Teratogen Definition

A teratogen is any agent that inducess an abnormality following fetal exposure during pregnancy. Teratogens are normally observed after a raised rate of a particular birth malformation. For example, in the beginning of 1960’s, a drug named as thalidomide was utilized to cure morning sickness. Exposure of the fetus during this early phase of development induced instances of phocomelia, a congenital defect in which the hands and feet are attached to abbreviated arms and legs.

Teratogens may also be found at home or the workplace. The result is related to type of agent, dose, and time of exposure. The first half of pregnancy is the most susceptible. Teratogenic agents comprise contagious agents (rubella, varicella, herpes simplex, cytomegalovirus, toxoplasma, syphilis, …); physiologic agents (hyperthermia, ionizing agents,… ); parental health factors (maternal PKU, diabetes,… ); environmental chemicals (organic mercury substances, herbicides and industrial dissolvers, polychlorinated biphenyl or PCB,… ); and medicines (prescription, recreational, over- the-counter ). Generally, if medicine is necessary, the minimum dose  must be used, a mixture drug therapies and first trimester exposures to be avoid.

Birth defects caused by teratogens

There are many causes of congenital defects comprising:

1) genetic factors (chromosomal abnormalities as well as single gene defects);

2) environmental factors (drugs, toxins, infectious etiologies, mechanical forces);

3) multifactorial etiologies including a mixture of environmental and genetic factors. 

Malformations can be single or multiple and have major or minor clinical significance. Single minor malformations are remarked in almost 14% of newborns. These defects are normally with no clinical result and can include features like a simian crease or ear tags. Specified minor defects suggest the probability of a joint major malformation. For instance, the finding of a single umbilical artery must suggest the probability of related congenital heart issues. The higher the number of minor defects, the higher the risk of a related major malformation. The more serious and the higher the amount of major defects, the higher the risk of an impulsive miscarriage or shortened life span. Genetic etiologies of defects Genetic factors are the most frequent causes of congenital malformations and account for almost one fourth of all congenital defects. Chromosomal abnormalities including numerical and structural abnormalities are a frequent cause of congenital malformations. Specified genetic syndromes are correlated with the most frequent of these chromosomal defects. Trisomy 21 is referenced as Down syndrome and has related characteristic facial features, congenital heart disease, growth retardation, and mental retardation. Monosomy of the X-chromosome is referenced as Turner syndrome and is correlated with webbing of the neck, lymphedema of the hands and feet, and later in life short stature and infertility. Trisomy 13 is correlated with midline malformations including cleft lip and cleft palate, central nervous system defects, microphthalmia, and congenital heart disease. Newborns with this disorder hardly live beyond the first year of life. Trisomy 18 is correlated with intrauterine growth restriction, clenched hands, rocker bottom feet, and congenital heart disease. Same trisomy 13, newborns with the syndrome also hardly live beyond the first year of life. Other chromosomal abnormalities including interstitial deletions, interstitial duplications, and unbalanced translocations are frequently correlated with congenital anomalies. The most frequent declines have named clinical syndromes with which they are associated. In addition to gross chromosomal abnormalities, there are many single gene defects that may result in congenital malformations. Some of these genes include developmentally essential transcription factors and genes essential in intermediary metabolism. Teratogenic agents induce almost 7% of congenital defects. A teratogenic agent is a chemical, infectious agent, physical condition, or insufficiency that, on fetal exposure, may modify fetal morphology or subsequent function. Teratogenicity depends upon the capability of the agent to traverse the placenta. Some medicines like heparin may not traverse the placenta due to its high molecular weight and are therefore not teratogenic. The embryo is most vulnerable to teratogenic agents during periods of accelerated differentiation. The phase of development of the embryo defines vulnerability to teratogens. The most crucial stage in the development of an embryo or in the growth of a specific organ is during the period of most rapid cell division. For instance, the crucial period for brain growth and development is from three to 16 weeks. However the brain’s differentiation remains to expand into infancy. Teratogens may produce mental retardation during both embryonic and fetal stages. Specified types of major defects and the times of development normally correlated with exposure to the teratogenic agent. Each organ of an embryo has a critical period during which its development can be disrupted. The type of congenital defect produced by an exposure depends upon which organ is most susceptible at the time of the teratogenic exposure. For example, high levels of radiation develop abnormalities of the central nervous system and eyes specifically at eight to 16 weeks after fertilization. Embryological timetables like the one above are helpful in studying the etiology of human malformations. However, it is wrong to assume that defects always result from a single event happening during a single critical sensitive period or that one may determine the exact day on which a malformation was produced. A teratogen is any agent that may result or increase the incidence of a congenital defect. 

Identification of human teratogens offers the possibility to prevent exposure at critical periods of development and avoid some types of congenital malformations. Generally, drugs, food additives, and pesticides are verified to determine their teratogenicity to reduce exposure of pregnant women to teratogenic agents. To show that a specific agent is teratogenic means to prove that the frequency of congenital defects in women exposed to the agent is prospectively greater than the background frequency in the general population. These data are oftentimes not available for humans and hence may not be determined in an unbiased fashion. Therefore, testing is frequently done in animal models and often times administered at higher than the habitual therapeutic doses. There are evidently species divergences between teratogenic effects, limiting this testing in animals. 

Based upon either anecdotic information on exposures in humans or on the basis of testing in animals, drugs are categorized as to their teratogenic potential. It must be emphasized that less than 2% of congenital defects are induced by drugs or chemicals. There are small amount of drugs that have been favorably involved as teratogenic agents that must be avoided either during or prior to conception. However, because of the unknown, subtle effects of some agents, women preparing to conceive or already pregnant refrain from taking any drugs that are not absolutely needed. Women are especially urged to avoid using all drugs during the first 8 weeks after conception unless there is a strong medical reason. Effects of teratogens during this stage of development frequently results in an “all or none effect.” That is, the effect of the teratogen, if it is to get any effect, will be so profound as to induce a spontaneous abortion.

Types of Teratogens

Some examples of teratogens known to induce human defects are listed below :

Nicotine

Nicotine does not develop congenital malformations but nicotine does have an effect on fetal growth. Maternal smoking is a well-established cause of intrauterine increase restriction. Heavy cigarette smokers were also probably to have a premature delivery. Nicotine contracts uterine blood vessels and causes decreased uterine blood flow thereby decreasing the supply of oxygen and nutrients available to the embryo. This compromises cell growth and can have an adverse effect on mental development. 

Alcohol

Alcohol is a frequent drug abused by women of childbearing age. Newborns of alcoholic mothers demonstrate prenatal and postnatal growth insufficiency, mental retardation, and other defects. There are delicate but classical facial features correlated with fetal alcohol syndrome comprising short palpebral fissures, maxillary hypoplasia, a smooth philtrum, and congenital heart disease. Even reasonable alcohol consumption consisting of 2 to 3 oz. of hard drink per day may produce the fetal alcohol effects. Binge drinking also probably has a harmful effect on embryonic brain developments at all times of gestation. 

Tetracycline

Tetracycline, the type of antibiotic, may traverse the placental membrane and is deposited in the embryo in bones and teeth. Tetracycline exposure may result in yellow spotting of the primary or deciduous teeth and diminished growth of the long bones. Tetracycline exposure after birth has the same effects. Anticonvulsant agents like phenytoin develop the fetal hydantoin symptom comprising inside uterus growth retardation, microcephaly, mental retardation, distal phalangeal hypoplasia, and particular facial characteristic. Anti-neoplastic or chemotherapeutic agents are supremely teratogenic as these agents impede rapidly dividing cells. These drugs must be avoided when it is possible but are occasionally utilized in the third trimester when they are urgently needed to treat the mother.

Retinoic acid or vitamin A derivatives

Retinoic acid or vitamin A derivatives are highly teratogenic in humans. Even at very small doses, oral drugs such as isotretinoin, used in the treatment of acne, are potent teratogens. The crucial period of exposure seems to be from the second to the fifth week of gestation. The most frequent defects comprise craniofacial dysmorphisms, cleft palate, thymic aplasia, and neural tube defects.

Thalidomide

The tranquilizer thalidomide is one of the most poplar and reputed teratogens. This hypnotic agent was utilized hugely in Europe in 1959, after which an estimated 7000 infants were born with the thalidomide syndrome or meromelia. The typical features of this syndrome comprise limb abnormalities that cover from absence of the limbs to rudimentary limbs to abnormally shortened limbs. Additionally, thalidomide  results in defects of other organs as well comprising absence of the internal and external ears, hemangiomas, inborn heart disease, and congenital urinary tract malformations. The crucial period of exposure seems to be 24 to 36 days after fertilization.

Contagious agents

Contagious agents can cause a variety of birth defects and mental retardation as well when they cross the placenta and enter the fetal blood stream. Congenital rubella or German measles consists of the triad of cataracts, cardiac malformation, and deafness. The earlier in the pregnancy that the embyro is exposed to maternal rubella, the greater the possibility that it will be affected. Most newborns exposed during the first four to five weeks after fertilization will get stigmata of this exposure. Exposure to rubella during the second and third trimester results in a much lower frequency of defect, but continues to pose a risk of mental retardation and hearing loss.

Congenital cytomegalovirus infection

Congenital cytomegalovirus infection is the most common viral infection of the fetus. Infection of the early embryo during the first trimester most frequently results in spontaneous termination. Exposure later in the pregnancy causes  inside the uterus growth retardation,  chorioretinitis, cerebral calcifications, micromelia, mental retardation, blindness, microcephaly and hepatosplenomegaly.

Ionizing radiation

Ionizing radiation can injure the developing embryo because of the cell death or chromosome injury. The severity of damage to the embryo relies on the dose absorbed and the stage of development at which the exposure happens. Study of survivors of the Japanese atomic bombing showed that exposure at 10 to 18 weeks of pregnancy is a time of greatest sensitivity for the developing brain. There is no justification that human congenital defects have been caused by diagnostic levels of radiation. However, efforts are made to reduce scattered radiation from diagnostic procedures like x-rays that are not near the uterus. The standard dose of radiation correlated with a diagnostic x-ray develops a minuscule risk to the fetus. However, all women of childbearing age are requested if they are pregnant before any exposure to radiation.

Maternal medical conditions

Maternal medical conditions may also develop teratogenic risks. Newborns of diabetic mothers have a raised incidence of congenital heart disease, renal, gastrointestinal, and central nervous system defects like neural tube malformations. Tight glycemic control during the third to sixth week post-conception is crucial.  Newborns of mothers with phenylketonuria who are not well controlled and have high levels of phenylalanine have a significant risk of mental retardation, low birth weight, and congenital heart disease.

Mechanical forces

Mechanical forces may also act as teratogens. Defects of the uterus may restrict fetal movements and be associated with congenital dislocation of the hip and clubfoot.  Oligohydramnios may have the same results and mechanically cause abnormalities of the fetal limbs. These abnormalities would be categorized as deformations or abnormal forms, shapes, or positions of body parts provoked by physical constraints. Amniotic bands are fibrous rings and also cause intrauterine amputations or defects of the limbs . These abnormalities would be categorized as disruptions or defects from interference with a properly developing organ system usually occurring later in gestation.

Multifactorial inheritance

Most frequent congenital malformations have familial distributions consistent with multifactorial inheritance. Multifactorial inheritance can be presented by a model in which liability to a disorder is a continuous variable that is dependent on a combination of environmental and genetic factors. Development of the malformation is dependent upon passing a threshold that is the sum of a combination of many of these factors. Traits that prove this mode of inheritance comprise cleft lip, cleft palate, neural tube defects, pyloric stenosis, and congenital dislocation of the hip.



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