N-nitrosodimethylamine (NDMA) is a chemical found in both industrial and natural processes and is classified as a probable carcinogen. In recent years, the FDA has had to recall many drugs such as Zantac and drugs used to treat diabetes due to traces of NDMA being found. The carcinogen can cause DNA damage that can lead to cancer.
MIT researchers report they have discovered in a mouse model that the enzyme, AAG, can help determine whether NDMA exposure will lead to damage and cancer. The researchers observed that too little activity of AAG leads to much higher cancer rates, while too much activity can produce tissue damage, especially in the liver. Measuring levels of AAG can aid doctors in predicting how people might respond to NDMA exposure.
The new study, “Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice,” was published in the journal Cell Reports and led by MIT postdoc Jennifer Kay.
“NDMA is a DNA-methylating agent that has been discovered to contaminate water, food, and drugs. The alkyladenine DNA glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we study Aag-knockout (Aag−/−) and Aag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine [3MeA]) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switches from cancer to lethality simply by changing AAG levels.”
This chemical causes specific types of DNA damage, one of which is a lesion of adenine. These lesions are repaired by AAG, enabling DNA polymerases to replace them with new ones. If AAG activity is very high and the polymerases cannot keep up with the repair, then the DNA may end up with too many unrepaired strand breaks, which can be fatal to the cell. But if AAG activity is too low, damaged adenines persist and can be read incorrectly by the polymerase, causing the wrong base to be paired with it.
The MIT researchers studied mice with high levels of AAG and mice with AAG knocked out. After exposure to NDMA, the mice with no AAG had many more mutations and higher rates of cancer in the liver, where NDMA has its greatest effect. Mice with high levels of AAG had fewer mutations and lower cancer rates. However, those mice had significant tissue damage and cell death in the liver.
Mice with normal amounts of AAG showed some mutations after NDMA exposure, but were much better protected against cancer and liver damage.
“Nature did a really good job establishing the optimal levels of AAG, at least for our animal model,” Engelward said. “What is striking is that the levels of one gene out of 23,000 dictates disease outcome, yielding opposite effects depending on low or high expression.”
People experience different ranges of AAG levels. Studies have found that some people can have up to 20 times more AAG activity than others. This suggests that people may respond very differently to damage caused by NDMA, Kay pointed out.
The researchers look forward to studying the effects of chronic, low-level exposure to NDMA in mice, to help them better understand how it can affect humans. “That’s one of the top priorities for us, to figure out what happens in a real-world, everyday exposure,” added Kay.
“…the results of this study provide a basis for advancements in predicting outcomes of exposure to DNA-alkylating agents that promise to help in both treating and preventing cancer,” concluded the researchers.
