Developmental toxicity induced during early stages of mammalian embryogenesis

Abstract

Both a conceptual and a practical borderland between teratology and mutagenesis is early embryogenesis, the period between fertilization and gastrulation. Radiation and a variety of chemicals adversely affect the early conceptus leading to in utero mortality and malformations. The post-fertilization period of susceptibility differs from exposures of gametes, the later producing excessive pre- and peri-implantational death and low rates of fetal anomalies predominated by growth retardation. In contrast mutagen exposure of the zygote induces peri-implantational death, pan-gestational death and fetal anomalies predominated by hydrops, abdominal wall defects, and eye aberrations. The mechanism for this pathology remains unclear. These same agents produce a broader range of phenotypic anomalies during the remainder of pre-gastrulation development with anomalies overlapping those induced during organogenesis. Retinoic acid and 5-azacytidine administered prior to gastrulation produce novel malformation syndromes indicative of gene expression modification. The rates and types of defects from mutagen treatment of both gametes and the early conceptus contrast with those resulting from embryonic treatment during organogenesis, and the mechanisms are likely to differ. The pre-gastrulation period has not been explored to the extent reported during gametogenesis or organogenesis. Pre-gastrulation teratology is a new area of investigation with relevance both to reproductive toxicology and to mammalian developmental biology.