Alcohol, DNA and disease

Article metrics

Acetaldehyde, a reactive metabolite of ethanol, can damage DNA unless properly processed. A biochemical pathway involved in Fanconi anaemia seems to be essential for protection against such damage. See Article p.53

Fanconi anaemia (FA) is a chromosome-breakage disease that causes developmental defects, sterility, bone-marrow failure and a highly elevated risk of cancer1. Mutations in 15 genes are known to be associated with this disorder, and the encoded proteins are all thought to operate in the 'FA pathway'. This pathway preserves genome integrity by ensuring the correct repair of certain types of DNA damage — in particular, damage caused by agents that generate DNA inter-strand crosslinks. But patients with FA have not necessarily been exposed to crosslinking agents, raising a long-standing question about the identity of the endogenous agents that generate FA-associated DNA damage. On page 53 of this issue, Langevin et al.2 provide some answers. Somewhat alarmingly, they also shed light on how ethanol could lead to DNA damage.

A clue about potential endogenous DNA-damaging agents associated with FA came from work3 showing that cells carrying FA-associated mutations are exceptionally sensitive to the crosslinking agent formaldehyde, which — like most other aldehydes — is highly reactive. Aldehydes are omnipresent in nature and are generated during normal metabolism. There is considerable in vitro evidence that certain aldehydes can damage DNA, and can even cause crosslinking4. To prevent such damage, organisms have evolved a battery of aldehyde dehydrogenase enzymes that efficiently convert aldehydes into less noxious products5.

Langevin et al.2 focused on the di-carbon aldehyde acetaldehyde, a degradation product of ethanol that, like several other alcohols, is itself produced during normal metabolism. They found that FA-mutant cell lines were highly sensitive to the addition of acetaldehyde, suggesting that endogenously generated acetaldehyde might be a driver of the features associated with FA.

The authors reasoned that if metabolically produced acetaldehyde is indeed a DNA-damaging agent normally counteracted by the FA pathway, then simultaneous absence of both the Aldh2 gene (which encodes Aldh2, the main detoxifying enzyme of acetaldehyde) and the Fancd2 gene — a key player in the FA pathway — should have a synergistic effect on the severity of the disease in mutant mice. (Note that, in contrast to humans with FA, mice with a defective FA pathway show hardly any overt symptoms, apart from reduced fertility and a mild susceptibility to cancer.)

When the authors attempted to generate double-mutant (Aldh2−/− Fancd2−/−) mice from Aldh2−/− mothers, no such offspring were produced because the embryos were not viable. This suggests that when aldehyde detoxification is defective, the FA pathway becomes essential for embryonic development, and vice versa (Fig. 1). However, a more detailed genetic analysis revealed that Aldh2+/− mothers, which can break down acetaldehyde, could give birth to live Aldh2−/− Fancd2−/− offspring, presumably because the developing embryos had access to maternal Aldh2 via the placenta. Nonetheless, the double-mutant mice were very unhealthy, often having developmental abnormalities and rapidly succumbing to acute leukaemia.

Figure 1: Acetaldehyde metabolism and the Fanconi anaemia pathway of DNA repair.

Acetaldehyde is generated naturally during metabolism, and its levels are further increased by external factors such as alcohol consumption. Normally, however, it is detoxified by aldehyde dehydrogenase enzymes such as ALDH2, which converts it into acetate. If this metabolic reaction is defective, acetaldehyde accumulation can damage DNA, causing inter-strand crosslinks. Langevin et al.2 describe another layer of control in the form of DNA repair by the Fanconi anaemia pathway, which protects against effects of DNA damage such as developmental defects, bone-marrow failure and predisposition to cancer.

In addition to acetaldehyde, Aldh2 can break down a diverse range of other aldehydes, many of which are also generated naturally and can damage DNA. To confirm that acetaldehyde accumulation alone is sufficient to cause disease in Aldh2−/− Fancd2−/− mice, Langevin et al. used ethanol, the immediate precursor of acetaldehyde. Exposure of pregnant mice to a single high dose of ethanol is known6 to cause fetal damage — it is an animal model for human fetal alcohol syndrome. The authors therefore tested whether a moderate dose of ethanol given to Aldh2+/− pregnant mice affects the development of the double mutants. In fact, most of the resulting Aldh2−/− Fancd2−/− embryos died, and the few that did survive had severe developmental defects.

The researchers2 then investigated the effect of ethanol exposure through drinking water on double-mutant mice born to mothers that had not been exposed to ethanol, and before they developed leukaemia. The effect was quite dramatic: the animals developed profound anaemia due to impaired bone-marrow function. This observation is particularly intriguing given that bone-marrow failure is a hallmark of FA in humans.

Langevin and colleagues' paper provides strong evidence that metabolically produced acetaldehyde is a potential driver of endogenous DNA damage, which is normally counteracted by acetaldehyde detoxification, in conjunction with DNA repair through the FA pathway (Fig. 1). It does not, however, address the question of whether acetaldehyde is the ultimate DNA-damaging agent. Although aldehydes can directly modify DNA chemically, it is possible that secondary factors are also involved. These could include the depletion of substrates (NAD+, glutathione) needed for detoxification reactions, or the generation of reactive oxygen species7, which can also damage DNA if not detoxified8. Moreover, Langevin et al. focused on only one aldehyde. Much may be learned from similar investigations into how cells counteract the effects of other aldehydes, such as formaldehyde.

This work2 provides a basis for understanding the pathogenesis of FA and may have consequences for treating individuals with the disease. For instance, patients could be advised to minimize their contact with sources of acetaldehyde and other aldehydes. Also, the symptoms of FA might be mitigated if patients' capacity for detoxifying aldehydes could be enhanced.

But perhaps most importantly, this study reinforces the great concern about the globally widespread consumption of alcohol. It underscores the idea that ethanol consumption is genotoxic through the accumulation of acetaldehyde, potentially causing fetal damage (for instance, fetal alcohol syndrome), bone-marrow dysfunction and increased prevalence of cancers, particularly those of the oral cavity and oesophagus. Notably, an estimated 500 million people worldwide are deficient in ALDH2 activity and so are prone to acetaldehyde accumulation and subsequent genotoxicity9. Improved understanding of how ethanol can damage DNA may affect present attitudes to alcohol consumption.


  1. 1

  2. 2

    Langevin, F., Crossan, G. P., Rosado, I. V., Arends, M. J. & Patel, K. J. Nature 475, 53–58 (2011).

  3. 3

    Ridpath, J. R. et al. Cancer Res. 67, 11117–11122 (2007).

  4. 4

    Lorenti Garcia, C. et al. Mutat. Res. 662, 3–9 (2009).

  5. 5

    Marchitti, S. A., Brocker, C., Stagos, D. & Vasiliou, V. Expert Opin. Drug Metab. Toxicol. 4, 697–720 (2008).

  6. 6

    Sulik, K. K., Johnston, M. C. & Webb, M. A. Science 214, 936–938 (1981).

  7. 7

    Novitskiy, G., Traore, K., Wang, L., Trush, M. A. & Mezey, E. Alcohol Clin. Exp. Res. 30, 1429–1435 (2006).

  8. 8

    Joenje, H. Mutat. Res. 219, 193–208 (1989).

  9. 9

    Brooks, P. J., Enoch, M.-A., Goldman, D., Li, T.-K. & Yokoyama, A. PLoS Med. 6, e50 (2009).

Download references

Author information

Correspondence to Hans Joenje.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Joenje, H. Alcohol, DNA and disease. Nature 475, 45–46 (2011) doi:10.1038/475045a

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.