Teratogenesis

Abstract

Teratogenesis is a process that causes birth defects or malformations in an embryo or foetus. Teratology is the study of the causes and underlying mechanisms leading to birth defects or malformations. These may include disorders without any obvious structural malformations, such as intellectual disabilities. A teratogen is a substance (from outside the body) that causes birth defects or malformations. Examples of teratogens include medicinal drugs, such as thalidomide; environmental toxins, for example cadmium as well as environmental pollutants, including pesticides and endocrine‐disrupting compounds. Other causes of teratogenesis include viruses, for example rubella and Zika virus; physical compression in utero and poor diet. Animal models are used to study the mechanisms by which teratogens result in birth defects or malformations, and these studies can also give insights into normal development. The study and understanding of teratogenesis is also essential for making safer and more targeted therapeutic drugs.

Key Concepts

  • Teratogenesis is the production of birth defects or malformations by external agents.
  • Teratology is the study of the mechanisms that give rise to birth defects or malformations.
  • There are many factors that can result in teratogenesis, including medicinal and recreational drugs, viral and bacterial infections and poor maternal health.
  • Teratogenesis is studied in animal models, for example mouse, chicken and rabbit embryos.
  • Understanding whether a chemical compound has teratogenic side effects is essential to ensure drug safety.
  • Many teratogens (agents that cause teratogenesis) act between weeks 2 and 8 of embryonic development, a period also known as the ‘critical period’ of development when the majority of tissues and organs are forming and being patterned, for example the limbs.

Keywords: thalidomide; animal models; the 3Rs; teratogen; time‐sensitive window; birth defects

Figure 1. Outward damage caused by thalidomide exposure of human embryos at different times during pregnancy. Thalidomide caused outward damage (e.g. to the limbs, ears and eyes) between day 20 and day 36 of embryonic development. Note that there is generally more widespread damage the earlier the exposure to thalidomide occurs in the time‐sensitive window. The action of thalidomide falls within the embryonic ‘critical period’ which is between 2 and 8 weeks of development when all the major tissues and organs are forming and these tissues are most sensitive to disruption. Reproduced from Vargesson 2015b © Wiley Periodicals, Inc. under the terms of the Creative Commons Attribution License.
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References

Ali Laghari Z, Ali Samo A, Waryani B, et al. (2015) Effects of a single dose of ethanol on survival rate and angiogenesis of chick embryo. Animal and Veterinary Sciences 3: 8–11.

Beedie SL, Rore HM, Barnett S, et al. (2016) In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems. Oncotarget 7 (22): 33237–33245.

Beedie SL, Diamond AJ, Fraga LR, Figg WD and Vargesson N (2017) Vertebrate embryos as tools for anti‐angiogenic drug screening and function. Reproductive Toxicology 70: 49–59. DOI: 10.1016/j.reprotox.2016.11.013.

Bradley MP and Nagamine CM (2017) Animal models of Zika Virus. Comparative Medicine 67 (3): 242–252.

Cassina M, Salviati L, Di Gianantonio E and Clementi M (2012) Genetic susceptibility to teratogens: State of the art. Reproductive Toxicology 34: 186–191.

Cugola FR, Fernandes IR, Russo FB, et al. (2016) The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534: 267–271.

Cullinane J, Bannigan J and Thompson J (2009) Cadmium teratogenesis in the chick: period of vulnerability using the early chick culture method, and prevention by divalent cations. Reproductive Toxicology 28 (3): 335–341.

Ema M, Ise R, Kato H, et al. (2010) Fetal malformations and early embryonic gene expression response in cynomolgus monkeys maternally exposed to thalidomide. Reproductive Toxicology 29 (1): 49–56.

Gilbert‐Barness E (2010) Teratogenic causes of malformations. Annals of Clinical & Laboratory Science 40: 99–114.

Goodfellow FT, Tesla B, Simchick G, et al. (2016) Zika virus induced mortality and microcephaly in chicken embryos. Stem Cells and Development 25 (22): 1691–1697.

Gupta R (ed) (2017) Reproductive and Developmental Toxicity, 2nd edn. Amsterdam: Elsevier.

Hyatt GA, Schmitt EA, Marsh‐Armstrong NR and Dowling JE (1992) Retinoic acid‐induced duplication of the zebrafish retina. Neurobiology 89: 8293–8297.

Ito T, Ando H, Suzuki T, et al. (2010) Identification of a primary target of thalidomide teratogenicity. Science 327: 1345–1350.

Jelínek R and Kistler A (1981) Effect of retinoic acid upon the chick embryonic morphogenetic systems. I. The embryotoxicity dose range. Teratology 23: 191–195.

Kelsey FO (1966) The evolution of new drug legislation. BMQ 17 (2): 72–81.

Knobloch J, Shaughnessy JD Jr and Ruther U (2007) Thalidomide induces limb deformities by perturbing the Bmp/Dkk1/Wnt signalling pathway. FASEB Journal 21 (7): 1410–1421.

Larsen HL and Janners MY (1987) Teratogenic effects of retinoic acid and dimethylsulfoxide on embryonic chick wing and somite. Teratology 36: 313–320.

McGrath EL, Rossi SL, Gao J, et al. (2017) Differential responses of human fetal brain neural stem cells to Zika virus infection. Stem Cell Reports 8 (3): 715–727. DOI: 10.1016/j.stemcr.2017.01.008.

Miner JJ, Cao B, Govero J, Smith AM, et al. (2016) Zika virus infection during pregnancy in mice causes placental damage and fetal demise. Cell 165: 1081–1091.

Oh Y, Zhang F, Wang Y, et al. (2017) Zika virus directly infects peripheral neurons and induces cell death. Nature Neuroscience 20 (9): 1209–1212. DOI: 10.1038/nn.4612.

Rasmussen SA, Jamieson DJ, Honein MA and Petersen LR (2016) Zika virus and birth defects – reviewing the evidence for causality. New England Journal of Medicine 374 (20): 1981–1987.

Sadler T (2012) Langmans Medical Embryology, 13th edn. Philadelphia, PA: Wolters Kluwer.

Schardein JL (2000) Chemically Induced Birth Defects, 3rd edn. New York: Marcel Dekker.

Schuler‐Faccini L, Ribeiro EM, Feitosa IM, et al. (2016) Possible association between Zika virus infection and microcephaly – Brazil, 2015. Morbidity and Mortality Weekly Report 65 (3): 59–62.

Smithells RW and Newman CG (1992) Recognition of thalidomide defects. Journal of Medical Genetics 29 (10): 716–723.

Stern RS, Rosa F and Baum C (1984) Isotretinoin and pregnancy. Journal of the American Academy of Dermatology 10 (5 Pt1): 851–854.

Sylvain NJ, Brewster DL and Ali DW (2010) Zebrafish embryos exposed to alcohol undergo abnormal development of motor neurons and muscle fibers. Neurotoxicology and Teratology 32: 472–480.

Therapontos C, Erskine L, Gardner ER, et al. (2009) 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.

Vargesson N (2009) Thalidomide‐induced limb defects: resolving a 50‐year old puzzle. BioEssays 31: 1327–1336.

Vargesson N (2013) Thalidomide embryopathy: an enigmatic challenge. ISRN Developmental Biology 2013, Article ID 241016, 18 pages. Available from: 10.1155/2013/241016.

Vargesson N (2015a) Thalidomide: The Drug with a Dark Side but an Enigmatic Future. Available from: https://theconversation.com/thalidomide‐the‐drug‐with‐a‐dark‐side‐but‐an‐enigmatic‐future‐50330

Vargesson N (2015b) Thalidomide‐induced teratogenesis: history and mechanisms. Birth Defects Research. Part C, Embryo Today 105 (2): 140–156.

Vargesson N (2016) Is Primodos ‘The Forgotten Thalidomide’? Available from: https://theconversation.com/is‐primodos‐the‐forgotten‐thalidomide‐50673

Vargesson N and Schuler‐Faccini L (2016) Proving that the Zika Virus Causes Microcephaly. Available from: https://theconversation.com/proving‐that‐the‐zika‐virus‐causes‐microcephaly‐53716

Vargesson N and Hootnick DR (2017) Arterial dysgenesis and limb defects: clinical and experimental examples. Reproductive Toxicology 70: 21–29.

Vianna F, Schuler‐Faccini L, Leite JC, et al. (2013) Recognition of the phenotype of thalidomide embryopathy in countries endemic for leprosy: new cases and review of the main dysmorphological findings. Clinical Dysmorphology 22: 59–62.

Whitsel AI, Johnson CB and Forehand CJ (2002) An in ovo chicken model to study the systemic and localized teratogenic effects of valproic acid. Teratology 66: 153–163.

Wilson JG (1973) Handbook of Teratology, 1st, vols. 1–3 edn. New York: Plenum Press.

Yamamoto FY, Filipak Neto F, Freitas PF, et al. (2012) Cadmium effects on early development of chick embryos. Environmental Toxicology and Pharmacology 34 (2): 548–555.

Further Reading

Colborn T, vom Saal FS and Soto AM (1993) Developmental effects of endocrine‐disrupting chemicals in wildlife and humans. Environmental Health Perspectives 101 (5): 378–384.

van Gelder MM, de Jong‐van den Berg LT and Roeleveld N (2014a) Drugs associated with teratogenic mechanisms Part II: a literature review of the evidence on human risks. Human Reproduction 29 (1): 168–183.

van Gelder MM, van Rooij IA, de Jong‐van den Berg LT and Roeleveld N (2014b) Teratogenic mechanisms associated with prenatal medication exposure. Thérapie 69 (1): 13–24. DOI: 10.2515/therapie/2014003.

Hazelden KP (2013) The developmental toxicity testing of biologics. Methods in Molecular Biology 947: 31–36. DOI: 10.1007/978-1-62703-131-8_3.

Zeller R (2010) The temporal dynamics of vertebrate limb development, teratogenesis and evolution. Current Opinion in Genetics and Development 20 (4): 384–390. DOI: 10.1016/j.gde.2010.04.014.

Zuniga A, Zeller R and Probst S (2012) The molecular basis of human congenital limb malformations. Wiley Interdisciplinary Reviews: Developmental Biology 1 (6): 803–822. DOI: 10.1002/wdev.59.

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How to Cite close
Vargesson, Neil, and Fraga, Lucas() Teratogenesis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026056]