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. 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.^[1]

Etymology[link]

The term stems from the Greek τέρας teras (genitive τέρατος teratos), meaning monster or marvel, and λόγος logos, meaning the word or, more loosely, the study of.^[2]

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.^[3] 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[link]

Teratogenesis[link]

The World Health Organization estimates that about 50% of all fertilized ova are lost within the first three weeks of development, and that 15% of all clinically recognizable pregnancies end in spontaneous abortions. Birth defects are known to occur in 3-6% of all newborns.^[4] 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.[5] And although significant progress has been made in identifying the etiology of some birth defects, approximately 65% have no known or identifiable cause.[6] Polygenic, multifactorial (environmental-genetic interactions) and synergistic interactions of teratogens fall into this category. However, it is extremely difficult to make accurate estimates of exposure risk due to the large number of pharmaceutical, industrial and agricultural chemicals which increases the risk of exposure to multiple agents and their potential synergistic effects, and human genetic heterogeneity which contributes greatly to the individual level of threshold susceptibility.^[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.[7]

Wilson's 6 principles[link]

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.^[6] 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[link]

It is estimated that 10% of all birth defects are caused by prenatal exposure to a teratogenic agent.^[7] 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[link]

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[link]

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.^[4]

Environmental Teratogenic Agents[link]

Approximately 10% of human malformations observed in the first year of life are caused by environmental agents, which have several characteristics in common - ^[4][5]

• 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. ^[4] 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.^[10]

• Caffeine

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. ^[4]

• Ethanol (Alcohol) (see fetal alcohol spectrum disorder)

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.^[5] 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. ^[4]

• 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. ^[4]

• Aminopterin, Methotrexate

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.^[5] 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. ^[4]

• Androgenic hormones

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.^[5]

• Enalapril

Enalapril belongs to a class of drugs which inhibit the rennin-angiotensin system and is widely prescribed for the treatment of hypertension. The mechanisms of action are blocking the conversion of angiotensin I into angiotensin II and/or blocking angiotensin II from acting on target organs.^[10] The use of these drugs by pregnant women in the second or third trimester has been associated with birth defects such as intrauterine growth retardation, craniofacial deformations, limb contractures and lung hypoplasia. A study on pregnant rhesus macaques has shown that the administration of enalapril between gestation days 122 and 126 causes fetal hypotension and decreased renal perfusion pressure, which results in reduced glomerular filtration pressure, oligohydramnios and its sequence of structural anomalies.^[10]

• Coumarin (Including Warfarin)

Coumarin in-utero exposure is known to cause risk of nasal hypoplasia, calcific stiffing of secondary epiphysis, and central nervous system abnormalities in 10 to 25% of exposed infants. Coumarin inhibits the formation of carboxyglutamyl residues, decreasing the ability of proteins to bind calcium. A useful animal model has not yet been reported.^[5]

• Cyclophosphamide

Defects caused by this agent include growth retardation, ectrodactyly, cardiovascular defects and other smaller anomalies. Experimental evidence gathered in rat, mice, rabbit and monkey models has shown a high susceptibility of the nervous system and mesenchymal tissues. The complex mechanism of action involves the production of phosphoramide mustard and acrolein from a 4-hydroxycyclophosphamide intermediate. These reaction products are though to produce teratogenic effects associated with exposures to cyclophosphamide by interacting with cellular DNA which results in cell death.^[11]

• Diethylstilbestrol

This synthetic oestrogen was used for nearly 30 years until 1970 to prevent threatened miscarriage and other pregnancy complications.^[11] Subsequent studies revealed clitoromomegaly and vaginal adenocarcinomas in female offspring following first trimester exposure.^[5] Teratogenic and transplacental carcinogenic effects have also been demonstrated in rat, mice and hamster models. ^[4]

• Phenytoin (diphenylhydantoin, Dilantin, Epanutin)

Chronic exposure to phenytoin during pregnancy has been suggested to present a risk of acquiring the fetal hydantoin syndrome which is manifested by intrauterine growth restriction and microcephaly. Other defects such as cleft lip and palate and congenital heart disease have also been reported. ^[4]

• Lithium carbonate

Lithium carbonate has been widely used as an antidepressant during the first half of the nineteenth century. It was first associated with congenital malformations in 1970. Malformations described by Dr.Weinstain in 1983, in the International Register of Lithium Babies included heart and large vessel anomalies, Epstein’s anomaly, neural tube defects, talipes, microtia, and thyroid anomalies. Lithium carbonate appears to be a human teratogen at the therapeutic dosages.^[12]

• Methimazole

Methimazole used to treat thyrotoxicosis can readily cross the placenta and has been associated with aplasia cutis.^[4]

• Tetracyclines

Antimicrobial tetracyclines prevent bacterial protein synthesis by inhibiting access of aminoacyl tRNA to the mRNA-ribosome complex. Tetracyclines can readily cross the placenta and they have been shown to cause teeth discolouration, depression of skeletal bone growth and extremely high doses may result in hypoplasia of tooth enamel. Tetracyclines can complex with calcium and organic matrix of newly forming bone.^[5]

• Thalidomide

Thalidomine was first synthesized in 1954 and marketed in 1956 in Germany. It was studied in rodents for a variety of toxicities, and even when administered at very high doses, no side effects were observed. With increasing sales in 46 counties, it was marketed for treatment of influenza and promoted as a remedy for sleeplessness.^[13] It was never approved in the United States for commercial sale; however thousands of samples were distributed to physicians. It was often prescribed to pregnant women to treat morning sickness. In 1961, a significant increase in congenital limb defects in exposed newborns became apparent. As a result, thalidomide was withdrawn from the market. Thalidomide contains both left- and right-handed isomers in equal amounts. The (R) enantiomer is effective against morning sickness, but the (S) is teratogenic. The enantiomers can interconvert in vivo.^[14] It is estimated that anywhere between 10 000 and 20 000 children were affected worldwide. This estimate does not include the number of miscarriages or still births which are attributable to thalidomide.^[15] Thalidomide embryopathy is characterized by variable degree of reduction deformities of the limbs, malformations of the ear, deafness, phocomelia, Fallot tetralogy, inguinal hernia, recto-vaginal fistula, cryptorchid testes, ectopic kidneys, absent or hypoplastic humerus, absent digits and many other developmental anomalies.^[13]

Since the thalidomide tragedy of the sixties, scientists around the world have been trying to elucidate thalidomide’s teratogenic mechanism of action. Some of these proposed mechanisms of action supported by data include: axial limb artery degeneration, B vitamin antagonism, cell death, cell-cell interactions, decreased mesonephric induction of chondrogenesis, direct effect on the limb bud, DNA intercalation, TNF-alpha antagonism and many others. What is known is that thalidomide is metabolised in the body through a non-enzymatic pathway which leads to spontaneous hydrolysis in the plasma.^[13] Today, there are 5000 thalidomide survivors worldwide and they are in their late forties. The stress placed on their body structures is causing further physical deterioration, resulting in new disabilities.^[16]

• Trimethadione

A fetal trimethadione syndrome is characterized by developmental delay, V-shaped eyebrows, low-set ears with anteriorly folded helix, high arched palate and irregular teeth.^[4]

• Progestins

Progestins are female sex hormones which are most commonly used as hormonal contraceptives. They have been reported to have teratogenic effects in humans such as masculinization of female external genitalia and a positive association between in utero exposure and cardiovascular defects, neural tube defects and limb defects.^[11]

• Aspirin

Chronic high exposure of pregnant women to aspirin has been associated with low birth weight and a variety of maternal and placental complications.^[4]

• Retinol (Vitamin A)

Vitamin A in the form of retinoic acid, is a potent teratogen. Its two primary modes of action have been established: direct cytotoxicity and interactions with DNA, which collectively cause a delay in differentiation and/or inhibition of protein synthesis.^[4] It is now appreciated that retinoids play a widespread critical role in developmental control. Some phenotypic abnormalities followed by excess Vitamin A included abnormal brachial arch development, ear malformations or cleft palate. Vitamin A deficiency in pigs resulted in offspring being born with no eyeballs.^[11]

• Vitamin D

Excess of Vitamin D during pregnancy has increased the incidence of a syndrome consisting of supravalvular aortic stenosis, elfin facies, and mental retardation in humans.^[4]

• Other: temazepam (Restoril; Normisson), nitrazepam (Mogadon), nimetazepam (Ermin), busulfan, captopril, etretinate, penicillamine, methoxyethyl ethers, Flusilazole, valproic acid, and many more.

Environmental chemicals

• Polychlorinated biphenyls (PCBs)

First teratogenic potential of PCBs was identified in Japan in 1968 when consumption of contaminated cooking oil by pregnant women resulted in pigmented children with low birth weights, pigmentation of gums, nails and groin, calcification of the skull, rocker bottom heal and conjunctivitis.^[5] “Yusho” meaning the oil disease is the English term for the PCB poisoning syndrome.^[4]

• Polychlorinated dibenzodioxins or 2,3,7,8- Tetrachlorodibenzo-p-dioxin (Dioxin)

TCDD is the most potent of the aromatic hydrocarbons. It is a contaminant of many industrial mixtures, such as Agent Orange which was sprayed over Vietnam.^[11] Aerial spraying in Zealand was associated with an increase in the incidence of talipes, however no epidemiologic studies support a causal relationship between TCDD and human malformations.^[4] TCDD has been shown to induce cleft palate and abnormalities of the kidneys and brain in mice.^[11]

• Polychlorinated dibenzofurans (PCDFs)

Very similar effects to TCDD. [23]

• Methylmercury

Mercury is known to interfere with metabolism and function by combining with phosphoryl, carboxyl, amide and amine groups resulting in enzyme inhibition and protein precipitation.^[5] The most documented case of human exposure took place in Japan in 1953 where the local population ingested fish caught in a bay heavily polluted by methylmercury. Resulting congenital abnormalities in infants born to exposed mothers included cerebral palsy and associated microcephaly.^[4]

• Other: ethidium bromide, polycyclic aromatic hydrocarbons (polynuclear aromatic hydrocarbons)

Ionizing radiation

• Iodine-131

Exposure to radioactive iodine creates a potential risk to the developing fetal thyroid, especially once it begins to concentrate iodine at 10 to 12 weeks of gestation.^[4]

• Radiation therapy

Damage to cell chromatin is the direct result of radiation. Most common malformations associated with therapeutic radiation in pregnant mothers include intrauterine growth retardation, gross malformations and embryonic cell death.^[5] The risk of major malformations is not increased by in utero exposure of 5 rads or less.^[4]

• Other: uranium, background radiation, diagnostic x-rays, Iodine-131

Infections[link]

Viral

• Cytomegalovirus
• Herpes virus
• Parvovirus B19
• Rubella virus (German measles)
• Venezuelan equine encephalitis virus

Bacterial

• Syphilis

Parasitic

• Toxoplasmosis

(An easy way to remember maternal infections is TORCH: Toxoplasmosis, Other agents, Rubella, CMV and HSV.)

Metabolic imbalance[link]

• Diabetes
• Folic acid deficiency
• Iodine deficiency
• Maternal Starvation
• Obesity
• Other: Hyperthermia, phenylketonuria, rheumatic disease, congenital heart block, virilizing tumors, Endemic cretinism

Mechanical Problems[link]

Mechanical problems of constraint which may increase the risk of congenital malformations include: velamentous cord insertion, amniotic bands, umbilical cord bands, uterine malformations, extrinsic pressure or uterine contractions, limb amputation or malposition and oligohydramnios.

Teratogenic outcomes[link]

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. 555

Plantae[link]

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[link]

Biology portal

• Carcinogen
• Congenital abnormalities
• Mutagen
• Mütter Museum

References[link]

External links[link]

• 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)^{[dead link]}
• List of known and suspected Teratogens (Hazard Database)