PRINCIPLES OF TOXICOLOGY - Biology East Borneo

11.3 DEVELOPMENTAL TOXICOLOGY 225ders, such as diabetes and phenylketonuria. In turn, genetically based developmental disorders stillsurpass all of the environmental phenomena that can affect development in terms of proportionalimportance within the population.This section will cover the toxicology relevant to all stages of development from fertilizationonward. This will include the action of toxicants on the mother that affect the ability to establish andmaintain pregnancy, as well as direct actions on the fetus. The developmental stages can be dividedinto 1) the preimplantation stage, where toxicity generally affects the entire organism and there istypically an all or none response (i.e., there is repair or the developing organism is aborted), and 2) thelater embryonic and fetal stages, where specific structural defects can occur. The most sensitive periodfor teratogenesis, the production of congenital defects, is during organogenesis in the embryonicperiod.Mammalian development can be thought of as an expansive flow diagram (Figure 11.5). Followingfertilization there is a very particular sequence of events that is followed, directed by the expressionof certain genes at certain times. From a toxicological point of view, disruptions during this relativelylinear phase generally derail the entire developmental sequence. Certain developmental steps serve asbranch points and once particular branches are followed, the occurrence of events on that branch willnot necessarily affect other branches. As development progresses, many smaller branches are reached,which may each relate to the development of certain tissues, cell types, or regions of a structure.Toxicologically, when specific sequences are affected, the response may be restricted to the featuresthat develop out of that particular sequence. This illustrates how very specific defects can occur inresponse to toxicants or other environmental factors and exhibit clear time dependence.Spontaneous Abortion and Embryonic LossRecent improvements in the ability to measure human chorionic gonadotropin, a very early indicatorof the presence of an embryo, have allowed reasonable estimates of early pregnancy loss. Overall,more than 50 percent of fertilized eggs/embryos are lost through spontaneous abortion. Around 30percent are lost after implantation but before the first menstrual period is missed. An additional 20–25percent are lost after they have been clinically recognized as a pregnancy. There are also probablysubstantial pre-implantation losses, but these are much harder to accurately estimate. Presented anotherway, it appears that the chance of achieving a full-term pregnancy for any one menstrual cycle in whichfertilization is likely to have occurred (based on non-contracepted intercourse with ovulation) is around25 percent.The preponderance of embryonic loss occurs during what was described as the linear phase ofdevelopment. Based on chromosomal analysis of spontaneously aborted embryos, approximatelytwo-thirds of this loss can be explained by gross genetic abnormalities. Around 10 percent can beattributed to a known environmental cause, and a cause cannot be determined for the remainder. Whilesome of the genetically associated loss could be related to environmentally mediated DNA damage, itis clear that most is due to major chromosomal aberrations associated with germ cell production andfusion. Once again, the potentially chemically induced responses are hidden within an extremely highbackground rate of embryonic loss.In general, the response to toxicological insult during the early embryonic stage is consideredto be an all or none event, where damage up to minor cell death is completely repairable and majorcellular disruption or death results in abortion of the pregnancy. This is based on the flexibilityof the cells in the early embryo, which allows them to functionally replace a few lost cells. Asdevelopment progresses, most cell lines become committed to a particular fate and such compensationis less likely.The limited responses available during early embryogenesis mean that typically the endpoint ofconcern for toxic exposures is spontaneous abortion. While this criterion has held over the years formost toxicants, there are recent experimental results which suggest that very early exposure to ethyleneoxide and some other mutagens may cause responses that are manifest much later in development.This implies that the exposure may result in a sublethal injury that is not repaired, nor are all of the