ReviewMolecular and biochemical mechanisms in teratogenesis involving reactive oxygen species☆
Introduction
This minireview is based upon a presentation in a workshop on New Approaches in the Assessment of Developmental Toxicology presented at the 10th International Congress of Toxicology in Tampere, Finland (July 2004). The potential involvement of reactive oxygen species (ROS) in teratogenesis is reviewed with respect to the use of mutant, transgenic and knockout mice and antisense oligonucleotides, in determining underlying pharmacological mechanisms of embryopathy. The use of genetically modified strains avoids the often unknown effects attending the use of chemical inhibitors, although such genetic alterations are not without their own compensating changes that may confound interpretation of the data. Short-term exposure to antisense oligonucleotides to inhibit protein expression, when practical, is highly specific and generally less complicating than genetically modified mice since less time is available for embryonic compensation. Mouse, rat and rabbit models together with multiple levels of complexity, including the use of purified proteins, cell culture, embryo culture and in vivo studies, are employed comprehensively to examine the potential relevance of molecular and biochemical mechanisms to teratological outcomes. Embryo culture, while methodologically demanding, allows for an assessment of embryonic determinants in the absence of maternal factors, along with more precise control of exposure levels, among other advantages. Its major disadvantage compared to in vivo studies is that the ultimate teratological relevance cannot be established within the period during which embryos can be viably cultured. Several models of ROS-initiating teratogens with differing advantages are employed, including drugs (phenytoin, thalidomide, methamphetamine), environmental chemicals (benzo[a]pyrene) and ionizing radiation (IR), the latter of which is highly penetrating and does not require enzymatic bioactivation. Details beyond the scope of this minireview, including earlier citations of the primary literature, are provided in the cited reviews. Most of the data discussed herein are from animal models. Little is known about the role of ROS in human teratogenesis.
Section snippets
General mechanisms
Many drugs and environmental chemicals exert their toxic effects by binding reversibly to a receptor, evoking an embryopathic response that is enhanced with an increasing concentration of the xenobiotic in the plasma and at the tissue receptor, with the effect declining as the plasma concentration decreases due to drug metabolism and elimination (Fig. 1). In this case, enhanced risk is commonly associated with excessive xenobiotic exposure levels and/or a deficiency in quantitatively major
Maternal and extra-embryonic determinants
Perhaps the most straightforward mechanism by which maternal determinants can contribute indirectly to the risk of ROS-dependent teratogenicity is via pathways that eliminate the parent compound or its stable metabolites before they can be transported across the placenta to the embryo. Most xenobiotics and/or their stable metabolites are conjugated with hydrophilic endogenous substrates such as glucuronic acid or sulfate, rendering them sufficiently water-soluble to be readily excreted in the
Conclusions
The embryopathic effects of ROS-initiating teratogens may involve both oxidative damage to embryonic cellular macromolecules and enhanced embryonic signal transduction (Fig. 2). Teratogenicity likely depends to a large extent upon a balance between the pathogenic pathways of xenobiotic bioactivation, oxidative macromolecular damage and signal transduction on one hand, and on the other, the protective pathways of maternal elimination, embryonic detoxification of xenobiotic reactive intermediates
Acknowledgments
The authors are grateful to Dr. Sonia M. F. de Morais (currently at Pfizer Global Research and Development, Groton, CT) and Fitzpatrick Obilo of the University of Toronto for assistance in the studies of benzo[a]pyrene embryopathies in Gunn rats, and to Drs. Lewis B. Holmes and G. V. Raymond of the Massachusetts General Hospital and Harvard University (Boston, MA) for providing the human amniocytes.
References (46)
- et al.
Inhibition of thalidomide teratogenicity by acetylsalicylic acid: evidence for prostaglandin H synthase-catalysed bioactivation of thalidomide to a teratogenic reactive intermediate
J. Pharmacol. Exp. Ther.
(1996) - et al.
Embryonic arrhythmia by inhibition of HERG channels: a common hypoxia-related teratogenic mechanism for antiepileptic drugs?
Epilepsia
(2002) - et al.
In utero origins of cancer: maternal dietary vitamin E, fetal oxidative DNA damage and postnatal carcinogenesis in p53 knockout mice
- et al.
Enhanced tumorigenesis in p53 knockout mice exposed in utero to high-dose vitamin E
Carcinogenesis
(2005) Reactive oxygen species in developmental toxicity: review and hypothesis
Teratology
(1996)- et al.
Further evidence for the role of free radicals in the limb teratogenicity of l-NAME
Teratology
(2002) - et al.
Free Radicals in Biology and Medicine
(1999) - et al.
Misregulation of gene expression by the redox-sensitive NF-kB-dependent limb outgrowth pathway by thalidomide
Dev. Dyn.
(2002) - et al.
In vitro and in vivo biotransformation and covalent binding of benzo(a)pyrene in rats with a genetic deficiency in bilirubin UDP-glucuronosyltransferase
J. Pharmacol. Exp. Ther.
(1992) - et al.
Free radical determinants of amphetamine neurodegeneration: prostaglandin H synthase-catalyzed free radical formation and reactive oxygen species-mediated oxidative DNA damage in neuronal degeneration and functional deficits
Toxicol. Sci.
(2004)
Methamphetamine-enhanced embryonic oxidative DNA damage and neurodevelopmental deficits
Free Radical Biol. Med.
Xenobiotic biotransformation bioactivation in organogenesis-stage conceptal tissues: implications for embryotoxicity and teratogenesis
Drug Metab. Rev.
Cytochrome P450-dependent biotransformation of xenobiotics in human and rodent embryonic tissues
Drug Metab. Rev.
The peroxynitrite pathway in development: phenytoin and benzo[a]pyrene embryopathies in inducible nitric oxide synthase (iNOS) knockout mice
Free Radical Biol. Med.
Antisense evidence for nuclear factor kB-dependent embryopathies initiated by phenytoin-enhanced oxidative stress
Mol. Pharmacol.
Genoprotection by UDP-glucuronosyltransferases in peroxidase-dependent, reactive oxygen species-mediated micronucleus initiation by the carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene
Cancer Res.
Genoprotection by UDP-glucuronosyltransferases in peroxidase-dependent, reactive oxygen species-mediated micronucleus initiation by the carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene
Cancer Res.
Phenytoin-initiated hydroxyl radical formation: characterisation by enhanced salicylate hydroxylation
Mol. Pharmacol.
Phenytoin embryotoxicity: protection by UDP-glucuronosyltransferases
Toxicol. Sci.
Peroxidase-dependent bioactivation and oxidation of DNA and protein in benzo[a]pyrene-initiated micronucleus formation
Free Radical Biol. Med.
UDP-glucuronosyltransferase-mediated protection against in vitro DNA oxidation and micronucleus formation initiated by phenytoin and its embryotoxic metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH)
J. Pharmacol. Exp. Ther.
UDP-glucuronosyltransferase-mediated protection against in vitro DNA oxidation and micronucleus formation initiated by phenytoin and its embryotoxic metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH)
J. Pharmacol. Exp. Ther.
Evidence for non-apoptotic pathways mediating phenytoin teratogenicity in mice
Fundam. Appl. Toxicol.
Cited by (207)
Prenatal metal levels and congenital anomalies of the kidney and urinary tract: The Japan Environment and Children's Study
2023, Science of the Total EnvironmentEvaluation of the oxidative toxicity induced by lead, manganese, and cadmium using genetically modified nrf2a-mutant zebrafish
2023, Comparative Biochemistry and Physiology Part - C: Toxicology and PharmacologyDevelopmental toxicity of prometryn induces mitochondrial dysfunction, oxidative stress, and failure of organogenesis in zebrafish (Danio rerio)
2023, Journal of Hazardous MaterialsDevelopmental impacts of Nrf2 activation by dimethyl fumarate (DMF) in the developing zebrafish (Danio rerio) embryo
2023, Free Radical Biology and MedicineCitation Excerpt :There was no difference in expression between control WT and Nrf2a m/m embryos. Developing embryos are highly susceptible to exogenous sources of redox modulation, and perturbation of redox balance has been linked many adverse outcomes related to pancreatic β cells and liver such as dysregulated glucose levels and insulin resistance [24–27]. In this study, DMF-induced Nrf2 activation during three critical windows of development was evaluated.
Nicosulfuron, a sulfonylurea herbicide, alters embryonic development and oxidative status of hatchlings at environmental concentrations in an amphibian species
2022, Ecotoxicology and Environmental Safety
- ☆
Research from the authors' laboratory presented in this review was funded by grants to PGW from the Canadian Institutes of Health Research. Current affiliations: YB, Therapeutic Products Directorate, Health Canada; CSC, Biotech and Health Services, Loewen, Ondaatje and McCutcheon Ltd., Toronto, ON; WJ, Covance Laboratories Inc., Vienna, VA; SK, Div. of Psychiatry, Toronto General Hospital; JCK, Research Institute, Toronto Hospital for Sick Children; PMK, Parteq Inc, Kingston, ON; RRL, Cancer Research Center, University of California San Francisco; CJN, Queen's University, Kingston, ON; TP, SRI International, Menlo Park, CA.