title: Maternal aldehyde elimination during pregnancy preserves the fetal genome.
abstract: Maternal metabolism provides essential nutrients to enable embryonic development. However, both mother and embryo produce reactive metabolites that can damage DNA. Here we discover how the embryo is protected from these genotoxins. Pregnant mice lacking Aldh2, a key enzyme that detoxifies reactive aldehydes, cannot support the development of embryos lacking the Fanconi anemia DNA repair pathway gene Fanca. Remarkably, transferring Aldh2(-/-)Fanca(-/-) embryos into wild-type mothers suppresses developmental defects and rescues embryonic lethality. These rescued neonates have severely depleted hematopoietic stem and progenitor cells, indicating that despite intact maternal aldehyde catabolism, fetal Aldh2 is essential for hematopoiesis. Hence, maternal and fetal aldehyde detoxification protects the developing embryo from DNA damage. Failure of this genome preservation mechanism might explain why birth defects and bone marrow failure occur in Fanconi anemia, and may have implications for fetal well-being in the many women in Southeast Asia that are genetically deficient in ALDH2.
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Nina
authors.initials: N
authors.lastname: Oberbeck
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Langevin
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: King
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: de Wind
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: gcrossan@mrc-lmb.cam.ac.uk.
authors.forename: Gerry P
authors.initials: GP
authors.lastname: Crossan
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Department of Medicine, Level 5, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address: kjp@mrc-lmb.cam.ac.uk.
authors.forename: Ketan J
authors.initials: KJ
authors.lastname: Patel
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism* / Q000633:toxicity; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D000831:Animals, Newborn; D004249:DNA Damage; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism*; D000431:Ethanol / Q000633:toxicity*; D005199:Fanconi Anemia / Q000473:pathology*; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics*; D005260:Female; D016678:Genome; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism
chemical_list: C120277:Fanca protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D007527:Isoenzymes; D000431:Ethanol; D000080924:Aldehyde Dehydrogenase 1 Family; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D000079:Acetaldehyde