Methamphetamine-enhanced embryonic oxidative DNA damage and neurodevelopmental deficits.
Methamphetamine (METH) causes dopaminergic nerve terminal degeneration and functional deficits in adult mice, but its neurodevelopmental effects are unclear. We investigated METH-initiated oxidative DNA damage in brain during the embryonic and fetal periods, and the postnatal histological and functional consequences. Pregnant CD-1 mice were treated with a single dose of METH (20 or 40 mg/kg ip) or its saline vehicle on Gestational Day 14 or 17. METH enhanced conceptal DNA oxidation, determined by 8-oxoguanine formation, in brain and liver by at least 2-fold at 1 h (P < 0.05), and more so in some fetal brains at 4 h. After birth, motor coordination on the rotarod apparatus in the METH-exposed offspring was impaired for at least 12 weeks (P < 0.05). Unlike in adults, this postnatal functional deficit in offspring exposed in utero to METH was not associated with degeneration of striatal dopaminergic nerve terminals at 12 weeks of age determined by tyrosine hydroxylase staining, suggesting a novel pathological mechanism in utero. This is the first evidence of oxidative DNA damage in embryonic and fetal brain caused by amphetamines, leading to long-term postnatal neurodevelopmental deficits via a mechanism different from that underlying the neurodegeneration observed in METH-exposed adults.
Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Winnie
W
Jeng
Andrea W
AW
Wong
Ryan
R
Ting-A-Kee
Peter G
PG
Wells
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D001923:Brain Chemistry; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D004622:Embryo, Mammalian; D005260:Female; D005333:Fetus; D006147:Guanine / Q000031:analogs & derivatives / Q000032:analysis; D007150:Immunohistochemistry; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000196:embryology; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000697:Central Nervous System Stimulants; D008694:Methamphetamine; C024829:8-hydroxyguanine; D006147:Guanine; D014446:Tyrosine 3-Monooxygenase