Role of teratogens in congenital anomalies and malformations


Abstract:

Crucial morphogenesis process during blastogenetic period may cause serious congenital anomalies at the stage of tissue development which is during 4-8weeks of fetal life. This may occur only if the foetus is exposed to teratogens during 14days of development period. Exposure of conception products to teratogenic substances is the major cause of non-genetic acquired diseases presenting itself at the time of birth. These teratogens can be drugs, toxins, chemicals, radiations, or microbes. These anomalies present with notable social and financial issues arise many questions that are difficult to reintegrate. This kind of exposure may lead to wide variety of effects like infertility, restricted fetal growth, miscarriage, structural defects, etc. Many studies are being made to expand scientific knowledge about congenital abnormalities and malformations in which avoidance of exposure to pregnant mothers has been an important part in prevention and management of these defects.


Introduction:

In utero exposure to teratogens may lead to 10-15% of congenital structural anomalies which is the result of adverse effect of environmental factors on fetal development which may lead to organ malformations; aberrations in growth, function and development; it can also lead to fetal death (in some cases). Organogenesis is the stage when rapid cellular division and migration occurs and these actively dividing cells are sensitive to adverse effects of pernicious agents. The effect of teratogens during postconceptional embryonic stage of first two weeks might present unyielding, as the implantation of defective embryo may fail and may lead to undisclosed abortion (figure:1) therefore, nullifying the possibility of congenital anomalies. Brent observed that it was unsuited to label any substance as teratogenic until we don’t know its route and exposure to which stage of pregnancy. The expression of teratogen depends on the effects of environmental agents on the fetus which depends on the physical and chemical nature of factors like route, length, and dosage of exposure. Disruptions are caused when a fetus is exposed to teratogenic substances and these health problems are difficult to reintegrate. Different systems have different susceptibility towards inhibiting agents.


Figure: 1; Prenatal sensitivity towards teratogens.

Reference: https://www.intechopen.com/online-first/the-pathogenesis-of-congenital-anomalies-roles-of-teratogens-and-infections


Teratogenic agents:

The agents interfering in the development of fetus or embryo are called teratogens and the fetus with malformed parts is called Terata. It ceases the pregnancy or produces a congenital misshappenness. These teratogens are further categorised into Radiation, Chemicals, Maternal infections and Drugs. The primary cause of teratogens is: disrupting biochemical metabolism and concession of blood circulation which leads to death. They destroy essential nutrients, interfere with mitosis and nucleic acid function, and degrade osmotic balance, energy production and membrane functions.


Radiation: When a cell is exposed to radiation during mitosis or DNA formation then there is a possibility of the cell to create chromosomal anomalies which leads to cellular disruptions and suppression of cell growth(Table:1). Cell and chromosomal injury can be caused in developing embryos due to ionizing radiations. No cell is studied to be completely unaffected by the radiations. Bergonie and Tribondeau reported that the most sensitive cells towards radiations are undifferentiated cells having highest mitotic activity. In utero radiation gives rise to microcephaly and mental retardation, increased incidence of hematopoietic malignancies and leukemia later in life.


Gestational period (in weeks) Effects

0-2 Miscarriage/or not affected

2-8 Congenital anomalies (related to eye, genital or skeletal system)

8-15 High risk of mental retardation, microcephaly and intellectual influence

16-25 Less chances of severe mental retardation


Table:1 Effects of radiation according to gestational age.

Maternal infection: In spite of having effective vaccines and specific diagnostic tests, congenital anomaly is still a problem for the developing fetus if a mother is exposed to viruses like: Herpes simplex virus, rubella, cytomegalovirus, human immunodeficiency virus, zika virus, syphilis, parvovirus, and varicella-zoster virus(Table:2). There is the possibility of the fetus to develop deafness, blindness, anomalies, malformations, growth retardation, neurodevelopmental abnormality and innate cardiac defects. These types of viruses and organism causing diseases are grouped under TORCH infections. The fetus and embryo are highly vulnerable to infections and diseases(during organogenesis) may lead to abortion, as the fetus is unable to synthesize IgG, IgM and IgA during first half of the pregnancy. Some pathogens may infect the mother or the fetus without showing any clinical symptoms which may lead to miscarriage, malformations, hydropy fetalis, and ill-timed rupture of cell.


Teratogen Effects

Rubella Heart disease, cataract, deafness

Parvovirus Fetal infection, fetal anemia, cardiac failure

Varicella-zoster virus Chicken pox (not very common)

Syphilis(Treponema palladium) Fetus may develop and born or may die

Zika virus Death of neurons, growth retardation

Cytomegalovirus Abnormal liver, growth retardation, nervous system anomaly

Toxoplasmosis(Toxoplasma gondii) Chronic destructive meningoencephalitis


Table:2 Some infection causing teratogens and their effects


Chemicals: Worldwide pollutants polychlorinated and polybrominated biphenyls are used as heat exchangers, insulating fluids, chemical additives and plasticizers. If a woman is infected from PCB, her children will be born with brown coloration and parchment like skin, conjunctivitis, low birth weight, dark colored nails, and natal teeth. When a fetus is exposed to higher levels of chemicals then there will be reduced birth weight and small head size with hypotonicity and hyporeflexia. Prenatal and postnatal retarded growth, delayed development, microcephaly, limb and cardiac defects are all related to the toluene embryopathy. Congenital anomalies may also be caused due to exposure to valproic acid which is commonly caused due to maternal ingestion of this product.


Drugs: Drugs may directly affect the fetus and can cause malformations (Table:3) or death. Exposure to drugs causes premature delivery, myometrial contractions, cease transfer of nutrients and oxygen to the fetus, alters transcription, and affects cell development. Drugs can also play a role in intrauterine fetal development by modifying the transcription signals which negatively affects transcription which further affects embryogenesis.


Drugs Effect

Lithium Ebstein’s anomaly toin syndrome(fetal)

Lithium Ebstein’s anomaly

Warfarin Nasal and limb hypoplasia, bone malformation, neurological defect

Sodium valproate Cleft palate, polydactyly

Aminopterin Limb and skeletal defects

Benzodiazepines Cleft palate

Warfarin Nasal and limb hypoplasia, bone malformation, neurological defect


Table:3 Effects of some teratogenic drugs


Non-teratogenic agents: There are some non teratogenic agents which were suspected to be teratogenic, the agents are: spermicides(does not affect the pregnancy), prenatal vitamins(helps to fulfil nutritional requirements), microwaves(microwaving food during pregnancy does not risks for birth defects) and acetaminophen(in pain killers). There is no association of these teratogens with malformations and abnormalities.


Summary:

The objective of this review is to summarise the cause of malformations occurred due to prenatal exposure to teratogens. Most of these teratogen induced anomalies can be prevented. Multiple factors are responsible for neonatal congenital malformation, occurrence of the disease and presentation of severity of in utero exposure to teratogens and infections. The response of an individual to a teratogen is very diverse and depends on the genetic sensitivity and exposure of the product of conception.


Vanshita Mehta

Dept. of Biochemistry and Biotechnology

St. Xavier's College, Ahmedabad



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