Teratology

A two-headed calf

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.

Etymology

The term stems from the Greek τέρᾰς téras (genitive τέρᾰτος tératos), meaning monster or marvel, and λόγος lógos, meaning the word or, more loosely, the study of^[1] .

As early as the 17th century, teratology referred to a discourse on prodigies and marvels of anything so extraordinary as to seem abnormal. In the 19th century, it acquired a meaning more closely 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 individuals with significant malformations. There are many pejorative terms that have historically been used to describe individuals with significant physical malformations. The 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.^[2] 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.

Animalia

Teratogenesis

Birth defects are known to occur in 3-5% of all newborns.^[3] 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.^[4] And although significant progress has been made in identifying the etiology of some birth defects, approximately 65% have no known or identifiable cause.^[5]

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 1960s, 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.

A review published in 2010 identified 6 main teratogenic mechanisms associated with medication use: folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption and specific receptor- or enzyme-mediated teratogenesis.^[6]

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.^[7] These principles guide the study and understanding of teratogenic agents and their effects on developing organisms:

1. Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors.
2. 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.
3. Teratogenic agents act in specific ways on developing cells and tissues to initiate sequences of abnormal developmental events.
4. 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.
5. There are four manifestations of deviant development (Death, Malformation, Growth Retardation and Functional Defect).
6. 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 prenatal exposure to a teratogenic agent.^[5] 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.^[8] 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.^[9]

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:

• Drugs and medications: tobacco, caffeine, drinking alcohol (ethanol) (see fetal alcohol spectrum disorder), isotretinoin (13-cis-retinoic acid, Roaccutane), temazepam (Restoril; Normisson), nitrazepam (Mogadon), nimetazepam (Ermin), aminopterin or methotrexate, androgenic hormones, busulfan, captopril, enalapril, coumarin, cyclophosphamide, diethylstilbestrol, phenytoin (diphenylhydantoin, Dilantin, Epanutin), etretinate, lithium, methimazole, penicillamine, tetracyclines, thalidomide, trimethadione, methoxyethyl ethers, Flusilazole, valproic acid, and many more.
• Environmental chemicals: polycyclic aromatic hydrocarbons (polynuclear aromatic hydrocarbons), polychlorinated biphenyls (PCBs), polychlorinated dibenzodioxins a.k.a dioxin, polychlorinated dibenzofurans (PCDFs), hexachlorobenzene hexachlorophene, organic mercury, ethidium bromide, etc.
• Ionizing radiation: atomic weapons fallout (Iodine-131, uranium), background radiation, diagnostic x-rays, radiation therapy
• Infections: cytomegalovirus, herpes virus, parvovirus B19, rubella virus (German measles), syphilis, toxoplasmosis, Venezuelan equine encephalitis virus. (An easy way to remember maternal infections is TORCH: Toxoplasmosis, Other agents, Rubella, CMV and HSV.
• Metabolic imbalance: alcoholism, endemic cretinism, diabetes, folic acid deficiency, iodine deficiency, hyperthermia, phenylketonuria, rheumatic disease and congenital heart block, virilizing tumors

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,^[10] nicotine,^[11] 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 Roaccutane), 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.^[12][13]

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. Exposure to a single agent can produce various abnormalities depending on the stage of development it occurs. Specific birth defects are not characteristic of any single agent.

Plantae

In botany, teratology investigates the theoretical implications of abnormal specimens. For example, the discovery of abnormal flowers—for example, flowers with leaves instead of petals, or flowers with staminoid pistils—furnished important evidence for the "foliar theory", the theory that all flower parts are highly specialised leaves.

See also

Biology portal

• Carcinogen
• Congenital abnormalities
• Mutagen

References

1. ^ "Online Etymology Dictionary". http://www.etymonline.com/index.php?term=logos. 
2. ^ Jones K.L., Smith D.W, Ulleland C.N., Streissguth A.P. (1973). "Pattern of malformation in offspring of chronic alcoholic mothers". Lancet 1 (7815): 1267–1271. PMID 4126070. 
3. ^ "Birth Defects & Genetics: Birth Defects". http://www.marchofdimes.com/pnhec/4439_1206.asp. Retrieved 2007-05-30. 
4. ^ Dicke JM (1989). "Teratology: principles and practice". Med. Clin. North Am. 73 (3): 567–82. PMID 2468064. 
5. ^ ^{a b} Ronan O'Rahilly, Fabiola Müller (2001). Human embryology & teratology. New York: Wiley-Liss. ISBN 0-471-38225-6. 
6. ^ van Gelder MM, van Rooij IA, Miller RK, Zielhuis GA, de Jong-van den Berg LT, Roeleveld N (January 2010). "Teratogenic mechanisms of medical drugs". Hum Reprod Update 16 (4): 378–94. doi:10.1093/humupd/dmp052. PMID 20061329. 
7. ^ James G. Wilson, (1973). Environment and Birth Defects (Environmental Science Series). London: Academic Pr. ISBN 0-12-757750-5. 
8. ^ Bracken MB, Holford TR (1981). "Exposure to prescribed drugs in pregnancy and association with congenital malformations". Obstetrics and gynecology 58 (3): 336–44. PMID 7266953. 
9. ^ King CR (1986). "Genetic counseling for teratogen exposure". Obstetrics and gynecology 67 (6): 843–6. doi:10.1097/00006250-198606000-00020. PMID 3703408. 
10. ^ Linnainmaa K (1983). "Sister chromatid exchanges among workers occupationally exposed to phenoxy acid herbicides 2,4-D and MCPA". Teratog., Carcinog. Mutagen. 3 (3): 269–79. doi:10.1002/1520-6866(1990)3:3<269::AID-TCM1770030306>3.0.CO;2-F. PMID 6137083. 
11. ^ Vaglenova J, Birru S, Pandiella NM, Breese CR (2004). "An assessment of the long-term developmental and behavioral teratogenicity of prenatal nicotine exposure". Behav. Brain Res. 150 (1-2): 159–70. doi:10.1016/j.bbr.2003.07.005. PMID 15033289. 
12. ^ Hunt JR (1996). "Teratogenicity of high vitamin A intake". N. Engl. J. Med. 334 (18): 1197. doi:10.1056/NEJM199605023341814. PMID 8602195. 
13. ^ Hartmann S, Brørs O, Bock J, et al. (2005). "Exposure to retinoic acids in non-pregnant women following high vitamin A intake with a liver meal". International journal for vitamin and nutrition research. Internationale Zeitschrift für Vitamin- und Ernährungsforschung. Journal international de vitaminologie et de nutrition 75 (3): 187–94. PMID 16028634. 

External links

• Society of Teratology
• European Teratology Society
• Organization of Teratology Information Specialists
• March of Dimes Foundation
• A Telling of Wonders: Teratology in Western Medicine through 1800 (New York Academy of Medicine Historical Collections)
• List of known and suspected Teratogens (Hazard Database)