Teratology is the study of abnormalities of physiological development. It is often thought of as the study of human birth defects, but it is much broader than that, taking in other non-birth developmental stages, including puberty; and other non-human life forms, including plants. A newer term developmental toxicity includes all manifestations of abnormal development, not only frank terata. These may include growth retardation or delayed mental development without any structural malformations.
It is estimated that 10% of all birth defects are caused by prenatal exposure to a teratogenic agent. These exposures include, but are not limited to, medication or drug exposures, maternal infections and diseases, and environmental and occupational exposures. Teratogen-caused birth defects are potentially preventable. Studies have shown that nearly 50% of pregnant women have been exposed to at least one medication during gestation. An additional study found that of 200 individuals referred for genetic counseling for a teratogenic exposure, 52% were exposed to more than one potential teratogen .
Teratogenic agents can be divided into two categories, environmental or genetic, based on their etiology. Each category of agents utilizes different pathological processes that result in embryopathology.
Genetic Teratogenic Agents
About 20–25% of human malformations observed in the first year of life are caused by genetic agents. Birth defects caused by these teratogenic agents have a range of pathological processes that are determined prior to conception, due to the presence of inherited or newly acquired genetic abnormalities. The causal mechanisms underlying these processes include, but are not limited to: gene deficiency, gene abnormality, chromosome rearrangement, chromosome deletion and chromosome excess. Although environmental factors may modify the development of the genetically abnormal embryo, the genetic abnormality is the major contributor to the pathologic process.
Environmental Teratogenic Agents
Approximately 10% of human malformations observed in the first year of life are caused by environmental agents, which have several characteristics in common: Stage sensitivity – There are three defined stages of human embryonic development which are divided into fertilization & implantation, organogenesis and fetal period. The susceptibility of the embryo as well as the degree of the adverse effect caused by the agent depends on the stage at which the exposure occurred.
- Dose response relationships – There exists a quantitative correlation between the magnitude of embryopathic effects and the dose of the teratogenic agent, such that the higher the dose, the more severe the teratogenic effect.
- Threshold effects – Refers to the level of exposure below which the incidence of malformations or death is not statistically greater than that of controls.
- Genetic variability – There are differences in the placental transport, metabolism, absorption and distribution of an agent in mammals and these differences must be accounted for when extrapolating data between different species.
- Infections – Dose and time of exposure cannot be demonstrated for replicating teratogenic agents.
A wide range of different chemicals and environmental factors are suspected or are known to be teratogenic in humans and in animals. A selected few include:
Social drugs, medications, nonprescription products
- Nicotine (Tobacco)
It is estimated that about 30% of all women of childbearing years smoke, and 25% of all women will continue on smoking during pregnancy. Many studies have been conducted in the past few decades which link maternal cigarette smoking during pregnancy with adverse pregnancy outcomes, including intrauterine growth retardation, preterm delivery, perinatal mortality, and spontaneous abortions.
High doses of caffeine have been reported to cause adverse developmental effects of the central nervous system. Although caffeine is not classified as a human teratogen, it is likely that excess consumption during gestation can result in embryotoxic effects.
Binge drinking during pregnancy is associated with birth defects such as intrauterine growth retardation, microcephaly, cardiac abnormalities and maxillary hypoplasia. Studies show that approximately one third of the children born to alcoholic mothers suffer from fetal alcohol syndrome and all affected children exhibit developmental delay. High risk of exposure constitutes chronic consumption of 6oz of alcohol per day. If the mother drinks less than 2 oz of alcohol per day, fetal alcohol syndrome is unlikely to develop. Acetate, an ethanol metabolite, is 10 000 more embryotoxic. It is likely that the mechanism of action of these two agents differs substantially. The primary effect of alcohol on the fetus is the inhibition of cell growth and altered placental transport of amino acids to the fetus, as demonstrated in the mice and rat animal models.
- Isotretinoin (13-cis-retinoic acid, Roaccutane)
Isotretinoin is a drug used to treat cystic acne. It is also a human teratogen which may cause ear malformations, facial abnormalities, cleft palate and open neural tube defect.
In utero exposure to amniopterin can result in growth retardation, abnormal cranial ossification, high arched palate, and the reduction in the derivatives of the first brachial arch. Methotrexate exposure during the first two months or for five days between the eight and ninth week can result in the absence of digits. Both of these agents are folic acid antagonists that interfere with the action of dihydrofolate reductase, resulting in cell death during the S phase of the cell cycle. Rat and mice blastomere cultures were used to study the effects of these agents.
Only tissues which contain receptors for androgens can be affected by their exposure. One common effect of a large dose of androgenic hormone exposure is the masculanization of female external genitalia. This masculanization is characterised by clitoromegally or enlargement of the clitoris. Fusion of the labia minora can also occur. Inadequate dose of androgenic hormones during male embryo development can result in the feminization of the male sex structures. Many animal models were used to demonstrate the adverse effects of androgen hormone excess or deficiency, including mice, rats, rabbits, hamsters and monkeys.