For some years, there has been increasing awareness that drinking alcohol can increase the risk of developing cancer. Now, research from a mouse study suggests an explanation for how that may happen ― drinking alcohol can lead to damage to DNA in stem cells.
Noting that some cancers are linked to DNA damage in stem cells, lead author Ketan J. Patel, MD, PhD, MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, United Kingdom, said: “While some damage occurs by chance, our findings suggest that drinking alcohol can increase the risk of this damage.”
The research was published online January 3 in Nature.
In the study, animals that lacked a key enzyme involved in processing the metabolic byproducts of alcohol consumption, as well animals without a key DNA repair protein, were both found to have experienced DNA damage after exposure to even small doses of ethanol. The researchers found rearranged chromosomes and permanently altered DNA sequences.
“Our study highlights that not being able to process alcohol effectively can lead to an even higher risk of alcohol-related DNA damage and therefore certain cancers,” Dr Patel said in a stament.
In the Cancer Research UK Science Blog, Dr Patel stated that in mice that lacked the enzyme that breaks down acetaldehyde, he and his colleagues “saw huge amounts of DNA damage” after just one dose of ethanol. Acetaldehyde is the main metabolic product of alcohol.
“Bits of DNA were deleted, bits were broken, and we even saw parts of chromosomes being moved about and rearranged,” he added.
Dr Patel noted: “While we didn’t look at whether these mice got cancer or not, previous studies have shown that the type of DNA damage we saw in these mice can considerably increase the risk of cancer.”
Linda Bauld, PhD, a Cancer Research UK expert on cancer prevention, who is also professor of health policy at the University of Stirling, commented in the press release: “This thought-provoking research highlights the damage alcohol can do to our cells, costing some people more than just a hangover.”
This thought-provoking research highlights the damage alcohol can do to our cells, costing some people more than just a hangover.
“We know that alcohol contributes to over 12,000 cancer cases in the UK each year, so it’s a good idea to think about cutting down on the amount you drink,” she said.
Details of the Research
The toxic effects of alcohol are thought to be caused by its oxidation to acetaldehyde, which is highly reactive toward DNA, the researchers explain.
Although acetaldehyde is oxidized to acetate by aldehyde dehydrogenase 2 (ALDH2), approximately 540 million people carry a polymorphism in the ALDH2 gene that is associated with aversive reactions to alcohol and an increased risk for esophageal cancer.
Despite this, many individuals with ADLH2 deficiency tolerate alcohol, potentially because of the protective effects of the DNA-crosslink repair protein FANCD2. Indeed, FANCD2 deficiency leads to Fanconi anemia, which causes abnormal development, bone-marrow failure, and cancer.
Hypothesizing that at least some of the alcohol-associated DNA damage occurs in hematopoietic stem cells (HSCs), and noting that humans and mice that lack DNA repair factors are prone to HSC loss, the team conducted a series of experiments in mice that lacked the ALDH2 and/or FANCD2 genes, along with wild-type animals.
The researchers administered diluted ethanol solutions either via injections or in drinking water. They then conducted chromosome analysis and DNA sequencing to examine the impact of acetaldehyde on genetic expression in the bone marrow, spleen, and blood, as well as on HSC populations.
The team found that in ALDH2-negative mice, exposure to aldehydes stimulated recombination repair, which was not seen in FANCD2-negative animals, suggesting that detoxification is the primary mechanism for prevention of DNA damage.
The results also showed that when aldehydes cause damage, cells employ both DNA-crosslink and homologous recombination repair mechanisms.
Further experimentation indicated that, despite that homologous recombination, the Fanconi anemia crosslink-repair pathway is required to prevent chromosome breakage and loss of blood homeostasis.
Moreover, the researchers found that in the absence of that repair mechanism, nonhomologous end-joining repair was needed in the mouse hematopoietic system to resist endogenous and acetaldehyde-induced DNA damage.
They discovered that HSCs from mice lacking the ALDH2 and FANCD2 genes were severely functionally compromised and shared features with aged cells.
Aldehyde damage in HSCs from these mice caused a range of interchromosomal changes, including an average of two rearrangements per genome, mediated by the mutagenic end-joining of DNA double-stranded breaks, in comparision with control cells.
The team found that aldehyde-induced DNA damage induced p53, resulting in attrition of HSCs. Although the deletion of p53 completely rescued HSC depletion, it did not alter the pattern or intensity of genome instability within individual stem cells.
“Our work implies that the relationship between p53, DNA repair and genome stability is more complex in stem cells than previously appreciated,” the team says. The researchers note that the findings have implications for individuals in whom ALDH2 activity is deficient.
“More generally, this research provides a simple plausible explanation for the established epidemiological link between alcohol consumption and enhanced cancer risk,” they add.
The research was funded by Cancer Research UK, Wellcome, and the Medical Research Council. Dr Patel is supported by the Medical Research Council and the Jeffrey Cheah Foundation. Two coauthors were supported by Cancer Research UK, and one coauthor was supported by the Wellcome Trust and King’s College, Cambridge.
Nature. Published online January 3, 2017. Abstract
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