Oxidative DNA damage and repair in teratogenesis and neurodevelopmental deficits.
Several teratogenic agents, including ionizing radiation and xenobiotics such as phenytoin, benzo[a]pyrene, thalidomide, and methamphetamine, can initiate the formation of reactive oxygen species (ROS) that oxidatively damage cellular macromolecules including DNA. Oxidative DNA damage, and particularly the most prevalent 8-oxoguanine lesion, may adversely affect development, likely via alterations in gene transcription rather than via a mutational mechanism. Contributions from oxidative DNA damage do not exclude roles for alternative mechanisms of initiation like receptor-mediated processes or the formation of covalent xenobiotic-macromolecular adducts, damage to other macromolecular targets like proteins and lipids, and other effects of ROS like altered signal transduction. Even in the absence of teratogen exposure, endogenous developmental oxidative stress can have embryopathic consequences in the absence of key pathways for detoxifying ROS or repairing DNA damage. Critical proteins in pathways for DNA damage detection/repair signaling, like p53 and ataxia telangiectasia mutated, and DNA repair itself, like oxoguanine glycosylase 1 and Cockayne syndrome B, can often, but not always, protect the embryo from ROS-initiating teratogens. Protection may be variably dependent upon such factors as the nature of the teratogen and its concentration within the embryo, the stage of development, the species, strain, gender, target tissue and cell type, among other factors.
Wells
Peter G
PG
Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. pg.wells@utoronto.ca
McCallum
Gordon P
GP
Lam
Kyla C H
KC
Henderson
Jeffrey T
JT
Ondovcik
Stephanie L
SL
D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology; D004247:DNA / Q000378:metabolism / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D004622:Embryo, Mammalian; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced* / Q000235:genetics; D006147:Guanine / Q000031:analogs & derivatives; D008658:Inactivation, Metabolic; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010672:Phenytoin / Q000494:pharmacology; D011506:Proteins / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013723:Teratogens / Q000494:pharmacology; D013792:Thalidomide / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000494:pharmacology; D015262:Xenobiotics / Q000494:pharmacology
D011506:Proteins; D017382:Reactive Oxygen Species; D013723:Teratogens; D016159:Tumor Suppressor Protein p53; D015262:Xenobiotics; D001564:Benzo(a)pyrene; D013792:Thalidomide; C024829:8-hydroxyguanine; D006147:Guanine; D010672:Phenytoin; D004247:DNA