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PMID: 21734703 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice.

Nature ·Vol. 475 ·No. 7354 ·2011-07-06 ·Pages 53-8

Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ

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.

MeSH Terms
Acetaldehyde/metabolism,toxicity Aldehyde Dehydrogenase/deficiency,genetics,metabolism Aldehyde Dehydrogenase, Mitochondrial Aldehydes/antagonists & inhibitors,metabolism,toxicity Alleles Animals B-Lymphocytes/drug effects,metabolism Bone Marrow/drug effects,pathology,physiopathology Cell Line Cell Survival/drug effects Chickens Clone Cells/drug effects DNA Damage/genetics DNA Repair/genetics Embryo Loss/chemically induced,etiology Embryo, Mammalian/abnormalities,drug effects,embryology Ethanol/metabolism,toxicity Fanconi Anemia/genetics,pathology Fanconi Anemia Complementation Group D2 Protein/deficiency,genetics,metabolism Female Fetal Alcohol Spectrum Disorders/etiology Gene Deletion Genes, Essential Hematopoiesis/drug effects Male Mice Mice, Inbred C57BL Precursor Cell Lymphoblastic Leukemia-Lymphoma/chemically induced,etiology Pregnancy Teratogens/metabolism,toxicity Weaning
Chemicals
Aldehydes Fancd2 protein, mouse Fanconi Anemia Complementation Group D2 Protein Teratogens Ethanol ALDH2 protein, mouse Aldehyde Dehydrogenase Aldehyde Dehydrogenase, Mitochondrial Acetaldehyde
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Langevin Frédéric
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
Crossan Gerry P
Rosado Ivan V
Arends Mark J
Patel Ketan J
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature10192
Published
2011-07-06
Epub
2011-00-06
Pages
53-8
Language
English
Region
England
NLM ID
0410462
Subset
IM
Grants
Medical Research Council · MC_U105178811 · United Kingdom
Corrections
CommentIn
PMID: 21734701
CommentIn
PMID: 22531379
External Links
PubMed source DOI: 10.1038/nature10192 View journal details
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