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Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species

Peter G Wells1, Yadvinder Bhuller, Connie S Chen

  • 1Faculty of Pharmacy, Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada. pg.wells@utoronto.ca

Toxicology and Applied Pharmacology
|August 6, 2005
PubMed

Insights

Reactive oxygen species (ROS) cause developmental pathologies by damaging cellular molecules. This review examines how xenobiotics and endogenous factors trigger ROS, leading to embryopathies, and explores protective mechanisms against this oxidative stress.

Area of Science:

  • Developmental toxicology
  • Oxidative stress research
  • Pharmacology

Background:

  • Developmental pathologies can arise from reactive oxygen species (ROS) that damage cellular components and disrupt signaling.
  • Endogenous and xenobiotic factors can enhance ROS formation, contributing to embryopathies.

Purpose of the Study:

  • To review the role of ROS in developmental pathologies using model drugs, environmental chemicals, and radiation.
  • To examine the mechanisms of ROS generation and their impact on embryonic development in various animal models.

Main Methods:

  • In vivo and embryo culture studies using mouse, rat, and rabbit models.
  • Investigation of xenobiotic bioactivation by embryonic enzymes like prostaglandin H synthases (PHSs) and lipoxygenases.
  • Analysis of genetic knockouts (PHS, G6PD, iNOS, Atm, p53, ogg1) and pharmacological interventions (inhibitors, antioxidants).

Main Results:

  • Xenobiotics are bioactivated to free radicals initiating ROS formation, leading to protein, lipid, and DNA oxidation.
  • Reduced embryopathies and DNA oxidation observed in PHS knockout mice and with PHS inhibitors, antioxidants, and free radical scavengers.
  • Species-specific susceptibility to thalidomide-induced embryonic DNA oxidation noted (rabbit vs. mouse).
  • Increased embryopathies in mice deficient in antioxidative enzymes (G6PD) or with depleted glutathione (GSH) pathways.
  • Inhibition of Ras/NF-kB pathways and deficiency in DNA damage response/repair genes (Atm, p53, ogg1) exacerbate embryopathies.
  • Endogenous oxidative stress in G6PD- or ATM-deficient mice also increases embryopathies.

Conclusions:

  • Embryonic prostaglandin H synthases and lipoxygenases play a key role in bioactivating xenobiotics to initiate ROS formation.
  • The balance of ROS formation, oxidative DNA damage, repair mechanisms, and ROS-mediated signaling are critical determinants of teratological risk.
  • Targeting ROS-mediated pathways offers potential strategies for preventing or mitigating xenobiotic-induced embryopathies.

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