Jun 23, 2006

A developmental role for ataxia-telangiectasia mutated in protecting the embryo from spontaneous and phenytoin-enhanced embryopathies in culture

Toxicological Sciences : an Official Journal of the Society of Toxicology
Yadvinder Bhuller, Peter G Wells

Abstract

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 furth...Continue Reading

  • References23
  • Citations14

Citations

Mentioned in this Paper

Embryo
Embryopathies
Anticonvulsants
Cell Cycle Proteins
Entire Embryo
Response to DNA Damage Stimulus
Nerve Degeneration
Oxidative Stress
Oxidative Stress Analysis
Reverse Transcriptase Polymerase Chain Reaction

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