Teratology

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Teratology is the study of abnormalities of physiological development in all organisms including plants during the entire life span. A sub discipline in Medical Genetics which focuses on the classification of congenital abnormalities is dysmorphology. The related term developmental toxicity includes all manifestations of abnormal development that are caused by environmental insult. These may include growth retardation, delayed mental development or other congenital disorders without any structural malformations. [1]

Contents

Teratogens are substances that may cause birth defects via a toxic effect on an embryo or fetus. [2] Known teratogens include: thalidomide, [3] mercury, [4] alcohol, [5] lead, [6] and polychlorinated biphenyls (PCBs). [7]

Etymology

The term was borrowed in 1842 from French tératologie, where it was formed in 1830 from the Greek τέραςteras (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. [8]

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 [9] ), 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.[ by whom? ] [10]

Mammalia

Teratogenesis

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. [11] 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. 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, [12] 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. [13] [ circular reference ] Current evidence suggests that craniofacial malformations occur via: apoptosis of neural crest cells, [14] interference with neural crest cell migration, [15] [16] as well as the disruption of sonic hedgehog (shh) signaling. [17]

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.

Alcohol

Alcohol is known to act as a teratogen. [18] Prenatal alcohol exposure (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. [19]

Humans

In humans, congenital disorders resulted in about 510,000 deaths globally in 2010. [20]

About 3% of newborns have a "major physical anomaly", meaning a physical anomaly that has cosmetic or functional significance. [21]

Vaccinating while pregnant

In humans, vaccination has become readily available, and is important to the prevention of some diseases like polio, rubella, and smallpox, among others. There has been no association between congenital malformations and vaccination, as shown in Finland in which expecting mothers received the oral polio vaccine and saw no difference in infant outcomes than mothers who had not received the vaccine. [22] However, it is still not recommended to vaccinate for polio while pregnant unless there is risk of infection. [23] Another important implication of this includes the ability to get the influenza vaccine while pregnant. During the 1918 and 1957 influenza pandemics, mortality in pregnant women was 45%. However, even with prevention through vaccination, influenza vaccination in pregnant women remains low at 12%. Munoz et al. demonstrated that there was no adverse outcome observed in the new infants or mothers. [24]

Causes

Causes of teratogenesis can broadly be classified as:

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. [26] Another notably deformed fossil was a specimen of the choristodere Hyphalosaurus , which had two heads- the oldest known example of polycephaly. [27]

Chick embryo limb development

Thalidomide is a teratogen known to be significantly detrimental to the development of certain body parts and organs in the body such as the eyes or the heart. [28] During embryogenesis it is observed that many different organisms experience different impacts of teratogens on organ morphogenesis and development overall. One of these organisms that are popular to study the malformations created by thalidomide are chick embryos. It is observed that thalidomide induces limb outgrowth deformities through inducing oxidative stress and thereby enhancing genetic signaling through irregular expression of bone morphogenic proteins, Bmp. [29] According to a study that was performed in 2007, the results revealed that with the increased oxidative stress thalidomide promotes, the up-regulation of the Bmp target gene and Wnt antagonist (Dkk1) this in turn inhibited canonical Wnt/B-catenin signaling and an increase in cell death was observed. The thalidomide induced cell death was significantly reduced when the introduction of inhibitors against Bmp, Dkk1 (Wnt antagonist), and Gsk3B (B-catenin antagonist) was administered into the chick embryos and cell death of the limb tissue was decreased. [30] These results helped to conclude that these three pathways significantly impacted by thalidomide for chick limb development and that the teratogenic outcomes of the limb development deficiencies thalidomide creates can be reversed if these three pathways are inhibited.

Mouse embryo 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 [31] 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. [32] 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. [33] 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. [34] 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. [35] 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. [36] 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. [37] 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.

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.

Types of deformations in vegetals

Plants can have mutations that leads to different types of deformations such as:

Galls are not part of the vegetal teratology as they are outgrowth due to external factors like insects bites or parasites.

See also

Related Research Articles

Phocomelia Medical condition

Phocomelia is a condition that involves malformations of human arms and legs. Although many factors can cause phocomelia, the prominent roots come from the use of the drug thalidomide and from genetic inheritance.

Birth defect Condition present at birth regardless of cause; human disease or disorder developed prior to birth

A birth defect, also known as a congenital disorder, is a condition present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth defects are divided into two main types: structural disorders in which problems are seen with the shape of a body part and functional disorders in which problems exist with how a body part works. Functional disorders include metabolic and degenerative disorders. Some birth defects include both structural and functional disorders.

Congenital heart defect Defect in the structure of the heart that is present at birth

A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. Signs and symptoms depend on the specific type of defect. Symptoms can vary from none to life-threatening. When present, symptoms may include rapid breathing, bluish skin (cyanosis), poor weight gain, and feeling tired. CHD does not cause chest pain. Most congenital heart defects are not associated with other diseases. A complication of CHD is heart failure.

Fetal alcohol spectrum disorder Group of conditions resulting from maternal alcohol consumption during pregnancy

Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person whose mother drank alcohol during pregnancy. Symptoms can include an abnormal appearance, short height, low body weight, small head size, poor coordination, behavioural problems, learning difficulties and problems with hearing or sight. Those affected are more likely to have trouble in school, legal problems, participate in high-risk activities and have problems with alcohol or other drugs. The most severe form of the condition is known as fetal alcohol syndrome (FAS). Other types include Partial Fetal Alcohol Syndrome (pFAS), Alcohol-Related Neurodevelopmental Disorder (ARND), Static Encephalopathy, Alcohol-Related Birth Defects (ARBD), and Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure (ND-PAE). Some accept only FAS as a diagnosis, seeing the evidence as inconclusive with respect to other types.

James G. Wilson (1915–1987) was an embryologist and anatomist, known for his Six Principles of Teratology. In 1960 he co-founded The Teratology Society, and was since then one of its most active members.

Environmental toxicants and fetal development is the impact of different toxic substances from the environment on the development of the fetus. This article deals with potential adverse effects of environmental toxicants on the prenatal development of both the embryo or fetus, as well as pregnancy complications. The human embryo or fetus is relatively susceptible to impact from adverse conditions within the mother's environment. Substandard fetal conditions often cause various degrees of developmental delays, both physical and mental, for the growing baby. Although some variables do occur as a result of genetic conditions pertaining to the father, a great many are directly brought about from environmental toxins that the mother is exposed to.

Encephalocele Neural tube defect in which the brain protrudes out of the skull

Encephalocele is a neural tube defect characterized by sac-like protrusions of the brain and the membranes that cover it through openings in the skull. These defects are caused by failure of the neural tube to close completely during fetal development. Encephaloceles cause a groove down the middle of the skull, or between the forehead and nose, or on the back side of the skull. The severity of encephalocele varies, depending on its location.

Neurodevelopmental disorders are a group of disorders that affect the development of the nervous system, leading to abnormal brain function which may affect emotion, learning ability, self-control, and memory. The effects of neurodevelopmental disorders tend to last for a person's lifetime.

Goldenhar syndrome Medical condition

Goldenhar syndrome is a rare congenital defect characterized by incomplete development of the ear, nose, soft palate, lip and mandible on usually one side of the body. Common clinical manifestations include limbal dermoids, preauricular skin tags and strabismus. It is associated with anomalous development of the first branchial arch and second branchial arch.

Retinoic acid Metabolite of vitamin A

Retinoic acid (used simplified here for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that mediates the functions of vitamin A1 required for growth and development. All-trans-retinoic acid is required in chordate animals, which includes all higher animals from fish to humans. During early embryonic development, all-trans-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages.

Limb development

Limb development in vertebrates is an area of active research in both developmental and evolutionary biology, with much of the latter work focused on the transition from fin to limb.

Congenital amputation is birth without a limb or limbs, or without a part of a limb or limbs.

<i>TBX5</i> (gene)

T-box transcription factor TBX5 is a protein that in humans is encoded by the TBX5 gene.

CYP26B1

Cytochrome P450 26B1 is a protein that in humans is encoded by the CYP26B1 gene.

Cheryll Anne Tickle is a distinguished British scientist, known for her work in developmental biology and specifically for her research into the process by which vertebrate limbs develop ab ovo. She is an Emeritus Professor at the University of Bath.

Fibrochondrogenesis Medical condition

Fibrochondrogenesis is a rare autosomal recessive form of osteochondrodysplasia, causing abnormal fibrous development of cartilage and related tissues.

Developmental toxicity

Developmental toxicity is any structural or functional alteration, reversible or irreversible, which interferes with homeostasis, normal growth, differentiation, development or behavior, and which is caused by environmental insult. It is the study of adverse effects on the development of the organism resulting from exposure to toxic agents before conception, during prenatal development, or post-natally until puberty. The substance that causes developmental toxicity from embryonic stage to birth is called teratogens. The effect of the developmental toxicants depends on the type of substance, dose and duration and time of exposure.

Mullerian duct anomalies are those structural anomalies caused by errors in müllerian-duct development during embryonic morphogenesis. Factors that precipitate include genetics, and maternal exposure to teratogens.

Richard Smithells

Richard Worthington Smithells was a British paediatrician and Emeritus professor of paediatrics at the University of Leeds. Smithells was most notable for research into neural tube defects, congenital abnormality registers, genetic counselling, and rubella in pregnancy and for later suggesting direct examination of the foetus by photography using ultrasonography.

Diabetic embryopathy Medical condition

Diabetic embryopathy refers to congenital maldevelopments that are linked to maternal diabetes. Prenatal exposure to hyperglycemia can result in spontaneous abortions, perinatal mortality, and malformations. Type 1 and Type 2 diabetic pregnancies both increase the risk of diabetes induced teratogenicity. The rate of congenital malformations is similar in Type 1 and 2 mothers because of increased adiposity and the age of women with type 2 diabetes. Genetic predisposition and different environmental factors both play a significant role in the development of diabetic embryopathy. Metabolic dysfunction in pregnant mothers also increases the risk of fetal malformations.

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