Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species.
Developmental pathologies may result from endogenous or xenobiotic-enhanced formation of reactive oxygen species (ROS), which oxidatively damage cellular macromolecules and/or alter signal transduction. This minireview focuses upon several model drugs (phenytoin, thalidomide, methamphetamine), environmental chemicals (benzo[a]pyrene) and gamma irradiation to examine this hypothesis in vivo and in embryo culture using mouse, rat and rabbit models. Embryonic prostaglandin H synthases (PHSs) and lipoxygenases bioactivate xenobiotics to free radical intermediates that initiate ROS formation, resulting in oxidation of proteins, lipids and DNA. Oxidative DNA damage and embryopathies are reduced in PHS knockout mice, and in mice treated with PHS inhibitors, antioxidative enzymes, antioxidants and free radical trapping agents. Thalidomide causes embryonic DNA oxidation in susceptible (rabbit) but not resistant (mouse) species. Embryopathies are increased in mutant mice deficient in the antioxidative enzyme glucose-6-phosphate dehydrogenase (G6PD), or by glutathione (GSH) depletion, or inhibition of GSH peroxidase or GSH reductase. Inducible nitric oxide synthase knockout mice are partially protected. Inhibition of Ras or NF-kB pathways reduces embryopathies, implicating ROS-mediated signal transduction. Atm and p53 knockout mice deficient in DNA damage response/repair are more susceptible to xenobiotic or radiation embryopathies, suggesting a teratological role for DNA damage, consistent with enhanced susceptibility to methamphetamine in ogg1 knockout mice with deficient repair of oxidative DNA damage. Even endogenous embryonic oxidative stress carries a risk, since untreated G6PD- or ATM-deficient mice have increased embryopathies. Thus, embryonic processes regulating the balance of ROS formation, oxidative DNA damage and repair, and ROS-mediated signal transduction may be important determinants of teratological risk.
Wells
Peter G
PG
Faculty of Pharmacy, Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada. pg.wells@utoronto.ca
Bhuller
Yadvinder
Y
Chen
Connie S
CS
Jeng
Winnie
W
Kasapinovic
Sonja
S
Kennedy
Julia C
JC
Kim
Perry M
PM
Laposa
Rebecca R
RR
McCallum
Gordon P
GP
Nicol
Christopher J
CJ
Parman
Toufan
T
Wiley
Michael J
MJ
Wong
Andrea W
AW
D000818:Animals; D005260:Female; D005333:Fetus / Q000187:drug effects; D015386:Hazardous Substances / Q000633:toxicity; D006801:Humans; D018811:Maternal Exposure; D011247:Pregnancy; D015032:Zinc / Q000172:deficiency
D015386:Hazardous Substances; D015032:Zinc