Teratogenicity

In contemporary usage, the term teratology generally refers to disfiguring birth defects or malformations. Another term for this is dysmorphology, meaning "the study of abnormal form."

Etymology
Teratology (from the Greek (genitive ), meaning monster, or marvel and, meaning word, speech) as early as 17th century referred to a discourse on prodigies and marvels, of anything so extraordinary as to seem abnormal. In 19th century, it acquired a meaning closer related to biological deformities, mostly in the field of botany. Currently, its most instrumental meaning is that of the medical study of teratogenesis, congenital malformations or grossly deformed individuals. Monster is a pejorative term for a grossly deformed individual, although it is interesting to note that, etymologically, this word is related to demonstration, and used to simply mean something worth looking at, for being unusual, without necessarily being pejorative.

Teratology as a medical term was popularized in the 1960s by Dr. David W. Smith of the University of Washington Medical School, one of the researchers who became known in 1973 for the discovery of Fetal alcohol syndrome. With greater understanding of the origins of birth defects, the field of teratology now overlaps with other fields of basic science, including developmental biology, embryology, and genetics.

Teratogenesis and teratology
Birth defects are known to occur in 3-5% of all newborns. They are the leading cause of infant mortality in the United States, accounting for more than 20% of all infant deaths. Seven to ten percent of all children will require extensive medical care to diagnose or treat a birth defect. Although significant progress has been made in identifying etiologic causes of some birth defects, approximately 65% have no known or identifiable cause.

It was previously believed that the mammalian embryo developed in the impervious uterus of the mother, protected from all extrinsic factors. However, after the thalidomide disaster of the 1960's, it became apparent and more accepted that the developing embryo could be highly vulnerable to certain environmental agents that have negligible or non-toxic effects to adult individuals.

Wilson's 6 principles
Along with this new awareness of the in utero vulnerability of the developing mammalian embryo came the development and refinement of The Six Principles of Teratology which are still applied today. These principles of teratology were put forth by Jim Wilson in 1959 and in his monograph Environment and Birth Defects. It is these principles that guide the study and understanding of teratogenic agents and their effects on developing organisms


 * Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors.
 * Susceptibility to teratogenesis varies with the developmental stage at the time of exposure to an adverse influence. There are critical periods of susceptibility to agents and organ systems affected by these agents.
 * Teratogenic agents act in specific ways on developing cells and tissues to initiate sequences of abnormal developmental events.
 * The access of adverse influences to developing tissues depends on the nature of the influence. Several factors affect the ability of a teratogen to contact a developing conceptus, such as the nature of the agent itself, route and degree of maternal exposure, rate of placental transfer and systemic absorption, and composition of the maternal and embryonic/fetal genotypes.
 * There are four manifestations of deviant development (Death, Malformation, Growth Retardation and Functional Defect).
 * Manifestations of deviant development increase in frequency and degree as dosage increases from the No Observable Adverse Effect Level (NOAEL) to a dose producing 100% Lethality (LD100).

Studies designed to test the teratogenic potential of environmental agents use animal model systems (e.g., rat, mouse, rabbit, dog, and monkey). Early teratologists exposed pregnant animals to environmental agents and observed the fetuses for gross visceral and skeletal abnormalities. While this is still part of the teratological evaluation procedures today, the field of Teratology is moving to a more molecular level, seeking the mechanism(s) of action by which these agents act. Genetically modified mice are commonly used for this purpose. In addition, pregnancy registries are large, prospective studies that monitor exposures women receive during their pregnancies and record the outcome of their births. These studies provide information about possible risks of medications or other exposures in human pregnancies.

Understanding how a teratogen causes its effect is not only important in preventing congenital abnormalities but also has the potential for developing new therapeutic drugs safe for use with pregnant women.

Teratology education
It is estimated that 10% of all birth defects are caused by a prenatal exposure or teratogen. 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
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:


 * Ionizing radiation: atomic weapons, radioiodine, radiation therapy


 * Infections: cytomegalovirus, herpes virus, parvovirus B-19, rubella virus (German measles), syphilis, toxoplasmosis, Venezuelan equine encephalitis virus


 * Metabolic imbalance: alcoholism, endemic cretinism, diabetes, folic acid deficiency, hyperthermia, phenylketonuria, rheumatic disease and congenital heart block, virilizing tumors


 * Drugs and environmental chemicals: 13-cis-retinoic acid, isotretinoin (Accutane), aminopterin, androgenic hormones, busulfan, captopril, enalapril, chlorobiphenyls (PCBs), Dioxin, coumarin, cyclophosphamide, diethylstilbestrol, diphenylhydantoin (Phenytoin, Dilantin, Epanutin), ethanol, ethidium bromide, etretinate, lithium, methimazole, organic mercury, penicillamine, tetracyclines, thalidomide, trimethadione, uranium, methoxyethyl ethers and valproic acid.

The status of some of the above substances (e.g. diphenylhydantoin) is subject to debate, and many other compounds are under varying degrees of suspicion. These include Agent Orange, nicotine, aspirin and other NSAIDs. Other compounds are known as severe teratogens based on veterinary work and animal studies, but aren't listed above because they have not been studied in humans, e.g. cyclopamine. Teratogenic effects also help to determine the pregnancy category assigned by regulatory authorities; in the United States, a pregnancy category of X, D, or C may be assigned if teratogenic effects (or other risks in pregnancy) are documented or cannot be excluded.

Isotretinoin (13-cis-retinoic-acid; brand name Accutane), which is often used to treat severe acne, is such a strong teratogen that just a single dose taken by a pregnant woman may result in serious birth defects. Because of this effect, most countries have systems in place to ensure that it is not given to pregnant women, and that the patient is aware of how important it is to prevent pregnancy during and at least one month after treatment. Medical guidelines also suggest that pregnant women should limit vitamin A intake to about 700 μg/day, as it has teratogenic potential when consumed in excess.

Teratogenic outcomes
Exposure to teratogens can result in a wide range of structural abnormalities such as cleft lip, cleft palate, dysmelia, anencephaly, ventricular septal defect. In most cases, specific agents produce a specific teratogenic response.