Experimental teratology

Abstract

It is concluded that the only entirely reliable test for teratogenicity of new drugs in man is clinical trial. Experimental teratology, nevertheless, has a very significant role in establishing guide lines for such tests and in the elucidation of mechanisms of teratogenic action. It also has made contributions to the understanding of normal developmental processes.The agents now known to have teratogenic capacity are multitudinous and may be generally categorized as follows: physical agents, infections, endocrine substances and states, vitamin deficiencies, analogues and antimetabolites, alkylating agents, antibiotics, and miscellaneous agents. The suggestion that any agent can be teratogenic if applied at the right time or dosage or in the right species is not accepted per se, and instead the more realistic proposal is made that a teratogenic agent must bear some specific relationship to the metabolic or homeostatic requirements of the growing embryo. Each effective agent produces a characteristic syndrome which is determined by the pathway of action of the agent and how that pathway relates to developmental events at the time of treatment.Two factors in teratogenesis are strictly embryological, namely, genotype and the developmental stage at the time of treatment. Genotype is the inescapable background against which all extrinsic teratogens act. Many induced malformations have been shown to be the result of an accentuated incidence of infrequently occurring spontaneous ones and the suggestion is made that all teratogens action, through, or in conjunction with an existing unstable genetic locus. Developmental stage determines which tissues in a susceptible embryo will respond to teratogenic stimulus at a given time. Preimplantation embryos are quite refractory to teratogenesis, the embryo becomes generally very susceptible about the time the three germ layers form and thereafter susceptibility diminishes as the degree of differentiation proceeds.The interrelation between the embryo and the maternal organism should be kept in mind but to date this has not been proven to be a major factor in teratogenesis. Maternal constitutional factors in some instances have an effect on incidence of malformations in the young. Maternal reaction to a teratogen has not been shown to affect the embryo and only rarely have teratogenic doses affected the mother more seriously than the embryo. The placenta has not been directly implicated in teratogenesis.Experimental teratology has passed through what might be characterized as a descriptive phase and appears now to be entering an analytical phase. Several promising but relatively unexplored new areas of investigation may lead to early advances in analytical teratology. These include: (1) protein specificity and immunelike reactions. (2) chemical and cytochemical analysis of abnormal embryos, (3) teratogenic interaction of two or more agents, (4) embryo transplants and explants, and (5) time-limited exposure to teratogens using specific antagonists followed by appropriate supplements.