ToxSci Advance Access originally published online on January 6, 2009
Toxicological Sciences 2009 108(1):4-18; doi:10.1093/toxsci/kfn263
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Oxidative Stress in Developmental Origins of Disease: Teratogenesis, Neurodevelopmental Deficits, and Cancer
,1
* Faculty of Pharmacy
Departments of Pharmacology and Toxicology
Surgery, University of Toronto, Toronto, Ontario, Canada
1 To whom correspondence should be addressed at Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 3M2. Fax: (416) 267-7797. E-mail pg.wells{at}utoronto.ca.
Received May 23, 2008; accepted December 11, 2008
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Abstract |
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In the developing embryo and fetus, endogenous or xenobiotic-enhanced formation of reactive oxygen species (ROS) like hydroxyl radicals may adversely alter development by oxidatively damaging cellular lipids, proteins and DNA, and/or by altering signal transduction. The postnatal consequences may include an array of birth defects (teratogenesis), postnatal functional deficits, and diseases. In animal models, the adverse developmental consequences of in utero exposure to agents like thalidomide, methamphetamine, phenytoin, benzo[a]pyrene, and ionizing radiation can be modulated by altering pathways that control the embryonic ROS balance, including enzymes that bioactivate endogenous substrates and xenobiotics to free radical intermediates, antioxidative enzymes that detoxify ROS, and enzymes that repair oxidative DNA damage. ROS-mediated signaling via Ras, nuclear factor kappa B and related transducers also may contribute to altered development. Embryopathies can be reduced by free radical spin trapping agents and antioxidants, and enhanced by glutathione depletion. Further modulatory approaches to evaluate such mechanisms in vivo and/or in embryo culture have included the use of knockout mice, transgenic knock-ins and mutant deficient mice with altered enzyme activities, as well as antisense oligonucleotides, protein therapy with antioxidative enzymes, dietary depletion of essential cofactors and chemical enzyme inhibitors. In a few cases, measures anticipated to be protective have conversely enhanced the risk of adverse developmental outcomes, indicating the complexity of development and need for caution in testing therapeutic strategies in humans. A better understanding of the developmental effects of ROS may provide insights for risk assessment and the reduction of adverse postnatal consequences.
Key Words: teratogenesis; neurodevelopmental deficits; cancer; oxidative stress; reactive oxygen species; phenytoin; benzo[a]pyrene; methamphetamine; thalidomide; ionizing radiation.
2 Current address: Loewen, Ondaatje and McCutcheon Ltd., Toronto, Ontario, Canada.
3 Current address: Nucro-Technics, Scarborough, Ontario, Canada.
4 Current address: Cantox Health International, Mississauga, Ontario, Canada.
An earlier version of this review was presented as a keynote lecture at the 11th International Congress of Toxicology, Montreal, Quebec, July 2007. Proceedings, No. K3.0, 2007.
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