# Teratology

Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology caused by teratogens and also in pharmacology and toxicology. Teratogens are substances that may cause non-heritable birth defects via a toxic effect on an embryo or fetus. Defects include malformations, disruptions, deformations, and dysplasia that may cause stunted growth, delayed mental development, or other congenital disorders that lack structural malformations. These defects can be recognized prior to or at birth as well as later during early childhood. The related term developmental toxicity includes all manifestations of abnormal development that are caused by environmental insult. The extent to which teratogens will impact an embryo is dependent on several factors, such as how long the embryo has been exposed, the stage of development the embryo was in when exposed (gestational timing), the genetic makeup of the embryo, and the transfer rate of the teratogen. The dose of the teratogen, the route of exposure to the teratogen, and the chemical nature of the teratogenic agent also contribute to the level of teratogenicity.

## Etymology

The term was borrowed in 1842 from the French tératologie, where it was formed in 1830 from the Greek τέρας teras (word stem τέρατ- terat-), meaning "sign sent by the gods, portent, marvel, monster", and -ologie (-ology), used to designate a discourse, treaty, science, theory, or study of some topic.
Old literature referred to abnormalities of all kinds under the Latin term Lusus naturae (lit. "freak of nature"). 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. Historically, people have used many pejorative terms to describe/label cases of significant physical malformations. In the 1960s, 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), popularized the term teratology. With the growth of understanding of the origins of birth defects, the field of teratology as of 2015 overlaps with other fields of science, including developmental biology, embryology, and genetics.
Until the 1940s, teratologists regarded birth defects as primarily hereditary. In 1941, the first well-documented cases of environmental agents being the cause of severe birth defects were reported.

## Teratogenesis
### Wilson's principles

In 1959 and in his 1973 monograph Environment and Birth Defects, embryologist James Wilson put forth six principles of teratogenesis to guide the study and understanding of teratogenic agents and their effects on developing organisms. These principles were derived from and expanded on by those laid forth by zoologist Camille Dareste in the late 1800s:
* 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 (LD$_{100}$).

## Causes

Common causes of teratogenesis include:
* Genetic disorders and chromosomal abnormalities
* Maternal health factors
** Nutrition during pregnancy (e.g., spina bifida resulting from folate deficiency)
** Metabolic disorders such as diabetes and thyroid disease
** Stress
* Chemical agents
** Prescription and recreational drugs (e.g., alcohol, thalidomide)
** Environmental toxins and contaminants (e.g., heavy metals such as mercury and lead, polychlorinated biphenyls (PCBs))
* Vertically transmitted infections such as rubella and syphilis
* Ionizing radiation such as X-rays and that emitted from nuclear fallout
* Temperatures outside the accepted range for a given organism

## Human pregnancy

In humans, congenital disorders resulted in about 510,000 deaths globally in 2010.
About 3% of newborns have a "major physical anomaly", meaning a physical anomaly that has cosmetic or functional significance. Developmental defects manifest in approximately 3% to 5% of newborns in the United States, between 2% to 3% of which are teratogen-induced. Congenital disorders are responsible for 20% of infant deaths. The most common congenital diseases are heart defects, Down syndrome, and neural tube defects. Trisomy 21 is the most common type of Down Syndrome. About 95% of infants born with Down Syndrome have this disorder and it consists of 3 separate copies of chromosomes. Translocation Down syndrome is not as common, as only 3% of infants with Down Syndrome are diagnosed with this type. VSD, ventricular septal defect, is the most common type of heart defect in infants. If an infant has a large VSD it can result into heart failure. Infants with a smaller VSD have a 96% survival rate and those with a moderate VSD have about an 86% survival rate. Lastly, NTD, neural tube defect, is a defect that forms in the brain and spine during early development. If the spinal cord is exposed and touching the skin it can require surgery to prevent an infection.

### Medicines
#### Acitretin

Acitretin is a retinoid and vitamin A derivative that is used in the treatment of psoriasis. Acitretin is highly teratogenic and noted for the possibility of severe birth defects. It was initially suggested as a replacement for Etretinate. It should not be used by pregnant women or women planning to get pregnant within 3 years following the use of acitretin. Sexually active women of childbearing age who use acitretin should also use at least two forms of birth control concurrently. Men and women who use it should not donate blood for three years after using it, because of the possibility that the blood might be used in a pregnant patient and cause birth defects. In addition, it may cause nausea, headache, itching, dry, red or flaky skin, dry or red eyes, dry or chapped lips, swollen lips, dry mouth, thirst, cystic acne or hair loss.

#### Etretinate

Etretinate (trade name Tegison) is a medication developed by Hoffmann–La Roche that was approved by the FDA in 1986 to treat severe psoriasis. It is a second-generation retinoid. It was subsequently removed from the Canadian market in 1996 and the United States market in 1998 due to the high risk of birth defects. It remains on the market in Japan as Tigason.
Isotretinoin
Isotretinoin is classified as a retinoid drug and is used as a treatment for severe acne. Prenatal exposure to isotretinoin can cause neurocognitive impairment in some children.

#### Vaccination

In humans, vaccination has become readily available, and is important for the prevention of various communicable diseases such as polio and rubella, among others. There has been no association between congenital malformations and vaccination — for example, a population-wide study in Finland in which expectant mothers received the oral polio vaccine found no difference in infant outcomes when compared with mothers from reference cohorts who had not received the vaccine. However, on grounds of theoretical risk, it is still not recommended to vaccinate for polio while pregnant unless there is risk of infection. An important exception to this relates to provision of the influenza vaccine while pregnant. During the 1918 and 1957 influenza pandemics, mortality from influenza in pregnant women was 45%. In a 2005 study of vaccination during pregnancy, Munoz et al. demonstrated that there was no adverse outcome observed in the new infants or mothers, suggesting that the balance of risk between infection and vaccination favored preventative vaccination.

#### Reproductive hormones and hormone replacement therapy

There are a number of ways that a fetus can be affected in pregnancy, specifically due to exposure to various substances. There are a number of drugs that can do this, specifically drugs such as female reproductive hormones or hormone replacement drugs such as estrogen and progesterone that are not only essential for reproductive health, but also pose concerns when it comes to the synthetic alternatives to these. This can cause a multitude of congenital abnormalities and deformities, many of which can ultimately affect the fetus and even the mother's reproductive system in the long term. According to a study conducted from 2015 till 2018, it was found that there was an increased risk of both maternal and neonatal complications developing as a result of hormone replacement therapy cycles being conducted during pregnancy, especially in regards to hormones such as estrogen, testosterone and thyroid hormone. When hormones such as estrogen and testosterone are replaced, this can cause the fetus to become stunted in growth, born prematurely with a lower birth weight, develop mental retardation, while in turn causing the mother's ovarian reserve to be depleted while increasing ovarian follicular recruitment.

#### Withdrawn drugs
##### Thalidomide

Thalidomide was once prescribed therapeutically from the 1950s to early 1960s in Europe as an anti-nausea medication to alleviate morning sickness among pregnant women. While the exact mechanism of action of thalidomide is not known, it is thought to be related to inhibition of angiogenesis through interaction with the insulin like growth factor(IGF-1) and fibroblast like growth factor 2 (FGF-2) pathways. In the 1960s, it became apparent that thalidomide altered embryo development and led to limb deformities such as thumb absence, underdevelopment of entire limbs, or phocomelia. Thalidomide may have caused teratogenic effects in over 10,000 babies worldwide.

### Recreational drugs
#### Alcohol

In the US, alcohol is subject to the FDA drug labeling Pregnancy Category X (Contraindicated in pregnancy). Alcohol is known to cause fetal alcohol spectrum disorder.
There are a wide range of affects that Prenatal Alcohol Exposure (PAE) can have on a developing fetus. Some of the most prominent possible outcomes include the development of Fetal Alcohol Syndrome, a reduction in brain volume, still births, spontaneous abortions, impairments of the nervous system, and much more. Fetal Alcohol Syndrome has numerous symptoms which may include cognitive impairments and impairment of the facial features. PAE remains the leading cause of birth defects and neurodevelopmental abnormalities in the United States, affecting 9.1 to 50 per 1000 live births in the U.S. and 68.0 to 89.2 per 1000 in populations with high levels of alcohol use.

#### Tobacco

Consuming tobacco products while pregnant or breastfeeding can have significant negative impacts on the health and development of the unborn child and newborn infant.

### Lead exposure during pregnancy

Long before modern science, it was understood that heavy metals could cause negative effects to those who were exposed. The Greek physician Pedanius Dioscorides described the effects of lead exposure as something that "makes the mind give way." Lead exposure in adults can lead to cardiological, renal, reproductive, and cognitive issues that are often irreversible, however, lead exposure during pregnancy can be detrimental to the long-term health of the fetus. Exposure to lead during pregnancy is well known to have teratogenic effects on the development of a fetus. Specifically, fetal exposure to lead can cause cognitive impairment, premature births, unplanned abortions, ADHD, and much more. Lead exposure during the first trimester of pregnancy leads to the greatest predictability of cognitive development issues after birth.
Low socioeconomic status correlates to a higher probability of lead exposure. A well-known recent example of lead poisoning — and the impacts it can have on a community — was the 2014 water crisis in Flint, Michigan. Researchers have found that female fetuses developed at a higher rate than male fetuses in Flint when compared to surrounding areas. The higher rate of female births indicated a problem because male fetuses are more sensitive to pregnancy hazards than female fetuses.

## Other animals
### Fossil record

Evidence for congenital deformities found in the fossil record is studied by paleopathologists, specialists in ancient disease and injury. Fossils bearing evidence of congenital deformity are scientifically significant because they can help scientists infer the evolutionary history of life's developmental processes. For instance, because a Tyrannosaurus rex specimen has been discovered with a block vertebra, it means that vertebrae have been developing the same basic way since at least the most recent common ancestor of dinosaurs and mammals. Other notable fossil deformities include a hatchling specimen of the bird-like dinosaur, Troodon, the tip of whose jaw was twisted. Another notably deformed fossil was a specimen of the Choristodera Hyphalosaurus, which had two heads- the oldest known example of polycephaly.

### Thalidomide and chick limb development

Thalidomide is a teratogen known to be significantly detrimental to organ and limb development during embryogenesis. It has been observed in chick embryos that exposure to thalidomide can induce limb outgrowth deformities, due to increased oxidative stress interfering with the Wnt signaling pathway, increasing apoptosis, and damaging immature blood vessels in developing limb buds.

### Retinoic acid and mouse limb development

Retinoic acid (RA) is significant in embryonic development. It induces the function of limb patterning of a developing embryo in species such as mice and other vertebrate limbs. For example, during the process of regenerating a newt limb an increased amount of RA moves the limb more proximal to the distal blastoma and the extent of the proximalization of the limb increases with the amount of RA present during the regeneration process. A study looked at the RA activity intracellularly in mice in relation to human regulating CYP26 enzymes which play a critical role in metabolizing RA. This study also helps to reveal that RA is significant in various aspects of limb development in an embryo, however irregular control or excess amounts of RA can have teratogenic impacts causing malformations of limb development. They looked specifically at CYP26B1 which is highly expressed in regions of limb development in mice. The lack of CYP26B1 was shown to cause a spread of RA signal towards the distal section of the limb causing proximo-distal patterning irregularities of the limb. Not only did it show spreading of RA but a deficiency in the CYP26B1 also showed an induced apoptosis effect in the developing mouse limb but delayed chondrocyte maturation, which are cells that secrete a cartilage matrix which is significant for limb structure. They also looked at what happened to development of the limbs in wild type mice, that are mice with no CYP26B1 deficiencies, but which had an excess amount of RA present in the embryo. The results showed a similar impact to limb patterning if the mice did have the CYP26B1 deficiency meaning that there was still a proximal distal patterning deficiency observed when excess RA was present. This then concludes that RA plays the role of a morphogen to identify proximal distal patterning of limb development in mice embryos and that CYP26B1 is significant to prevent apoptosis of those limb tissues to further proper development of mice limbs in vivo.

### Rat development and lead exposure

There has been evidence of teratogenic effects of lead in rats as well. An experiment was conducted where pregnant rats were given drinking water, before and during pregnancy, that contained lead. Many detrimental effects, and signs of teratogenesis were found, such as negative impacts on the formation of the cerebellum, fetal mortality, and developmental issues for various parts of the body.

## Plants

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. In plants, such specimens are denoted as 'lusus naturae' ('sports of nature', abbreviated as 'lus.'); and occasionally as 'ter.', 'monst.', or 'monstr.'.

### Types of deformations in plants

Plants can have mutations that leads to different types of deformations such as:
* Fasciation: Development of the apex (growing tip) in a flat plane perpendicular to the axis of elongation
* Variegation: Degeneration of genes, manifesting itself among other things by anomalous pigmentation
* Virescence: Anomalous development of a green pigmentation in unexpected parts of the plant
* Phyllody: Floral organs or fruits transformed into leaves
* Witch's broom: Unusually high multiplication of branches in the upper part of the plant, mainly in a tree
* Pelorism: Zygomorphic flower regress to their ancestral actinomorphic symmetry
* Proliferation: Repetitive growth of an entire organ, such as a flower

## Research

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. One example of this is the use of mammalian animal models to evaluate the molecular role of teratogens in the development of embryonic populations, such as the neural crest, which can lead to the development of neurocristopathies. 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. Prenatal alcohol exposure (PAE) can produce craniofacial malformations, a phenotype that is visible in Fetal Alcohol Syndrome. Current evidence suggests that craniofacial malformations occur via: apoptosis of neural crest cells, interference with neural crest cell migration, as well as the disruption of sonic hedgehog (shh) signaling.
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.