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

Abstract

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 ϩ/Ϫ OGG1-deficient females caused a drug dose-and gene dose-dependent increase in 8-oxoG levels in OGG1-deficient fetal brains ( p Ͻ 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 Ͻ 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.

Cockayne Syndrome B Protects Against Methamphetamine-Enhanced Oxidative DNA Damage in Murine Fetal Brain and Postnatal Neurodevelopmental Deficits

“…A previous report supported an OGG1-independent accessory role for CSB in 8- (34). Thus, the less dramatic increases in 8-oxoG observed in this study of Csb m=m mice, compared with our previous studies in CD-1 and Ogg1 À=À mice (22,52), may be accounted for by the substantially higher intrinsic OGG1-dependent 8-oxoG repair activity in the Csb strain, together with the secondary independent role that CSB plays in 8-oxoG repair. The enhanced susceptibility to oxidative DNA damage in METH-exposed fetal brains from Csb m=m mice was not observed in fetal liver, and may reflect tissue-specific differences in CSB function, ROS formation and=or activity of antioxidative enzymes.…”

“…The increase in oxidative DNA damage, as well as susceptibility to postnatal motor coordination deficits, in CSBdeficient offspring exposed to METH compared to wild-type littermates was not as dramatic as in CD-1 outbred mice and Ogg1 knockout mice (22,52). To investigate the mechanism responsible for the relative resistance of the Csb þ=þ mice to METH-initiated 8-oxoG formation and subsequent postnatal motor coordination deficits, we compared 8-oxoG repair capacity in the fetal brain of the Csb þ=þ mice to that in the more sensitive CD-1 strain.…”

“…Unlike adult mice treated with METH, striatal dopaminergic nerve terminal degeneration is not detected in mice exposed to the drug in utero. Also, oxoguanine glycosylase 1 (Ogg1) knockout mice, which are deficient in base excision repair (BER) of 8-oxoG, are more susceptible to METHenhanced oxidative DNA damage and postnatal neurodevelopmental deficits, indicating that oxidative DNA damage plays a role in the pathogenic mechanism of METH (52).…”

Combined Exercise and Insulin-Like Growth Factor-1 Supplementation Induces Neurogenesis in Old Rats, but Do Not Attenuate Age-Associated DNA Damage

“…80,81 In the present study, it was observed that aging increases the levels of 8-oxoG in hippocampus of rats, which potentially could jeopardize brain function. 82,83 Indeed, the repair of 8-oxoG is a high priority of cells for survival. The total protein content of OGG1 was increased in aged rats, which could be a cellular attempt to combat the enhanced levels of 8-oxoG, but, in this case, without significant success.…”

Reduced 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy)-Initiated Oxidative DNA Damage and Neurodegeneration in Prostaglandin H Synthase-1 Knockout Mice

“…The mutagenic role of 8-oxo-dG in cancer is generally appreciated, but this oxidative macromolecular lesion also may affect gene transcription, resulting in neurodegeneration. For example, we recently found that postnatal neurodevelopmental deficits caused by in utero exposure to METH are enhanced in knockout mice deficient in oxoguanine glycosylase 1 (OGG1), the major enzyme for repairing 8-oxo-dG (32). A similar process may occur in adults exposed to MDMA since METH also is bioactivated by PHSs (30).…”