Biology:Teratology

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Short description: Study of developmental anomalies


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. Teratogens are substances that may cause non-heritable birth defects via a toxic effect on an embryo or fetus.[1] Defects include malformations, disruptions, deformations, and dysplasia that may cause stunted growth, delayed mental development, or other congenital disorders that lack structural malformations.[2] The related term developmental toxicity includes all manifestations of abnormal development that are caused by environmental insult.[3] 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, the genetic makeup of the embryo, and the transfer rate of the teratogen.[4]

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.[5]

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),[6] 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.[7]

Teratogenesis

Wilson's principles of teratogenesis

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.[8] These principles were derived from and expanded on by those laid forth by zoologist Camille Dareste in the late 1800s:[8][9]

  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).

Research into teratogenesis

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,[10] 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,[11] interference with neural crest cell migration,[12][13] as well as the disruption of sonic hedgehog (shh) signaling.[14]

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.

Causes

Common causes of teratogenesis include:[15][16]

Humans

In humans, congenital disorders resulted in about 510,000 deaths globally in 2010.[22]

About 3% of newborns have a "major physical anomaly", meaning a physical anomaly that has cosmetic or functional significance.[23] Congenital disorders are responsible for 20% of infant deaths.[24] The most common congential 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.[25] 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.[26] Infants with smaller VSD has a 96% of survival rate and those with a moderate VSD have about an 86% chance of 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.[27]

Alcohol use in pregnancy

Main page: Medicine:Fetal alcohol spectrum disorder

Alcohol is known to act as a teratogen.[28] 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.[29]

Vaccination in pregnancy

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.[30] However, on grounds of theoretical risk, it is still not recommended to vaccinate for polio while pregnant unless there is risk of infection.[31] 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 favoured preventative vaccination.[32]

Other animals

Fossil record

Further information: Biology:Paleopathology

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.[33] Another notably deformed fossil was a specimen of the choristodere Hyphalosaurus, which had two heads- the oldest known example of polycephaly.[34]

Chick embryo limb development

Thalidomide is a teratogen known to be significantly detrimental to organ and limb development during embryogenesis.[35] 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.[18][36]

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.[37] 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.[37] 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.[37] 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.[37] 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.[37] 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.[37] 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.

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.[38] In plants, such specimens are denoted as 'lusus naturae' ('sports of nature', abbrevated as 'lus.'); and occasionally as 'ter.', 'monst.', or 'monstr.'.[39]

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

See also

References

  1. ↑ "Teratology and drug use during pregnancy". WebMD. 23 February 2016. http://emedicine.medscape.com/article/260725-overview#showall. 
  2. ↑ Gilbert, Scott F.; Epel, David (2015). Ecological developmental biology: the environmental regulation of development, health, and evolution (2nd ed.). Sunderland, MA: Sinauer Associates, Inc. Publishers. 
  3. ↑ "Developmental Toxicology". Casarett and Doull's Toxicology : the basic science of poisons (5th ed.). New York: McGraw-Hill, Health Professions Division. 1996. pp. 301–331. ISBN 978-0-07-105476-8. 
  4. ↑ MCAT biology review 2023–2024 : online + book. Alexander Stone Macnow, Kaplan Publishing, Kaplan Test Prep, inc Scientific American (2023-2024 ed.). Fort Lauderdale, Florida. 2022. ISBN 978-1-5062-8295-4. OCLC 1334083218. https://www.worldcat.org/oclc/1334083218. 
  5. ↑ teratology innthe Merriam-Webster Dictionary
  6. ↑ "Pattern of malformation in offspring of chronic alcoholic mothers". Lancet 1 (7815): 1267–1271. June 1973. doi:10.1016/S0140-6736(73)91291-9. PMID 4126070. 
  7. ↑ "Birth Defects". Howmed.net. 24 July 2011. http://howmed.net/anatomy/embryology/birth-defects/. "Until 1940, it was assumed that congenital defects were caused primarily by hereditary factors. In 1941, the first well-documented cases were reported that an environmental agent (rubella virus) could produce severe anatomic anomalies." 
  8. ↑ 8.0 8.1 Environment and Birth Defects (Environmental Science Series). London: Academic Pr. 1973. ISBN 0-12-757750-5. https://archive.org/details/environmentbirth00wils. 
  9. ↑ "James G. Wilson's Six Principles of Teratology | The Embryo Project Encyclopedia" (in en). https://embryo.asu.edu/pages/james-g-wilsons-six-principles-teratology. 
  10. ↑ "The role of teratogens in neural crest development". Birth Defects Research 112 (8): 584–632. May 2020. doi:10.1002/bdr2.1644. PMID 31926062. 
  11. ↑ "Teratogens and craniofacial malformations: relationships to cell death". Development 103 (Suppl): 213–231. 1988. doi:10.1242/dev.103.Supplement.213. PMID 3074910. https://cdr.lib.unc.edu/downloads/f7623n81g. 
  12. ↑ "5-mehtyltetrahydrofolate rescues alcohol-induced neural crest cell migration abnormalities". Molecular Brain (67). 16 September 2014. 
  13. ↑ "Stage-dependent effects of ethanol on cranial neural crest cell development: partial basis for the phenotypic variations observed in fetal alcohol syndrome". Alcoholism: Clinical and Experimental Research 19 (6): 1454–1462. December 1995. doi:10.1111/j.1530-0277.1995.tb01007.x. PMID 8749810. 
  14. ↑ Boschen KE (19 October 2019). "Prenatal alcohol exposure disrupts Shh pathway and primary cilia genes in the mouse neural tube". bioRxiv 10.1101/649673.
  15. ↑ "Teratogens | The Embryo Project Encyclopedia" (in en). https://embryo.asu.edu/pages/teratogens. 
  16. ↑ 16.0 16.1 16.2 Gilbert-Barness, Enid (20 March 2010). "Teratogenic Causes of Malformations" (in en). Annals of Clinical & Laboratory Science 40 (2): 99–114. ISSN 0091-7370. PMID 20421621. http://www.annclinlabsci.org/content/40/2/99. 
  17. ↑ "The neurodevelopmental consequences of prenatal alcohol exposure". Advances in Neonatal Care (Medscape) 5 (4): 217–229. August 2005. doi:10.1016/j.adnc.2005.04.007. PMID 16084479. 
  18. ↑ 18.0 18.1 "Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation". Proceedings of the National Academy of Sciences of the United States of America 106 (21): 8573–8578. May 2009. doi:10.1073/pnas.0901505106. PMID 19433787. Bibcode: 2009PNAS..106.8573T. 
  19. ↑ "The toxicity and teratogenicity of mercuric mercury in the pregnant rat". Archives of Toxicology 58 (4): 243–248. April 1986. doi:10.1007/BF00297114. PMID 3718227. 
  20. ↑ "Teratogen update: lead and pregnancy". Birth Defects Research. Part A, Clinical and Molecular Teratology 73 (6): 409–420. June 2005. doi:10.1002/bdra.20127. PMID 15880700. 
  21. ↑ "Teratogen update: polychlorinated biphenyls". Teratology 55 (5): 338–347. May 1997. doi:10.1002/(SICI)1096-9926(199705)55:5<338::AID-TERA6>3.0.CO;2-V. PMID 9261928. 
  22. ↑ "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet 380 (9859): 2095–2128. December 2012. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604. http://www.cobiss.si/scripts/cobiss?command=DISPLAY&base=cobib&rid=1537267652&fmt=11. [yes|permanent dead link|dead link}}]
  23. ↑ Kumar, Abbas and Fausto (eds.), Robbins and Cotran's Pathologic Basis of Disease, 7th edition, p. 470.
  24. ↑ CDC (21 December 2022). "Data & Statistics on Birth Defects | CDC" (in en-us). https://www.cdc.gov/ncbddd/birthdefects/data.html. 
  25. ↑ CDC (18 November 2022). "Facts about Down Syndrome | CDC" (in en-us). https://www.cdc.gov/ncbddd/birthdefects/downsyndrome.html. 
  26. ↑ "Ventricular Septal Defect (VSD) (for Parents) – Nemours KidsHealth". https://kidshealth.org/en/parents/vsd.html#:~:text=Infants%20with%20a%20large%20VSD,by%20bacteria%20in%20the%20bloodstream. 
  27. ↑ "Neural Tube Defects" (in en). 8 August 2021. https://www.hopkinsmedicine.org/health/conditions-and-diseases/neural-tube-defects. 
  28. ↑ "Alcohol and Pregnancy". 27 April 2019. https://americanpregnancy.org/pregnancy-health/pregnancy-and-alcohol/. 
  29. ↑ "Fetal Alcohol Exposure and the Brain". https://pubs.niaaa.nih.gov/publications/aa50.htm. 
  30. ↑ "Oral polio vaccination during pregnancy: no increase in the occurrence of congenital malformations". American Journal of Epidemiology 138 (6): 407–414. September 1993. doi:10.1093/oxfordjournals.aje.a116873. PMID 8213746. 
  31. ↑ "Guidelines for Vaccinating Pregnant Women". Centers for Disease Control and Prevention: Advisory Committee on Immunization Practices (ACIP). 13 January 2021. https://www.cdc.gov/vaccines/pregnancy/hcp/guidelines.html#polio. "Although no adverse effects of IPV have been documented among pregnant women or their fetuses, vaccination of pregnant women should be avoided on theoretical grounds. However, if a pregnant woman is at increased risk for infection and requires immediate protection against polio, IPV can be administered in accordance with the recommended schedules for adults." 
  32. ↑ "Safety of influenza vaccination during pregnancy". American Journal of Obstetrics and Gynecology 192 (4): 1098–1106. April 2005. doi:10.1016/j.ajog.2004.12.019. PMID 15846187. 
  33. ↑ Molnar, R. E., 2001, Theropod paleopathology: a literature survey: In: Mesozoic Vertebrate Life, edited by Tanke, D. H., and Carpenter, K., Indiana University Press, p. 337-363.
  34. ↑ "Cretaceous choristoderan reptiles gave birth to live young". Die Naturwissenschaften 97 (4): 423–428. April 2010. doi:10.1007/s00114-010-0654-2. PMID 20179895. Bibcode: 2010NW.....97..423J. 
  35. ↑ Vargesson, Neil (4 June 2015). "Thalidomide‐induced teratogenesis: History and mechanisms" (in en). Birth Defects Research Part C: Embryo Today: Reviews 105 (2): 140–156. doi:10.1002/bdrc.21096. ISSN 1542-975X. PMID 26043938. 
  36. ↑ "Thalidomide induces limb deformities by perturbing the Bmp/Dkk1/Wnt signaling pathway". FASEB Journal 21 (7): 1410–1421. May 2007. doi:10.1096/fj.06-7603com. PMID 17283219. 
  37. ↑ 37.0 37.1 37.2 37.3 37.4 37.5 37.6 "Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb". Developmental Cell 6 (3): 411–422. March 2004. doi:10.1016/S1534-5807(04)00062-0. PMID 15030763. 
  38. ↑ "Historical interpretations of flower induction and flower development". Understanding flowers and flowering : an integrated approach (Second ed.). Oxford. 2014. ISBN 978-0-19-966159-6. https://academic.oup.com/book/3507/chapter/144709757. 
  39. ↑ Vázquez, Francisco María (October 2014). Turland, Nicholas J.; Wiersema, John H.. eds. "(023–024) Proposals to add a new Article and some Examples under Article 5" (in en). Taxon 63 (5): 1142. doi:10.12705/635.21. ISSN 0040-0262. OCLC 6896520971. https://onlinelibrary.wiley.com/doi/pdf/10.12705/635.21. Retrieved 24 October 2023. 

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