BIOCHEMICAL TOXICOLOGY OF CHEMICAL TERATOGENESIS

Although exposure during pregnancy to many drugs and environmental che micals is known to cause in utero death of the embryo or fetus, or ini tiate birth defects (teratogenesis) in the surviving offspring, surpri singly little is known about the underlying biochemical and molecular mechanisms, or the determinants of teratological susceptibility, parti cularly in humans. In vitro and in vivo studies based primarily on rod ent models suggest that many potential embryotoxic xenobiotics are act ually proteratogens that must be bioactivated by enzymes such as the c ytochromes P450 and peroxidases such as prostaglandin H synthase to te ratogenic reactive intermediary metabolites. These reactive intermedia tes generally are electrophiles or free radicals that bind covalently (irreversibly) to, or directly or indirectly oxidize, embryonic cellul ar macromolecules such as DNA, protein, and lipid, irreversibly alteri ng cellular function. Target oxidation, known as oxidative stress, oft en appears to be mediated by reactive oxygen species (ROS) such as hyd roxyl radicals. The precise nature of the teratologically relevant mol ecular targets remains to be established, as do the relative contribut ions of the various types of macromolecular lesions. Teratological sus ceptibility appears to be determined in part by a balance among pathwa ys of maternal xenobiotic elimination, embryonic xenobiotic bioactivat ion 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 othe rwise compromised embryonic pathways for detoxification, cytoprotectio n, and repair, the embryo is relatively susceptible to reactive interm ediates, and teratogenesis via this mechanism can occur from exposure to therapeutic concentrations of drugs, or supposedly safe concentrati ons of environmental chemicals. Greater insight into the mechanisms in volved in human reactive intermediate-mediate teratogenicity, and the determinants of individual teratological susceptibility, will be neces sary to reduce the unwarranted embryonic attrition from xenobiotic exp osure.