Teratology

Teratology is the study of abnormalities of

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

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

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

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

• Genetic disorders and chromosomal abnormalities
• Maternal health factors
  • Nutrition during pregnancy (e.g., spina bifida resulting from folate deficiency^[16])
  • Metabolic disorders such as diabetes and thyroid disease
  • Stress
• Chemical agents
  • Prescription and recreational drugs (e.g.,
    alcohol,^[17] thalidomide^[16][18]
    )
  • Environmental toxins and contaminants (e.g., heavy metals such as mercury^[19] and lead,^[20] polychlorinated biphenyls (PCBs)^[21])
• 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^[22]

Human pregnancy

In

About 3% of newborns have a "major physical anomaly", meaning a physical anomaly that has cosmetic or functional significance.[24] Congenital disorders are responsible for 20% of infant deaths.^[25] 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.^[26] 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.^[27] Infants with a smaller VSD have a 96% survival rate and those with a moderate VSD have about an 86% survival rate.^{[citation needed]} 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.^[28]

Medicines

Acitretin

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.^[33] However, on grounds of theoretical risk, it is still not recommended to vaccinate for polio while pregnant unless there is risk of infection.^[34] 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.^[35]

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

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.^[40] 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.^[40] Thalidomide may have caused teratogenic effects in over 10,000 babies worldwide.^[41][42]

Recreational drugs

Alcohol

In the US,

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.[43] Fetal Alcohol Syndrome has numerous symptoms which may include cognitive impairments and impairment of the facial features.^[43] 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.^[44]

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.^[45]

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.^[46] Exposure to lead during pregnancy is well known to have teratogenic effects on the development of a fetus.^[47] Specifically, fetal exposure to lead can cause cognitive impairment, premature births, unplanned abortions, ADHD, and much more.^[48] Lead exposure during the first trimester of pregnancy leads to the greatest predictability of cognitive development issues after birth.^[49]

Low socioeconomic status correlates to a higher probability of lead exposure.^[50] 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.^[51]

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

Thalidomide and chick limb development

Thalidomide is a teratogen known to be significantly detrimental to organ and limb development during embryogenesis.^[54] 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][55]

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.^[56] 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.^[56] 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.^[56] 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.^[56] 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.^[56] 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.^[56] 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.^[56] 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.^[57]

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.^[58] In plants, such specimens are denoted as 'lusus naturae' ('sports of nature', abbreviated as 'lus.'); and occasionally as 'ter.', 'monst.', or 'monstr.'.^[59]

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

• Carcinogen
• Congenital abnormalities
• Mutagen
• Polydactyly
• Retinoic acid
• Teratoma
• Thalidomide

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External links

Wikimedia Commons has media related to Teratology.

• Society of Teratology
• European Teratology Society Archived 5 April 2010 at the Wayback Machine
• 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)
• The Reproductive Toxicology Center Database