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, 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 , meaning "sign sent by the gods, portent, marvel, monster", and -ologie, 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. 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, popularized the term teratology. With the growth of understanding of the origins of birth defects, the field of teratology 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

Teratogenesis occurs when the development of an embryo is altered negatively due to the presence of teratogens. Teratogens are the causes of teratogenesis. Common examples of teratogens include genetic disorders, maternal nutrition and health, and chemical agents such as drugs and alcohol. Lesser known examples that will be covered include stress, caffeine, and deficiencies in diet and nutrition. Although teratogens can affect a fetus during any time in the pregnancy, one of the most sensitive time frames for them to be exposed to the developing embryo is during the embryonic period. This period is in effect from about the fourteenth day following when a female's egg is implanted into a specific place in the reproductive organs and sixty days after conception. Teratogens are able to cause abnormal defects through certain mechanisms that occur throughout the development of the embryo.

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 19th century:
  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.
  6. Manifestations of deviant development increase in frequency and degree as dosage increases from the No Observable Adverse Effect Level to a dose producing 100% lethality.
The mechanisms of these teratogens lie in specific alterations to genes, cells, and tissues within the developing organism that cause deviation from normal development and can result in functional defects, growth stunts, malformation, and even death. Finally, susceptibility to teratogens is more elevated during specific, critical periods during development.

Oxidative stress

The natural metabolic processes of the human body produce highly reactive oxygen-containing molecules called reactive oxygen species. Being highly reactive, these molecules can oxidatively damage fats, proteins, and DNA, and alter signal transduction. Teratogens such as thalidomide, methamphetamine, and phenytoin are known to enhance ROS formation, potentially leading to teratogenesis
ROS damage a certain class of reactions called redox reactions, which are chemical processes in which substances change their oxidation states by donating or accepting electrons. In these reactions, ROS act as strong oxidizing agents. They accept electrons from other molecules, causing those molecules to become oxidized. This shifts the balance of redox reactions in cells, inducing oxidative stress when ROS levels are high, leading to cellular damage.
Developmental processes such as rapid cell division, cell differentiation into different types, and apoptosis rely on pathways that involve communication between cells through a process called signal transduction. These pathways' proper functioning is highly dependent on a certain class of reactions called redox reactions; many of these pathways are vulnerable to disruption due to oxidative stress. Therefore, one mechanism by which teratogens induce teratogenesis is by triggering oxidative stress and derailing redox-dependent signal transduction pathways in early development.
Folate plays key roles in DNA methylation and in synthesis of nitrogenous bases found in DNA and RNA. These processes are crucial for cell division, cell growth, gene regulation, protein synthesis, and cell differentiation. All these processes ensure normal fetal development. Since the developing fetus requires rapid cell growth and division, the demand for folate increase during pregnancy, which if not met, can lead to teratogenic complications.

Epigenetic modifications

Epigenetic modifications are any heritable modifications to the expression of genes in the DNA that do not include direct code alteration of the base genome. These modifications can include heritable alterations in transcriptional and translational processes of certain genes and even their interactions with other genes. Many known teratogens affect fetal development by inducing these epigenetic modifications including turning on/off transcriptional processes of certain genes, regulating the location and distribution of proteins inside the cell, and regulating cell differentiation by modifying which mRNA molecules are translated into protein.
During embryo development, a temporary organ called a placenta forms in the womb, connecting the mother to the fetus. The placenta provides oxygen and nutrients to the developing fetus throughout the pregnancy. Environmental influences such as under-nutrition, drugs, alcohol, tobacco smoke, and even abnormal hormonal activity can lead to epigenetic changes in the placental cells and harm the fetus in the long term, though specific mechanisms by which developmental damage takes place remains unclear.

Causes

Common causes of teratogenesis include:
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% and 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 three 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.