDMA-induced double-strand breaks, rapid cell repopulation, and widespread mutations not seen in adults. This happens because rapidly dividing cells encounter DNA damage faster than they can repair it.
The researchers also found that the results changed when cell division increased in adult mice. When adults were treated with thyroid hormone, which stimulates the growth of liver cells, their cells began accumulating mutations at a similar rate to that seen in boys. Previous research from Engelward’s lab has also shown that inflammation promotes cell division, suggesting that conditions that stress the liver may increase its vulnerability to NDMA.
“I would never want to say that adults are completely immune to NDMA,” Volk says. “Heredity, age, and diet all affect susceptibility to carcinogens. In adults, viral infections, high-fat diets, and chronic heavy drinking can affect growth in the liver and make you more susceptible to NDMA.”
The research team is currently studying how high-fat diets affect cancer risk in animals exposed to NDMA.
This research involved multiple Massachusetts Institute of Technology laboratories and was funded by the National Institute of Environmental 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.
