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ToxSci Advance Access published online on June 21, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl045
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received January 3, 2006
Accepted May 31, 2006

Reproductive and Developmental Toxicology

A Developmental Role for Ataxia Telangiectasia Mutated (Atm) in Protecting the Embryo from Spontaneous and Phenytoin-Enhanced Embryopathies in Culture

Yadvinder Bhuller 1 and Peter G. Wells 2 *

1 Faculty of Pharmacy University of Toronto, Toronto, Ontario, Canada
2 Faculty of Pharmacy University of Toronto, Toronto, Ontario, Canada; Dept. of Pharmacology University of Toronto, Toronto, Ontario, Canada

* To whom correspondence should be addressed.
Peter G. Wells, E-mail: pg.wells{at}utoronto.ca


  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 Atm (Ataxia Telangiectasia Mutated) 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.

Keywords: Atm; ataxia telangiectasia; oxidative stress; reactive oxygen species; phenytoin; development; embryopathy; developmental toxicology.
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