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Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice
Frédéric Langevin1, Gerry P Crossan, Ivan V Rosado
1MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
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.
Insights
The Fanconi anaemia DNA repair pathway protects against acetaldehyde, a carcinogen from ethanol metabolism. Impaired repair and acetaldehyde metabolism lead to developmental issues, bone marrow failure, and leukemia in mice.
Area of Science:
- Biochemistry
- Genetics
- Toxicology
Background:
- Reactive aldehydes, such as acetaldehyde, are carcinogenic byproducts of metabolism.
- Acetaldehyde accumulation can cause DNA damage and is linked to fetal alcohol syndrome and Fanconi anaemia.
- The Fanconi anaemia pathway is crucial for DNA repair.
Purpose of the Study:
- To investigate the role of the Fanconi anaemia DNA repair pathway in counteracting acetaldehyde-induced genotoxicity.
- To determine the impact of impaired acetaldehyde metabolism and DNA repair on embryonic development and health in mice.
Main Methods:
- Utilized genetically modified mice with deficiencies in the Fanconi anaemia pathway (Fancd2) and acetaldehyde metabolism (Aldh2).
- Examined embryonic development, sensitivity to ethanol exposure, and long-term health outcomes, including bone marrow failure and leukemia.
- Assessed the interplay between Aldh2 and Fancd2 in response to acetaldehyde exposure.
Main Results:
- Aldh2 deficiency is essential for Fancd2(-/-) embryonic development.
- Mice with combined Aldh2 and Fancd2 deficiencies (Aldh2(-/-)Fancd2(-/-)) exhibit extreme sensitivity to in utero ethanol exposure.
- Postnatal exposure to ethanol in double-deficient mice rapidly causes bone marrow failure, and these mice spontaneously develop acute leukemia.
Conclusions:
- The Fanconi anaemia DNA repair pathway is critical for mitigating acetaldehyde genotoxicity.
- Acetaldehyde-mediated DNA damage likely contributes to fetal alcohol syndrome, Fanconi anaemia complications, and cancer predisposition.
- Combined defects in DNA repair and acetaldehyde metabolism create a severe vulnerability to ethanol and accelerate disease onset.
