Establishing the Embryonic Axes: Prime Time for Teratogenic Insults

Abstract

A long standing axiom in the field of teratology states that the teratogenic period, when most birth defects are produced, occurs during the third to eighth weeks of development post-fertilization. Any insults prior to this time are thought to result in a slowing of embryonic growth from which the conceptus recovers or death of the embryo followed by spontaneous abortion. However, new insights into embryonic development during the first two weeks, including formation of the anterior-posterior, dorsal-ventral, and left-right axes, suggests that signaling pathways regulating these processes are prime targets for genetic and toxic insults. Establishment of the left-right (laterality) axis is particularly sensitive to disruption at very early stages of development and these perturbations result in a wide variety of congenital malformations, especially heart defects. Thus, the time for teratogenic insults resulting in birth defects should be reset to include the first two weeks of development.

Keywords: birth defects; embryonic axes; heart defects; heterotaxy; laterality; situs inversus.

Figure 1

Graph showing susceptible period of teratogenesis when birth defects can be induced. Originally it was thought that the third to eighth weeks after fertilization were the most sensitive time (blue). However, recent advances in our understanding of key events regulating embryogenesis, especially those involving axes formation, has demonstrated the period of greatest susceptibility should include at least the second week and probably the first as well (yellow).