A developmental role for ataxia-telangiectasia mutated in protecting the embryo from spontaneous and phenytoin-enhanced embryopathies in culture.
Ataxia-telangiectasia (A-T) is characterized by impaired recognition and repair of DNA damage and increased sensitivity to ionizing radiation (IR), cancer, and neurodegeneration. We previously showed pregnant knockout mice lacking the A-T gene product ataxia-telangiectasia mutated (Atm) are highly susceptible to the embryopathic effects of IR, which damages DNA, possibly via generation of reactive oxygen species (ROS). Here we show that Atm more broadly protects against both spontaneous and phenytoin-enhanced embryopathies. In the absence of drug exposure, cultured embryos from pregnant Atm knockout mice showed more embryopathies than wild-type littermates, with a gene dose-dependent decrease in susceptibility from -/- to +/- to +/+ embryos (p < 0.05). A similar but significantly enhanced gene dose-dependent pattern of embryopathic susceptibility was evident in Atm knockout embryos exposed to the ROS-initiating teratogen phenytoin (p < 0.05). These results provide the first evidence that Atm has a broad developmental importance beyond IR embryopathies, possibly by protecting the embryo from constitutive and xenobiotic-enhanced oxidative stress, with even heterozygotes showing increased risk. This developmental role of Atm further implicates DNA damage in ROS-mediated teratogenesis and DNA damage response and repair as risk factors for individual susceptibility.
Bhuller
Yadvinder
Y
Faculty of Pharmacy, and Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
Wells
Peter G
PG
D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D010672:Phenytoin / Q000633:toxicity*; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D000927:Anticonvulsants; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D010672:Phenytoin; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases