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Oxidative damage in chemical teratogenesis

P G Wells1, P M Kim, R R Laposa

  • 1Faculty of Pharmacy, University of Toronto, Ont., Canada. pg.wells@utoronto.ca

Mutation Research
|January 22, 1998
PubMed
Summary

Xenobiotics cause birth defects by creating reactive oxygen species (ROS) that damage DNA and other molecules. Antioxidants and enzymes protect against this damage, suggesting oxidative stress contributes to teratogenicity.

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Area of Science:

  • Toxicology
  • Developmental Biology
  • Biochemistry

Background:

  • Xenobiotic teratogenicity is linked to bioactivation by enzymes like cytochromes P450, prostaglandin H synthase (PHS), and lipoxygenases (LPOs).
  • These enzymes generate reactive intermediates that can damage cellular macromolecules, leading to in utero death or birth defects.

Purpose of the Study:

  • To investigate the role of free radical-initiated, reactive oxygen species (ROS)-mediated oxidative damage in xenobiotic teratogenicity.
  • To examine genotoxicity and DNA repair mechanisms in response to teratogenic agents.

Main Methods:

  • Utilized mouse and rabbit models in vivo and in embryo culture, alongside in vitro enzyme assays and cultured rat skin fibroblasts.
  • Studied the effects of known teratogens like benzo[a]pyrene (B[a]P), phenytoin, and thalidomide.

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  • Employed electron spin resonance spectrometry, salicylate hydroxylation, and measured biomarkers of oxidative damage (e.g., 8-hydroxy-2'-deoxyguanosine).

    • Main Results:

    • Teratogens were bioactivated to free radical metabolites initiating ROS formation, causing DNA, protein, and lipid oxidation, and embryotoxicity.
    • Inhibition of PHS, free radical trapping agents (PBN), and antioxidants (caffeic acid, vitamin E) reduced teratogenicity and oxidative damage.
    • Superoxide dismutase (SOD) and catalase blocked ROS-initiated embryotoxicity, highlighting the critical role of ROS.

    Conclusions:

    • Oxidative macromolecular damage plays a significant role in the teratogenic mechanisms of xenobiotics bioactivated to reactive intermediates.
    • Endogenous oxidative stress, exacerbated by deficiencies in antioxidant enzymes (G6PD) or DNA repair (p53), contributes to embryopathies.
    • Targeting oxidative stress pathways may offer therapeutic strategies for preventing xenobiotic-induced birth defects.