ToxSci Advance Access originally published online on May 19, 2006
Toxicological Sciences 2006 93(1):146-155; doi:10.1093/toxsci/kfl022
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Variable In Vivo Embryoprotective Role for Ataxia-Telangiectasia–Mutated against Constitutive and Phenytoin-Enhanced Oxidative Stress in Atm Knockout Mice
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* Faculty of Pharmacy and Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 3M2
Received January 6, 2006; accepted April 30, 2006
Knockout mice lacking the ataxia-telangiectasia–mutated (Atm) protein exhibit impaired detection and repair of DNA damage and increased embryopathies from ionizing radiation in vivo, and vehicle or phenytoin in embryo culture. Here we determined if Atm-deficient mice are more susceptible in vivo to phenytoin embryopathies. Wild-type (+/+) or heterozygous (+/–) Atm knockout dams were mated with +/– males, pregnant dams were treated with phenytoin (65 mg/kg ip) or its vehicle, and resorptions and fetuses were genotyped and characterized. This strain proved resistant to phenytoin-initiated cleft palates but not to other spontaneous and phenytoin-enhanced embryopathies. With vehicle-treated +/– dams, fetal body weight was lower in homozygous Atm-null (–/–) fetuses compared to +/– and +/+ littermates (p < 0.05). Phenytoin enhanced this Atm-dependent embryopathic pattern (p < 0.05). It also enhanced DNA oxidation in –/– Atm-deficient embryos compared to its +/– Atm-deficient (p < 0.001) and +/+ Atm-normal (p < 0.001), phenytoin-exposed littermates and to its –/– vehicle controls (p < 0.01). Postpartum lethality was greater in both +/– and –/– Atm-deficient fetuses compared to +/+ littermates, independent of treatment (0.05 < p < 0.1). By maternal genotype, +/– Atm-deficient dams had fewer implantations than +/+ dams, independent of treatment, and phenytoin decreased litter size (p < 0.05). Conversely, phenytoin-exposed +/+ fetuses were more likely than –/– littermates to die in utero (p < 0.05), and in +/+ dams fetal resorptions and postpartum lethality were variably higher and enhanced by phenytoin (p < 0.05). Despite variable actions in vivo, the embryoprotective effects of Atm suggest a role for reactive oxygen species and oxidative DNA damage in some spontaneous and phenytoin-enhanced embryopathies.
Key Words: Atm; ataxia-telangiectasia; oxidative stress; reactive oxygen species; phenytoin; development; embryopathy; developmental toxicology.
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