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The Journal of Neuroscience, September 3, 2008, 28(36):9047-9054; doi:10.1523/JNEUROSCI.2557-08.2008

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Development/Plasticity/Repair
Oxoguanine Glycosylase 1 Protects Against Methamphetamine-Enhanced Fetal Brain Oxidative DNA Damage and Neurodevelopmental Deficits

Andrea W. Wong,¹ Gordon P. McCallum,¹ Winnie Jeng,¹ and Peter G. Wells^1,2

¹Faculty of Pharmacy, and ²Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada M5S 2M2

Correspondence should be addressed to Peter G. Wells, Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 2M2. Email: pg.wells{at}utoronto.ca

In utero methamphetamine (METH) exposure enhances the oxidative DNA lesion 7,8-dihydro-8-oxoguanine (8-oxoG) in CD-1 fetal mouse brain, and causes long-term postnatal motor coordination deficits. Herein we used oxoguanine glycosylase 1 (ogg1) knock-out mice to determine the pathogenic roles of 8-oxoG and OGG1, which repairs 8-oxoG, in METH-initiated neurodevelopmental anomalies. Administration of METH (20 or 40 mg/kg) on gestational day 17 to pregnant +/– OGG1-deficient females caused a drug dose- and gene dose-dependent increase in 8-oxoG levels in OGG1-deficient fetal brains (p < 0.05). Female ogg1 knock-out offspring exposed in utero to high-dose METH exhibited gene dose-dependent enhanced motor coordination deficits for at least 12 weeks postnatally (p < 0.05). Contrary to METH-treated adult mice, METH-exposed CD-1 fetal brains did not exhibit altered apoptosis or DNA synthesis, and OGG1-deficient offspring exposed in utero to METH did not exhibit postnatal dopaminergic nerve terminal degeneration, suggesting different mechanisms. Enhanced 8-oxoG repair activity in fetal relative to adult organs suggests an important developmental protective role of OGG1 against in utero genotoxic stress. These observations provide the most direct evidence to date that 8-oxoG constitutes an embryopathic molecular lesion, and that functional fetal DNA repair protects against METH teratogenicity.

Key words: methamphetamine; oxoguanine glycosylase (OGG1); oxidative DNA damage; 8-oxoguanine; DNA repair; neurodevelopment

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Received June 5, 2008; accepted July 22, 2008.

Correspondence should be addressed to Peter G. Wells, Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 2M2. Email: pg.wells{at}utoronto.ca

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]

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