Teratogen

Definition

A teratogen is any environmental influence that adversely affects the normal development of the fetus.

Description

Abnormal fetal development may result from exposure to a teratogen. There are four different teratogen categories: physical agents (radiation and hyperthermia), metabolic conditions affecting the mother, infection, and drugs (like thalidomide) and alcohol.

Physical agents

Hyperthermia

Women whose body temperature is raised while pregnant may have abnormalities result in their fetus. The rise in body temperature can be caused by infection or by spending time in hot areas such as a sauna or hot tub.

Ionizing radiation–mutagens versus teratogens

Any outside agent (like radiation) interfering with the process of development is considered a teratogen. Development is the process in which a tiny mass of undifferentiated cells (the embryo) multiplies and differentiates into the kidney, liver, heart, bone, muscles, and so on. Mutagens, however, are agents that directly affect and disrupt DNA , the genetic blueprint of an organism. Some agents, like radiation, are mutagens and teratogens. Ionizing radiation can cause defects either in development or it can damage DNA directly.

Metabolic disease

Infants of women with metabolic disorders have increased risks for abnormalities. Diabetic women, for example, are three to four times more likely to have fetuses with congenital abnormalities than infants of mothers without diabetes . The metabolic disease of the mother can have genetic or other causes.

Infection

There are a number of known infectious organisms which are teratogenic to the fetus, some of which cause damage directly, and some of which damage the fetus by causing a fever and raising the temperature of the mother.

Alcohol and drugs

Thalidomide

A dramatic example of a teratogen is thalidomide. In the early 1960s it was shown that more than 7,000 women who took the anti-nausea drug thalidomide during their pregnancy had children with very short or absent arms and legs. Other abnormalities were also seen in the children, such as the absence of ears, as well as heart and intestinal malformations. Affected infants were born to women who took thalidomide during the critical time period, also known as the period of susceptibility.

Period of susceptibility: The example of thalidomide

Thalidomide also teaches the importance of timing in the action of teratogens. Only a small amount of thalidomide was necessary to cause birth defects, but it had to be taken between 34 and 50 days after conception in order to harm the embryo. The time when teratogens can act, in this case from day 34 to day 50 after conception, is called the period of susceptibility. Since organ development in the unborn child occurs at different times, it was shown that taking thalidomide on different days caused the infants to have a variety of defects (heart vs. ears vs. limb formation). Drugs very often affect specific parts of the process of development. Before, or after, the processes take place, the drug will have no effect. Of course many teratogens, like thalidomide, work on a number of different developmental processes at different times (sometimes they are consecutive times, or they may be non-consecutive: for example from days 16 to 20 and days 24 to 48). The period of susceptibility of the fetus to most teratogens is between the third and eighth week after conception.

Dose and duration: The example of alcohol

The most common teratogen, alcohol, illustrates the important concept that the dose of a teratogen (for example, the number of alcoholic drinks a mother has) and duration of exposure to a teratogen (for example, the number of days a mother drinks alcohol) both play an important role in the effect of a teratogen. Alcohol can have a wide range of effects on a fetus, from no mental change or very mild mental changes (usually a small dose of alcohol) to full-blown fetal alcohol syndrome , in which the infant is severely retarded. Even two glasses of alcohol can be teratogenic to a fetus, but the mental retardation and characteristic facial changes seen in full-blown fetal alcohol syndrome generally requires the mother to drink 2-3 oz of alcohol per day for a sustained period of time (the exact amount of time is not known) during pregnancy. Thus, dose and duration help determine the severity of a teratogen's effects.

Other factors that affect teratogens

Although the dose and duration are important in determining how much of an effect alcohol will have on the fetus, other factors have an impact, too. When normal mice and mutant mice are given the same dose of a particular teratogen, the mutant mice are affected much more severely. This means that in humans, the genetic makeup of the fetus helps determine to what extent the teratogen will affect the fetus. A fetus with one particular set of genes might be severely affected by the mother drinking one glass of alcohol, while another fetus may be unaffected by the first or even second glass of alcohol. The outcome of teratogens probably depends on a combination of factors: the mother's condition (genetic or otherwise), the genetic background of the fetus, and the dose and duration of the teratogen. However, the importance of each factor probably varies greatly from teratogen to teratogen and from individual to individual.

Although the discussion of these teratogenic concepts has revolved around examples from the category of drugs and alcohol, the concepts may be applied to any of the categories of teratogens.

Demographics

Exact numbers of infants affected by teratogens are difficult to estimate. Langman's Medical Embryology states 4-6% of all infants will have major developmental or genetic abnormalities. This source estimates that of the children with major abnormalities, 10% can be attributed to teratogens, 20-25% can be attributed to genetic and environmental influences, and 40-60% of the abnormalities are due to unknown causes (possibly teratogenic). That means as many as 95% of all major birth disorders may involve teratogens.

Diagnosis

The diagnosis varies from teratogen to teratogen. Some genetic diseases and teratogens can present with the same abnormalities and symptoms. If the gene causing the disorder has been isolated and is well understood, the difference between a genetic and a teratogenic disorder may be established. Many abnormalities in children go unexplained. In these cases, teratogen exposure should be considered.

Treatment, prevention, and the period of susceptibility

Treatment options and how well they work vary widely according to the teratogen. The best course is to prevent teratogen exposure, or reduce the exposure as much as possible. Prevention is complicated because very often women may not realize they are pregnant until the middle of the period of susceptibility. Substances that are not harmful to an adult, like the derivatives of retinoic acid found in a number of skin creams, alcohol, and many prescription drugs, can be extremely harmful to the fetus. Retinoic acid, for example, has a period of susceptibility from days 20-35 after conception—a time when many women might not realize they are pregnant.

Thus, women who are engaging in activities that can lead to pregnancy and want to avoid any potential damage to their fetus should attempt to avoid teratogenic substances (including a large number of over-thecounter, prescription, and illegal drugs). Alternatively, women can also prevent most damage to the fetus by closely monitoring their pregnancy status and avoiding teratogens as soon as pregnancy occurs.

Partial list of teratogens

Drugs and chemicals:

• alcohol
• aminoglycosides
• aminopterin
• antithyroid agents
• bromine
• cortisone
• diethylstilbesterol (DES)
• diphenylhydantoin
• heroin
• lead
• methylmercury
• penicillamine
• retinoic acid (Isoretinoin, Accutane)
• tetracycline
• thalidomide
• trimethadione
• valproic acid
• warfarin

Physical agents:

• hyperthermia (fever, sauna)
• ionizing radiation (x rays)

Infectious organisms:

• Coxsackie virus
• Cytomegalovirus
• Herpes simplex virus
• Parvovirus
• Rubella
• Toxoplasma gondii
• Treponema pallidum (syphilis)

Metabolic conditions in the mother

• autoimmune disease
• diabetes
• malnutrition
• phenylketonuria

Resources

BOOKS

Gilbert, Scott F. Developmental Biology. Sunderland, MA: Sinauer Associates, 1994, pp. 633-645.

Sadler, T.W. Langman's Medical Embryology. Baltimore, Williams and Williams, 1995, pp. 122-143.

PERIODICALS

Incardona, J.P., and H. Roelink. "The Role of Cholesterol in Shh Signaling and Teratogen-induced Holoprosencephaly." Cellular and Molecular Life Sciences 57, no. 12 (November 2000): 1709-19.

Machado, A.F., et al. "Teratogenic Response to Arsenite During Neurulation: Relative Sensitivities of C57BL/6J and SWV/Fnn Mice and Impact of the Splotch Allele." Toxicological Sciences 51, no. 1 (September 1999): 98-107.

Sampson, P.D., et al. "On Categorization in Analyses of Alcohol Teratogenesis." Environmental Health Perspectives 108, Supplement 3 (June 2000): 421-428.

WEBSITES

Organization of Teratology Information Services. <http://www.otispregnancy.org/index.html>.

Michael V. Zuck, PhD

Teratogen

Teratogen means, in Greek, "monster forming." Teratogens are chemicals that cause abnormalities in embryos. The most well-known is thalidomide, a drug originally designed to combat morning sickness in pregnant women. It caused the long bones in the arms or legs of fetuses to not develop properly, resulting in babies with severely stunted arms or legs.

Teratogen is a type of mutagen that causes mutations in somatic cells (cells that are not part of the reproductive system). Mutagens induce mutations of deoxyribonucleic acid (DNA ), the hereditary material in cells. The damage of DNA may either kill the cells or, when misrepaired, produce abnormal sequences that will be passed on to daughter cells. This may result in birth defects by injuring developing organs or by disorganizing growth and differentiation.

Apart from thalidomide, the steroid hormones have also been identified as teratogens. The use of male sex hormones as a treatment for breast cancer has resulted in the masculinization of a number of female fetuses when such treatment was commenced prior to the twelfth week of gestation. In addition, the accepted practice of using progesterone from natural sources for the treatment of miscarriage led to the widespread use of synthetic hormones between 1950 and 1960. The result was the birth of more than 600 female babies with equivocal or frankly masculinized external genitalia. It

was found later that these synthetic compounds had appreciable androgenic (related to the male sex hormone) activity.

There are other chemicals suspected of being teratogenic because they are occasionally associated with malformations in the offspring of women treated during pregnancy. These include anticonvulsants and some oral hypoglycemics when taken at high doses during pregnancy. It is, however, very difficult to determine the teratogenesis of a drug. Long and costly surveys must be done on a very large population to associate a particular drug with birth defects.

see also Deoxyribonucleic Acid; Kelsey, Frances Kathleen Oldham; Mutagen; Toxicity.

Joseph Bariyanga

Bibliography

Wilson, James G. (1973). "Present Status of Drugs as Teratogens in Man." Teratology: International Journal of Abnormal Development 7: 3–15.

Internet Resources

"OTIS Fact Sheets." Organization of Teratology Information Services. Available from <http://www.otispregnancy.org>.

Teratogen

A teratogen is an environmental agent that can cause abnormalities in a developing organism resulting in either fetal death or congenital abnormality. The human fetus is separated from the mother by the placental barrier, but the barrier is imperfect and permits a number of chemical and infectious agents to pass to the fetus.

Well known teratogens include (but are not limited to) alcohol , excess vitamin A and retinoic acid, the rubella virus, and high levels of ionizing radiation . Perhaps the best known teratogenic agent is the drug thalidomide , which induced severe limb abnormalities known as phocomelia in children whose mothers took the drug.

See also Birth defects; Embryo and embryonic development; Fetal alcohol syndrome.

Teratogen

A teratogen is an environmental agent that can cause abnormalities in a developing organism resulting in either fetal death or congenital abnormality. The human fetus is separated from the mother by the placental barrier, but the barrier is imperfect and permits a number of chemical and infectious agents to pass to the fetus.

Well known teratogens include (but are not limited to) alcohol, excess vitamin A and retinoic acid, the rubella virus, and high levels of ionizing radiation. Perhaps the best known teratogenic agent is the drug thalidomide, which induced severe limb abnormalities known as phocomelia in children whose mothers took the drug.

See also Birth defects; Embryo and embryonic development; Fetal alcohol syndrome.

Teratogen

An environmental agent that can cause abnormalities in a developing organism resulting in either fetal death or congenital abnormality. The human fetus is separated from the mother by the placental barrier, but the barrier is imperfect and permits a number of chemical and infectious agents to pass to the fetus. Well known teratogens include (but are not limited to) alcohol, excess vitamin A and retinoic acid , the rubella virus , and high levels of ionizing radiation . Perhaps the best known teratogenic agent is the drug thalidomide, which induced severe limb abnormalities known as phocomelia in children whose mothers took the drug.

See also Birth defects; Environmental health; Mutagen