Biochemical Toxicology of Chemical Teratogenesis

Abstract

Referee: Barbara F. Hales, Ph.D., Dept. of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada

Although exposure during pregnancy to many drugs and environmental chemicals is known to cause in utero death of the embryo or fetus, or initiate birth defects (teratogenesis) in the surviving offspring, surprisingly little is known about the underlying biochemical and molecular mechanisms, or the determinants of teratological susceptibility, particularly in humans. In vitro and in vivo studies based primarily on rodent models suggest that many potential embryotoxic xenobiotics are actually proteratogens that must be bioactivated by enzymes such as the cytochromes P450 and peroxidases such as prostaglandin H synthase to teratogenic reactive intermediary metabolites. These reactive intermediates generally are electrophiles or free radicals that bind covalently (irreversibly) to, or directly or indirectly oxidize, embryonic cellular macromolecules such as DNA, protein, and lipid, irreversibly altering cellular function. Target oxidation, known as oxidative stress, often appears to be mediated by reactive oxygen species (ROS) such as hydroxyl radicals. The precise nature of the teratologically relevant molecular targets remains to be established, as do the relative contributions of the various types of macromolecular lesions. Teratological susceptibility appears to be determined in part by a balance among pathways of maternal xenobiotic elimination, embryonic xenobiotic bioactivation and detoxification of the xenobiotic reactive intermediate, direct and indirect pathways for the detoxification of ROS (cytoprotection), and repair of macromolecular lesions. Due largely to immature or otherwise compromised embryonic pathways for detoxification, cytoprotection, and repair, the embryo is relatively susceptible to reactive intermediates, and teratogenesis via this mechanism can occur from exposure to therapeutic concentrations of drugs, or supposedly safe concentrations of environmental chemicals. Greater insight into the mechanisms involved in human reactive intermediate-mediated teratogenicity, and the determinants of individual teratological susceptibility, will be necessary to reduce the unwarranted embryonic attrition from xenobiotic exposure.

Key Words:

• electrophiles teratogenesis
• chemical developmental toxicology
• reactive intermediates
• reactive oxygen species
• oxidative stress
• benzo[a]pyrene
• phenytoin
• thalidomide
• free radicals
• cytochromes P450
• prostaglandin H synthase
• elimination
• cytoprotection
• molecular targets
• repair