Review
Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species

https://doi.org/10.1016/j.taap.2005.01.061Get rights and content

Abstract

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.

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)

  • W.K. Yu et al.

    Evidence for lipoxygenase-catalyzed bioactivation of phenytoin to a teratogenic reactive intermediate: in vitro studies using linoleic acid-dependent soybean lipoxygenase, and in vivo studies using pregnant CD-1 mice

    Toxicol. Appl. Pharmacol.

    (1995)
  • R.R. Arlen 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)
  • F. Azarbayjani et al.

    Embryonic arrhythmia by inhibition of HERG channels: a common hypoxia-related teratogenic mechanism for antiepileptic drugs?

    Epilepsia

    (2002)
  • C.S. Chen et al.

    In utero origins of cancer: maternal dietary vitamin E, fetal oxidative DNA damage and postnatal carcinogenesis in p53 knockout mice

  • C.S. Chen et al.

    Enhanced tumorigenesis in p53 knockout mice exposed in utero to high-dose vitamin E

    Carcinogenesis

    (2005)
  • A.G. Fantel

    Reactive oxygen species in developmental toxicity: review and hypothesis

    Teratology

    (1996)
  • A.G. Fantel et al.

    Further evidence for the role of free radicals in the limb teratogenicity of l-NAME

    Teratology

    (2002)
  • B. Halliwell et al.

    Free Radicals in Biology and Medicine

    (1999)
  • J.M. Hansen et al.

    Misregulation of gene expression by the redox-sensitive NF-kB-dependent limb outgrowth pathway by thalidomide

    Dev. Dyn.

    (2002)
  • Z. Hu 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)
  • W. Jeng 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)
  • M.R. Juchau et al.

    Xenobiotic biotransformation bioactivation in organogenesis-stage conceptal tissues: implications for embryotoxicity and teratogenesis

    Drug Metab. Rev.

    (1992)
  • M.R. Juchau et al.

    Cytochrome P450-dependent biotransformation of xenobiotics in human and rodent embryonic tissues

    Drug Metab. Rev.

    (1998)
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    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.

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