ToxSci Advance Access published online on May 19, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl022
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
* To whom correspondence should be addressed. 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, or 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). Phenytoin 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 ROS and oxidative DNA damage in some spontaneous and phenytoin-enhanced embryopathies.
Received January 6, 2006
Accepted April 30, 2006
Reproductive and Developmental Toxicology
Variable In Vivo Embryoprotective Role for Ataxia Telangiectasia-Mutated (Atm) Against Constitutive and Phenytoin-Enhanced Oxidative Stress in Atm Knockout Mice
Yadvinder Bhuller 1,
Winnie Jeng 1,
and
Peter G. Wells 2 *
2 Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Dept. of Pharmacology, University of Toronto, Toronto, Ontario, Canada
Peter G. Wells, E-mail: pg.wells{at}utoronto.ca
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. G. Wells, G. P. McCallum, C. S. Chen, J. T. Henderson, C. J. J. Lee, J. Perstin, T. J. Preston, M. J. Wiley, and A. W. Wong Oxidative Stress in Developmental Origins of Disease: Teratogenesis, Neurodevelopmental Deficits, and Cancer Toxicol. Sci., March 1, 2009; 108(1): 4 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W. Wong, G. P. McCallum, W. Jeng, and P. G. Wells Oxoguanine Glycosylase 1 Protects Against Methamphetamine-Enhanced Fetal Brain Oxidative DNA Damage and Neurodevelopmental Deficits J. Neurosci., September 3, 2008; 28(36): 9047 - 9054. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Bhuller and P. G. Wells A Developmental Role for Ataxia-Telangiectasia Mutated in Protecting the Embryo from Spontaneous and Phenytoin-Enhanced Embryopathies in Culture Toxicol. Sci., September 1, 2006; 93(1): 156 - 163. [Abstract] [Full Text] [PDF]
|
|