Teratogenesis – Definition, Factors, Mechanism

What is Teratogenesis?

• Teratogenesis, also known as teratogenicity, refers to the process by which congenital birth defects occur due to exposure to certain factors during pregnancy. These factors can include biological infections (such as viral or protozoan infections), physical agents (like ionizing radiation or excessive heat), pharmacological drugs (such as thalidomide or corticosteroids), industrial pollutants (like toluene or cadmium), maternal substance use (such as alcohol or nicotine), and maternal health problems (like diabetes mellitus or rheumatoid arthritis).
• The field of teratology is dedicated to the scientific study of congenital malformations and their causes. It focuses on understanding how environmental agents disrupt the normal development of the fetus, leading to the occurrence of birth defects. Researchers in teratology investigate the mechanisms through which these agents interfere with the intricate processes of embryonic and fetal development.
• Various factors can contribute to teratogenesis. Biological infections can directly affect fetal development by crossing the placenta and interfering with cellular processes. Physical agents, such as radiation or excessive heat, can cause DNA damage or disrupt the normal functioning of cells, leading to malformations. Pharmacological drugs taken during pregnancy can have teratogenic effects on the developing fetus, altering critical developmental pathways. Industrial pollutants present in the environment can also pose a risk if pregnant women are exposed to them. Maternal substance use, including alcohol and nicotine, can have detrimental effects on fetal development. Additionally, certain maternal health conditions, such as diabetes mellitus or rheumatoid arthritis, can increase the risk of birth defects.
• Understanding teratogenesis is essential for preventing and minimizing the occurrence of congenital malformations. It involves studying the effects of various environmental agents on embryonic and fetal development to identify potential teratogens. This knowledge helps inform public health policies and guidelines to protect pregnant women and their unborn children.
• In summary, teratogenesis refers to the process through which congenital birth defects occur due to exposure to biological infections, physical agents, pharmacological drugs, industrial pollutants, maternal substance use, or maternal health problems during pregnancy. Teratology as a scientific discipline investigates the causes of congenital malformations and aims to understand how environmental agents disrupt normal development.

Teratogenic Agents

1. Infectious agents

• Infectious agents can play a significant role in teratogenesis, contributing to the development of congenital birth defects when pregnant women are infected. Several types of infections have been identified as teratogenic, including viral infections, spirochetal infections, and protozoal infestations.
• Viral infections such as rubella, herpes simplex, and cytomegalovirus (CMV) have been associated with an increased risk of congenital anomalies when contracted during pregnancy. Rubella infection, particularly during the first trimester, can lead to serious birth defects, including hearing and vision impairments, heart abnormalities, and developmental delays. Herpes simplex virus and CMV infections have also been linked to various congenital malformations.
• Spirochetal infections, specifically syphilis, pose a significant teratogenic risk. If left untreated, syphilis can be transmitted from the mother to the fetus, leading to congenital syphilis. This condition can result in a range of adverse outcomes, including skeletal abnormalities, dental defects, vision and hearing impairments, and neurological complications.
• Protozoal infestations, such as toxoplasmosis, can also have teratogenic effects. Toxoplasmosis is primarily acquired through the ingestion of contaminated food or exposure to infected animals. If a pregnant woman becomes infected, the parasite can cross the placenta and affect the developing fetus. Congenital toxoplasmosis can cause severe neurological and ocular abnormalities, including intellectual disability, seizures, vision impairments, and hearing loss.
• In addition to these specific infections, maternal influenza exposure during the first trimester has been associated with an increased risk of various non-chromosomal congenital anomalies. These anomalies can include neural tube defects, hydrocephalus, congenital heart anomalies, cleft lip, digestive system abnormalities, and limb defects.
• Preventing and managing infectious agents during pregnancy is crucial to minimize the risk of teratogenesis. Pregnant women are often advised to take precautions to avoid exposure to potential sources of infection, practice good hygiene, and receive appropriate vaccinations. Early detection and treatment of infections, especially those known to be teratogenic, are essential to protect the health and well-being of both the mother and the developing fetus.
• In conclusion, infectious agents such as viral infections (e.g., rubella, herpes simplex, CMV), spirochetal infections (e.g., syphilis), and protozoal infestations (e.g., toxoplasmosis) can have teratogenic effects when contracted during pregnancy. These infections can lead to a range of congenital anomalies and birth defects, emphasizing the importance of preventive measures and early detection in ensuring healthy pregnancies and reducing the risk of adverse outcomes.

2. Physical agents

• Physical agents, particularly radiation, can have teratogenic effects on the developing fetus. Exposure to ionizing radiation during pregnancy can pose a risk to the normal development of the embryo or fetus. It is important to note that the teratogenic effect of radiation is cumulative, meaning that the total dose received over time contributes to the potential harm.
• In various health testing procedures that involve the use of radiation, the level of ionizing radiation used is typically kept as low as possible to minimize potential risks. However, it is worth noting that even the radiation doses used in these procedures are in close proximity to the threshold for teratogenicity, especially during the first trimester of pregnancy when organ development is most vulnerable.
• There is a general assumption that the risk associated with human radiation exposure is directly proportional to the total radiation dose received. This means that higher doses of radiation carry a greater risk of teratogenic effects. Therefore, it is crucial to carefully consider and limit radiation exposure during pregnancy to ensure the safety and well-being of the developing fetus.
• Healthcare professionals and radiology technicians follow strict guidelines and protocols to minimize radiation exposure for pregnant women. They take precautions such as shielding the abdomen during X-ray examinations or using alternative imaging techniques that do not involve ionizing radiation whenever possible.
• It is important for expectant mothers to inform healthcare providers about their pregnancy status to ensure appropriate precautions are taken during any medical procedures or imaging tests. By being aware of the potential teratogenic effects of radiation and taking necessary steps to minimize exposure, healthcare professionals can contribute to the overall safety of both the mother and the developing fetus.
• In summary, physical agents, particularly radiation, can be teratogenic. The teratogenic effect of radiation is cumulative, and even low doses used in health testing procedures can approach the threshold for teratogenicity, particularly in the first trimester. The risk associated with radiation exposure is generally considered proportional to the total radiation dose received. Therefore, it is essential to carefully manage and limit radiation exposure during pregnancy to safeguard the normal development of the fetus and mitigate potential teratogenic risks.

3. Chemical agents

Chemical agents, including certain medications and substances, can have teratogenic effects on the developing fetus. These agents can disrupt normal development and contribute to the occurrence of birth defects. Here are some key points about different chemical agents and their teratogenic effects:

1. Medications:
   • P-glycoprotein polymorphisms, which are involved in drug transportation across the placenta, have been associated with an increased risk of fetal birth defects caused by medications taken during pregnancy.
   • Several mechanisms are linked to medication-induced teratogenesis, including folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption, and specific receptor- or enzyme-mediated teratogenesis.
   • Antiepileptic drugs (AEDs) are commonly used to treat epilepsy and other conditions in women of childbearing age. Discontinuation of AEDs during pregnancy is generally not advised due to the risk of seizures. However, some AEDs, like valproate, have been associated with impaired cognitive development and increased autism incidence, while others, such as carbamazepine, lamotrigine, levetiracetam, or phenytoin, may have more favorable cognitive and behavioral outcomes.
   • Sodium phenytoin (PTH) is known to have teratogenic effects, including malformations of the toes, fingers, kidneys, face, and neural tube closure defects.
   • Valproic acid (VPA), used to treat epilepsy, bipolar disorder, and migraine, can induce teratogenicity, particularly neural tube anomalies. Newer generation AEDs like lamotrigine, topiramate, and gabapentin also show signals for congenital jaw or oral malformations.
2. Vitamin A and its derivatives:
   • Excess intake of vitamin A, specifically retinoic acid (RA) or retinol, during pregnancy can lead to malformations in the skull, face, limbs, eyes, and central nervous system of the fetus.
   • Isotretinoin, an oral medication derived from vitamin A, used for severe acne treatment, can cause fetal abnormalities, including cleft lips, ear and eye defects, and mental retardation.
3. Other substances:
   • Mefloquine, an antimalarial drug, is considered safe during the second and third trimesters of pregnancy. However, in early gestation in rats, it has been shown to cause minimal brain ventricle extension, renal pelvis abnormalities, and delayed ossification in fetuses.
   • Miltefosine, a drug used to treat visceral leishmaniasis, has potential teratogenic effects that can interfere with fetal development.
   • Ritodrine, used to prevent premature labor, can cause cardiovascular problems in the fetus when used excessively. Combining ritodrine with nifedipine has been shown to reduce the toxic and teratogenic effects of nifedipine alone on embryos.

4. Environmental pollutants

Environmental pollutants can have harmful effects on the developing fetus. Here are examples of two common environmental pollutants and their teratogenic effects:

1. Toluene:
   • Toluene is an organic solvent widely used in industries.
   • Many women of childbearing age may be exposed to toluene in occupational settings or through inhalation abuse, such as episodic, binge exposures to high concentrations.
   • High levels of toluene exposure during pregnancy have been associated with retardation of mental health and growth in the fetus.
   • Prolonged exposure to low concentrations of toluene or acute exposure to high concentrations can pose risks to the developing fetus.
2. Cadmium (Cd):
   • Cadmium is a heavy metal pollutant and a known teratogen.
   • Teratogenic effects of Cd have been observed in chick embryos and may occur due to various mechanisms, including impaired endogenous nitrous oxide (NO) production, increased oxidative stress, and activated apoptotic pathways.
   • Cd exposure during pregnancy can lead to decreased fetal body weight and reduced bone lengths of the forelimbs and hindlimbs.
   • Additionally, high levels of Cd exposure may increase the risk of abortion.

5. Tipsiness of mother

The consumption of certain substances by pregnant women can have detrimental effects on the developing fetus. Here is information about the teratogenic effects of substances consumed by expectant mothers:

1. Alcohol:
   • Prenatal alcohol consumption is considered a teratogenic agent.
   • Genetic factors play a role in influencing the development of fetal alcohol spectrum disorders (FASDs) in both humans and animals.
   • MicroRNAs, along with their target genes, are involved in the pathogenesis of fetal alcohol syndrome (FAS).
   • Sociobehavioral risk factors, such as low socioeconomic status, can contribute to the permissiveness of FAS. These factors, combined with biological factors like decreased antioxidant status, interact with alcohol to provoke FAS and alcohol-related birth defects (ARBDs) in vulnerable fetuses.
2. Nicotine:
   • Maternal nicotine consumption is teratogenic and can lead to an increased incidence of attention hyperactivity disorder (ADHD) in the offspring.
   • There is a correlation between the teratogenic effects of alcohol and tobacco and the risk of anorectal atresia, a congenital malformation.
   • Smoking during pregnancy also increases the risk of Sudden Infant Death Syndrome (SIDS), which refers to the sudden and unexpected death of an infant under 12 months of age, typically occurring during sleep. It is related to failures in auto-resuscitation, normal heart rate, and breathing.
3. Cocaine:
   • Cocaine abuse during pregnancy can have severe consequences for the fetus.
   • It significantly reduces fetal weight and increases the rate of malformations.
   • Cocaine abuse can also augment the stillbirth rate due to abrupt placentae, which refers to the detachment of the placenta from the uterine wall before delivery.
   • When cocaine and alcohol are simultaneously ingested, the liver forms cocaethylene or ethylbenzoylecgonine. This substance is more toxic to myocardial cells than cocaine alone and acts as a potent stimulant and dopamine uptake blocker.

6. Maternal health problems

Maternal health problems can have significant implications during pregnancy. Here is some information about specific maternal health conditions and their effects on the developing fetus:

1. Diabetes Mellitus:
   • Diabetes mellitus, both pre-existing and gestational, is a cause for concern during pregnancy.
   • Teratogenesis, the development of congenital anomalies, is associated with diabetes in expectant mothers.
   • Offspring of obese diabetic women are at an increased risk of congenital anomalies.
   • The use of oral antihyperglycemic agents is not recommended during pregnancy.
   • Adopting a healthy diet and engaging in regular exercise before pregnancy can help optimize pre-pregnancy weight and reduce the risk of congenital anomalies.
   • Cardiac and neural tube defects are among the most commonly observed malformations in fetuses of pre-gestational diabetic mothers.
2. Multiple Sclerosis (MS):
   • Pregnant women with multiple sclerosis should carefully consider the risks and benefits of ongoing therapy for both their own health and the well-being of the fetus.
   • The immunosuppressant drugs mitoxantrone and fingolimod are teratogenic and should only be prescribed with strict and effective contraception.
3. Rheumatoid Arthritis (RA):
   • Pregnant women with rheumatoid arthritis can generally use immune-modulating medications with low risk, which can lead to optimal outcomes.
   • Some women with RA may have a higher risk of miscarriage or giving birth to low-birth-weight babies.

Sl. No.	Drugs	Teratogenic Effects
1.	Aminopterin, Methotrexate	CNS and limb malformations
2.	Anticholinergic drugs	Neonatal meconium ileus
3.	Anti-thyroid drugs	Foetal and neonatal goiter, hypothyroidism, aplasia cutis
4.	Angiotensin-converting –	Prolonged renal failure, decreased skull ossification, renal tubular dysgenesis
	enzyme inhibitors
5.	Carbamazepine	Neural tube defects
6.	Danazol & other	Masculinization in female fetuses
	androgenic drugs
7.	Hypoglycemic drugs	Neonatal hypoglycemia
8.	Lithium	Ebstein’s anomaly
9.	Misoprostol	Moebius sequence
10.	Nonsteroidal anti-inflammatory drugs	Constriction of the ductus arteriosus, necrotizing enterocolitis
11.	Phenytoin	Growth retardation, CNS deficits
12.	Psychoactive drugs (e.g. barbiturates, opioids and benzodiazepines)	Neonatal withdrawal syndrome when drug is taken in late pregnancy
13.	Systemic retinoids (isotretinoin & etretinate)	CNS, craniofacial, cardiovascular defects
14.	Tetracycline	Anomalies of teeth and bone
15.	Thalidomide	Limb-shortening defects, internal organ defects
16.	Valproic acid	Neural tube defects
17.	Warfarin	Skeletal and CNS defects, Dandy-Walker syndrome

Stage Sensitivity for Teratogenicity

Stage Sensitivity for Teratogenicity refers to the specific periods during prenatal development when the embryo or fetus is most vulnerable to the harmful effects of teratogenic agents. These stages can be categorized as follows:

i. Pre-Differentiation Stage: During this stage, which typically lasts from 5 to 9 days depending on the species, the embryo is relatively resistant to teratogenic agents. These agents either cause complete cell death, resulting in the demise of the embryo, or they have no observable effect. Even if some harmful effects occur, the surviving cells have the ability to compensate and develop into a normal embryo.

ii. Embryonic Stage: The embryonic stage is characterized by intensive cell differentiation, mobilization, and organization. It is during this period that organogenesis, the formation of most organs, takes place. Consequently, the embryo is highly susceptible to the effects of various teratogens. In rodents, this stage generally ends between the 10th and 14th day of gestation, while in humans, it extends until the 14th week of gestation. However, not all organs are equally susceptible during the same period. For example, in rats, most organs are most vulnerable between days 8 and 12, although the palate and urinogenital organs may be more susceptible at a later stage.

Studies conducted by J. G. Wilson in 1965 on rat embryos treated with teratogens on the 10th day of gestation revealed the following incidences of malformations:

• Brain defects: 35%
• Eye defects: 33%
• Heart defects: 24%
• Skeletal defects: 18%
• Urinogenital defects: 6%

iii. Fetal Stage: During the fetal stage, the focus is on growth and functional maturation rather than organ development. Teratogens are less likely to cause morphological defects at this stage, but they may induce functional abnormalities. While morphological defects are typically detectable at birth or shortly thereafter, functional abnormalities such as impairment of the central nervous system (CNS) may not be diagnosed until some time after birth.

Mode of Action of Teratogens

The mode of action of teratogens involves various mechanisms that can disrupt normal cellular processes and development. Some of these mechanisms include:

1. Interference with Nucleic Acids: Certain teratogenic agents can interfere with the replication, transcription, or translation of nucleic acids. Alkylating agents, antimetabolites, intercalating agents, and amino acid antagonists are examples of teratogens that can disrupt these processes and affect normal development.
2. Inhibition of Enzymes: Teratogens can inhibit specific enzymes involved in crucial biochemical pathways. For example, 5-fluorouracil inhibits thymidylate synthase, which can interfere with cell differentiation and growth. Other examples include 6-aminonicotinamide, which inhibits glucose-6-phosphate dehydrogenase, and folate antagonists that inhibit dihydrofolate reductase.
3. Deficiency of Energy Supply and Osmolarity: Certain teratogens can disrupt the energy supply required for metabolism by restricting the availability of essential substrates. This can occur through dietary deficiencies or the presence of analogs that act as antagonists for vitamins and essential amino acids. Hypoxia, carbon monoxide (CO), carbon dioxide (CO2), and other agents can also be teratogenic by depriving the developing embryo of necessary oxygen and causing osmolar imbalances. These imbalances can lead to edema, mechanical distortion, tissue ischemia, and subsequent malformations. Physical agents such as radiation, hypothermia, hyperthermia, and mechanical trauma can also cause malformations.

It is important to note that the mode of action of many teratogens is still uncertain, and the effects of potential teratogens can vary depending on factors such as bio-activating mechanisms, stability, and detoxifying capabilities of embryonic tissues. Therefore, conducting appropriate experimental testing to evaluate the teratogenicity of toxic substances is essential.

Testing Procedures

Testing procedures for evaluating the teratogenic effects of substances involve the use of animals, administration of the teratogenic agent, and careful observation and evaluation of the outcomes. Here are the key elements of testing procedures:

Selection of Animals:

• Young, mature, and healthy animals are preferred for teratogenic tests.
• Prima gravida females are commonly used.
• Rats, rabbits, and hamsters are the most frequently used animals due to their availability, ease of handling, small size, and short gestational period.
• Pigs are occasionally used due to their phylogenetic similarity to humans.
• Nonhuman primates, such as monkeys, are suggested by WHO due to their closer phylogenetic proximity to humans.
• Dogs and cats have also been used by some researchers.

Administration of Teratogenic Agent: Dosage:

• Typically, at least three dosages are used, with the lowest dosage falling between the two extremes.
• Two control groups are included: one receiving the vehicle or physiological saline, and the other receiving a substance known to have teratogenic activity. These control groups provide information on spontaneous malformation incidence and the sensitivity of the animals under the experimental conditions.
• Historical control data may also be used.

Route and Timing:

• Test compounds are administered using routes that mimic human exposure situations. For food additives and contaminants, the chemical is preferably incorporated into animal feeds. Oral drugs are commonly administered via gastric gavage.
• The timing of substance administration is crucial and is typically during the period of organogenesis when the embryo is most susceptible. The timing varies between species.

Observations:

• Pregnant animals should be examined daily for signs of toxicity, and females showing signs of impending abortion or premature delivery should be closely monitored.
• Fetuses are surgically removed from the mother approximately one day before the expected delivery to prevent cannibalism and allow for counting of resorption sites and dead fetuses.
• Various observations and measurements are made and recorded, including the number and position of corpora lutea, implantations, resorptions, dead and live fetuses, sex, weight, length, and abnormalities of each fetus.

Detailed Examinations:

• Each fetus is examined for external defects, and a subset of fetuses is examined for skeletal abnormalities or visceral defects.
• Skeletal structure in larger animals may be examined using X-rays.

Delayed Effects:

• In cases where teratogens are suspected to have effects on the central nervous system or genitourinary system, a sufficient number of pregnant females are allowed to deliver their pups. These pups can be nursed by their biological mothers (potentially exposed to the teratogens via milk) or foster mothers, to determine the effects of postnatal exposure.
• Neuromotor and behavioral tests may be conducted to detect central nervous system effects.

Evaluation of Teratogenic Effects:

• Aberrations and malformations are categorized based on their significance and impact on development and survival.
• Factors such as resorption, fetal toxicity, and other parameters are considered in the evaluation process.
• Analysis of results involves comparing treated and control groups using statistical analysis based on the number of litters with malformed fetuses, resorptions, or dead fetuses.

Extrapolation to Humans:

• Results from teratogenic studies in animals cannot be directly extrapolated to humans due to differences in species sensitivity and mechanisms of teratogenesis.
• However, testing chemicals for teratogenicity in animals is still necessary, considering that all chemicals known to be teratogenic in humans have shown activity in certain animals.
• The severity of abnormalities should be considered along with the incidence when assessing the teratogenic effects of a chemical.

In Vitro Tests:

• In vitro tests, such as cell culture and organ culture, can provide insights into the mode of action of teratogens, although they are not yet in routine use for teratogenicity testing.

It is important to note that ethical considerations and regulations govern the use of animals in teratogenic testing, and alternative methods, such as in vitro and computational models, are being developed to reduce the reliance on animal testing while ensuring the safety of potential teratogens.

FAQ