Cockayne syndrome B protects against methamphetamine-enhanced oxidative DNA damage in murine fetal brain and postnatal neurodevelopmental deficits.
Methamphetamine (METH) increases the oxidative DNA lesion 8-oxoguanine (8-oxoG) in fetal mouse brain, and causes postnatal motor coordination deficits after in utero exposure. Like oxoguanine glycosylase 1 (OGG1), the Cockayne syndrome B (CSB) protein is involved in the repair of oxidatively damaged DNA, although its function is unclear. Here we used CSB-deficient Csb(m/m) knockout mice to investigate the developmental role of DNA oxidation and CSB in METH-initiated neurodevelopmental deficits. METH (40 mg/kg intraperitoneally) administration to pregnant Csb females on gestational day 17 increased 8-oxoG levels in Csb(m/m) fetal brains (p < 0.05). CSB modulated 8-oxoG levels independent of OGG1 activity, as 8-oxoG incision activity in fetal nuclear extracts was identical in Csb(m/m) and Csb(+/+)mice. This CSB effect was evident despite 7.1-fold higher OGG1 activity in Csb(+/+) mice compared to outbred CD-1 mice. Female Csb(m/m) offspring exposed in utero to METH exhibited motor coordination deficits postnatally (p < 0.05). In utero METH exposure did not cause dopaminergic nerve terminal degeneration, in contrast to adult exposures. This is the first evidence that CSB protects the fetus from xenobiotic-enhanced DNA oxidation and postnatal functional deficits, suggesting that oxidatively damaged DNA is developmentally pathogenic, and that fetal CSB activity may modulate the risk of reactive oxygen species-mediated adverse developmental outcomes.
McCallum
Gordon P
GP
Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada.
Wong
Andrea W
AW
Wells
Peter G
PG
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000196:embryology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D000075223:Poly-ADP-Ribose Binding Proteins; D011247:Pregnancy
D000697:Central Nervous System Stimulants; D000075223:Poly-ADP-Ribose Binding Proteins; D008694:Methamphetamine; C024829:8-hydroxyguanine; D006147:Guanine; C513075:Ercc6 protein, mouse; D045643:DNA Repair Enzymes