Some aspects of teratogenesis and mutagenesis in mammalian embryos

Abstract

Mammalian embryonic tissue is an especially sensitive target for attack by a variety of drugs and environmental substances. Therefore, elucidation of the mechanism of toxic action at the molecular and cellular level is of considerable interest. Since developmental processes are complex, there is a need for simpler model systems that allow the study of toxic action at this level. The model system should be complex enough to include typical morphogenetic events. Such a system is presented in which the differentiation of limb buds of embryos (mice, rats, rabbits, etc.) from the blastema stage to recognizable cartilaginous bone anlagen representing scapula, humerus, ulna, and radius and the hand skeleton can be studied. This system is suitable for studying chondrogenesis and differentiation of cartilage at the cellular as well as the morphogenetic level, under both normal and pathological conditions. The induction of clear‐cut “malformations” is possible in vitro. Some pharmacokinetic aspects are also discussed as they bear on the course of embryotoxic actions. The interaction of alkylating agents with fetal tissues was studied and compared with corresponding reactions in adult tissues. Finally, an example is given of the elucidation of a special embryotoxic action at the molecular and cellular level. It has been found in our laboratory that chloramphenicol as well as thiamphenicol, or other drugs capable of inhibiting mitochondrial protein synthesis trigger a special toxic event in developing mammalian embryos of fetuses that results in an all‐or‐none effect with respect to fetal mortality‐without malformations being induced in the surviving fetuses. Thus, fetomortality is clearly separable from teratogenic actions. A better understanding of the mode of action of such embryotoxic drugs and of the reasons for the special susceptibility of embryonic tissues to certain toxic events may help to reduce hazardous reactions occurring in humans.