Teratogens | Factors Causing Physical Defects In Foetus

Teratogens are substances or environmental factors that cause the development of abnormal cell masses during foetal growth, resulting in physical defects in the foetus. These are the agents that cause congenital, structural malformations in a developing embryo.

Developmental toxicity is any morphological or functional alteration caused by the chemical or physical insult that interferes with normal growth, homeostasis, development, differentiation, or behavior.

Teratogens

Teratology is a specialized area of embryology. It is the study of the etiology of abnormal development (the study of birth defects). Teratogens, therefore, are substances and other factors that cause malformations in the developing conceptus. Teratogens can cross the placental barrier and cause an increase in the incidence of physical malformations and behavioral and cognitive defects.

It is estimated that approximately 10%–15% of congenital structural anomalies are the result of the adverse effect of environmental factors on prenatal development.

This means that approximately 1 in 250 new-borns have structural defects caused by environmental exposure and, presumably, a larger number of children have growth retardation or functional abnormalities resulting from non-genetic causes, in other words, from the effects of teratogens.

 When describing teratogens, one may think of three basic characteristics of teratogens:

  1. A given teratogen may be organ-specific.
  2. It may be species-specific.
  3. It can be dose-specific.

 Each organ of an embryo has a critical period during which its development may be disrupted. The type of congenital malformation produced by an exposure depends upon which organ is most susceptible at the time of the teratogenic exposure. For instance, high levels of radiation produce abnormalities of the central nervous system and eyes specifically at eight to 16 weeks after fertilization.

TERATOGEN   FERTILIZATION AGE (DAYS)   MALFORMATION
  Rubella Virus 0-60   Cataract or heart diseases
 0->120 Deafness
  Thalidomide (drug formerly used for treating morning sickness)  21-40 Reduction defects of extremities
  Androgens   >90   Clitoral hypertrophy and labial fusion
Warfarin (an anticoagulant drug)   <100   Hypoplasia of nose and stippling of epiphyses
 Diethylstilbesterol (synthetic estrogen)   >100   Possible mental retardation
Radioiodine therapy   >65-70  Foetal thyroidectomy
 Goitrogens and iodides   >180 Foetal goiter
Tetracycline (antibiotic)   >120 Dental enamel staining of primary teeth
>150   Staining of crowns of permanent teeth

Some Examples Of Teratogens

  • Thalidomide

Thalidomide is a sedative-hypnotic drug that was marketed for morning sickness, nausea, and insomnia. Women who had taken the drug from 35 to 50 gestation days, gave birth to offspring suffering from a wide range of different malformations, mainly amelia (absence of limbs) or phocomelia (severe shortening of limbs).

Other malformations included the absence of the ear pinna with deafness, defects of the muscles of the eye and face, and malformations of the heart, bowel, uterus, and the gallbladder. The compound was withdrawn from the market after about 10,000 cases were reported.

  •  Accutane (Isotretinoin)

Accutane is a member of a family of drugs called retinoids, which are related to vitamin A. It is approved to treat serious forms of acne. These painful and disfiguring forms of acne do not respond to other acne treatments. Accutane is very effective, but its use is associated with several risks, including birth defects.

Even at very low doses, oral medications such as isotretinoin, used in the treatment of acne, are potent teratogens. The critical period of exposure appears to be from 2nd to the 5thweek of gestation. The most common malformations include craniofacial dysmorphisms, cleft palate, thymic aplasia, and neural tube defects.

  •  Diethylstilbestrol (DES)

DES is a synthetic oestrogen that inhibits ovulation by affecting the release of pituitary gonadotropins. Some of its uses include treatment for hypogonadism, primary ovarian failure, and in some cases of prostate cancer. During the period between 1940 and 1970, DES was used to help maintain pregnancy.

In utero exposure to DES has been associated with abnormal development of the uterus. It has also been associated with certain types of tumors. Women who were exposed in utero often developed vaginal neoplasia, vaginal adenosis, and cervical erosion. Effects were not seen in offsprings until they reached puberty.

Clear cell carcinoma of the vagina is a type of adenocarcinoma found in young women who are exposed to diethylstilbestrol in utero. The reproductive organ of males can also be affected subsequent to in utero exposure. The outcomes include hypotrophic testes, poor semen volume, and quality.

  •  Alcohol-Foetal Alcohol Syndrome

Alcohol is a common drug abused by women of childbearing age. Foetal alcohol syndrome (FAS) is a pattern of mental and physical defects that develops in some offspring when exposed to alcohol in utero. The first trimester is the most susceptible period. Some babies with alcohol-related birth defects, such as lower birth weight and body size and neurological impairments, do not have all of the classic FAS symptoms.

These outcomes are often referred to as foetal alcohol effects (FAE). In addition to growth retardation, the most common outcomes of foetal alcohol syndrome include psychomotor dysfunction and craniofacial anomalies. The observed growth deficiencies are associated with an inability of the baby to catch up due to a slower than normal rate of development.

Other infrequent outcomes include skeletal malformations such as deformed ribs and sternum, scoliosis, malformed digits, and microcephaly. Distinctive facial anomalies have been associated with a diagnosis of foetal alcohol syndrome: small eye openings, epicanthal folds, failure of eyes to move in the same direction, short upturned nose, the flat or absent groove between nose and upper lip, and thin upper lip.

Visceral deformities may also be present: heart defects, genital malformations, kidney, and urinary defects. A common concurrent manifestation of FAS includes central nervous system defects. These include an irregular arrangement of neurons and connective tissue. Mental retardation may also be present and associated with learning disabilities as well as difficulties in controlling body coordination.

  •  Infectious Agents 

 Infectious agents can also cause a variety of birth defects and mental retardation when they cross the placenta and enter the foetal bloodstream. Congenital rubella or German measles consists of cataracts, cardiac malformation, and deafness.

The earlier in the pregnancy that the embryo is exposed to maternal rubella, the greater the likelihood that it will be affected. Most infants exposed during the first four to five weeks after fertilization will have a probability of this exposure.

Congenital cytomegalovirus infection is the most common viral infection of the foetus. The infection of the early embryo during the first trimester most commonly results in spontaneous termination of the pregnancy.

 Ionizing radiation can injure the developing embryo due to cell death or chromosome injury (mutations). The severity of damage to the embryo depends on the dose absorbed and the stage of development at which the exposure occurs. A study of the various survivors of the atomic bombing in Japan demonstrated that exposure at 10 to 18 weeks of pregnancy is a period of greatest sensitivity for the developing brain.

Mechanical forces can also act as teratogens. Malformations of the uterus may restrict foetal movements and be associated with congenital dislocation of the hip and clubfoot.

 Testing Protocols Of Teratogens

Formal testing guidelines were established after the thalidomide teratogenicity case. In 1966 guidelines were established by the FDA: Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use. Since then, new streamlined testing protocols have been developed with international acceptance.

A newer approach, International Conference of Harmonization (ICH) (13.6.2), relies on the investigator to determine the model to access reproductive/developmental toxicity. However, the most widely published and practiced version of teratogenicity testing is the FDA version of testing, which is also known as the segment studies.

 FDA GUIDELINES FOR REPRODUCTION STUDIES FOR SAFETY EVALUATION OF DRUGS FOR HUMAN USE:

Multigenerational Study: This type of study involves the continuous exposure of a rodent species (usual mice) to the drug under examination. The parental animals are exposed shortly after weaning (30–40 days of age). At reproductive maturity, the animals are mated. The first generation is produced (F1).

From these a second-generation, F2 is produced and then subsequently an F3 generation. The effects of the test are monitored through each generation. The measured parameters include fertility, litter size, and neonatal viability. This is a time-consuming effort that usually takes about two years for the entire study to be completed.

Single-Generation Studies: Single-generation studies are short-term studies conducted in three segments

  • Segment I: Evaluation of Fertility and Reproductive Performance

Male rodents are treated (with the drug under examination) for 70 days (to expose for one spermatogenic cycle), and non-pregnant females for 14 days (to exposure for several oestrous cycles). Treatment is continued in the females during mating, pregnancy, and lactation.

Fifty percent of the females are killed, and the foetuses are examined for the presence of malformations. The other 50% are allowed to give birth. After weaning, these offspring are killed and necropsied.

  • Segment II: Assessment of Developmental Toxicity

This involves the treatment of pregnant females only during the period covering implantation through organogenesis (typically from gestational days 6 to 15 in mice with 18-day gestational periods). One day prior to birth, the animals are killed, and foetuses are examined for viability, body weight, and presence of any malformation.

  • Segment II: Postnatal Evaluation

Pregnant animals are treated from the last trimester of pregnancy until weaning. Evaluation of parturition process, late foetal development, neonatal survival, and growth, as well as the presence of any malformations, is done.

Understanding the mechanisms of the induction of birth defects is key to determine how to prevent these effects. Further, increasing the accuracy of experimental animal extrapolation will aid in the interpretation of experimental data to more accurately determine the risk of a given compound to elicit birth defects in humans.

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