By Dr. Rahmat Awang
The Sun, September 5, 1995
Teratogens can either physical or chemical agents that cause the foetus to become malformed (a common term used is congenital malformation or birth defects) or abnormal. Physical agents in this respect comprises of radiation, very low temperature, high fever and mechanical trauma whereas chemical agents cover the whole range of products from agricultural-industrial chemicals to drugs. Alcohol and tobacco too can be fetotoxic (see Healthtrack, Aug 29).
Teratogenesis may be induced when at least two conditions are met. Firstly, the teratogen must get into contact with the developing foetus. Secondly, the time these are in contact must be during the phase where the organ systems are in process of being formed. This critical phase is the first 3 months following conception, also known as the first trimester.
The abnormality that results also depends on what organ system is undergoing the most rapid development at the time of contact between the agent and the foetus. In this respect, different kind of teratogenic effects may be seen with a similar exposure. This phenomenon has been demonstrated in rats exposed to high doses of vitamin A. Exposure on the eight day of gestation results in skeletal malformation whereas exposure on the 12th day results in cleft palate.
The diagram 1 shows the result of an experiment that was conducted using rats to demonstrate the varied teratogenic effects encountered upon exposure of the same chemical substance. In humans, a similar pattern could also be envisaged.
The possible effects from exposure to any potential teratogens can be more easily seen if the various developmental stages of the embryo is understood.
Diagram 2 is intended to show the development of foetus during human pregnancies.
From the time when conception occurs, a sequence of events may take place over the usual nine months and 10 days of uterine life. During this period, many of the developmental steps can be disrupted. The exception applies to the first few days from conception to implantation (up to ninth day). During these few days, the embryo seems to be fairly well protected against any potential teratogenic effects.
The effects on the ovum has been described as "all or none effects". The agent either kills the ovum if the dose is lethal does not apparent to it at all (as minor injury can be repaired completely) if the dose is sublethal. This stage of embryogenesis is called the predifferentiation stage.
The embryonic stage that follows, signals the beginning of organogenesis which progresses up to the 14th week of pregnancy (first trimester). This period of human organ systems development is in fact the period where the embryo is most vulnerable to a teratogenic asssult.
During this time, major morphological changes may occur from exposure to a potential teratogen. Otherwise, by the 12th week, the foetus may take the form of a fully formed human all the organ systems formed and functioning. From the 14th week onwards until term (known as the foetal stage), the foetus continues to grow while refinement of physical features and organ functions takes place during the stages of histogenesis and functional maturation. At this stage, the likelihood of producing congenital malformation is very small, though not entirely impossible. Instead, functional abnormalities such as arrested mental development seems to be the rule.
How these malformations occur are still as yet uncertain. A number of mechanisms have been proposed but many are still subjected to considerable discussion since much of the human data on this subject are based on case reports which in a number of instances are very difficult to interpret.
While animal studies may be useful in determining relative toxicity of an agent they cannot be extrapolated directly to humans. In addition, it is also important for us to appreciate that an exposure to a potential teratogen will not always end up with teratogenesis.
Our present knowledge about embroyonic toxicology does not allow us to predict with any degree of certainty when a particular chemical will produce a teratogenic effect on a foetus.
However, based on documented reports of exposures and effects, we should be able to address the question of relative risks for a specific population.
