Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice

TLDR: The results show that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd2−/− embryos, and that these embryos are unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double-deficient mice rapidly precipitates bone marrow failure.

Abstract: Reactive aldehydes are common carcinogens. They are also by-products of several metabolic pathways and, without enzymatic catabolism, may accumulate and cause DNA damage. Ethanol, which is metabolised to acetaldehyde, is both carcinogenic and teratogenic in humans. Here we find that the Fanconi anaemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Our results show that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd2−/− embryos. Nevertheless, acetaldehyde-catabolism-competent mothers (Aldh2+/− ) can support the development of double-mutant (Aldh2−/−Fancd2−/− ) mice. However, these embryos are unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double-deficient mice rapidly precipitates bone marrow failure. Lastly, Aldh2−/−Fancd2−/− mice spontaneously develop acute leukaemia. Acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well as to abnormal development, haematopoietic failure and cancer predisposition in Fanconi anaemia patients. Individuals with Fanconi anaemia exhibit developmental defects, stem-cell failure and a strong predisposition to leukaemia. Cells derived from patients with Fanconi anaemia are susceptible to DNA damage caused by DNA crosslinking agents such as cisplatin and mitomycin C. These are cancer chemotherapeutics, so cells are not normally exposed to them, prompting the question: what is the natural source of DNA damage repaired by this pathway? Experiments with mice deficient in Fancd2 (one of several Fanconi anaemia genes) and Aldh2 (which encodes an enzyme that detoxifies aldehydes) suggest that acetaldehyde is an endogenous source of DNA damage in Fanconi anaemia, contributing to cancer predisposition and haematopoeitic failure. Intriguingly, these mouse models also suggest a possible mechanism for the damaging effects of fetal alcohol exposure during pregnancy.