Teratogen

Introduction

Teratogen is a substance, organism, physical agent, or deficiency state present during gestation that is capable of inducing abnormal postnatal structure or function (biochemical, physiologic or behavioral) by interfering with normal embryonic or fetal development and thus, disturbs fetal development if fetal exposure to these agents occurs during pregnancy. A child born with any kind of malformation or with any birth defect may create societal problems and therefore this subject needs concern (Blackburn, 2007). It is manifested that approximately 3% of all human newborns have a congenital anomaly requiring medical attention and approximately 1/3 rd of these conditions can be considered as life threatening. Of hospitalized children 40% are due to prenatal malformation (Thomas, 2004). We are only at the tip of the ice-berg to explore out all the reasons of these malformations. 25% are associated with gene mutation, 5% are associated with chromosomal aberrations, and 10% of the anomalies are due to teratogenic agents (Thomas, 2004). It is evident that huge gaps exist between our understanding and the role these agents play to cause human malformation (Thomas, 2004).

Any agent can be categorized as a teratogenic agent if it is capable of creating congenital defect. A congenital defect or anomaly is a kind of major or minor deviation from normal morphology or function and are generated during fetal or embryonic development (Jones, 2004). Minor defects are found in 2-3% of the population while large morphological types of congenital defects like cleft palate or meningomyelocele are the defects that alter function. A change in functions is also attributed to molecular mechanisms. Altered function of nervous and endocrine systems or in postnatal function is the main concern for both experimental and human teratology (Thomas, 2004).

Koch’s postulates find application in defining an agent to be teratogenic:

1. The agent must be present during the critical periods of development.
2. The agent should produce congenital defects in an experimental animal. The defect rate should be statistically higher in treated group than in the control animals receiving same vehicle or procedure.
3. One must get the proof that the agent in an unaltered state acts on the embryo-fetus either directly or indirectly through the placenta. Biochemistry and in vitro culture are used for the assessment (Thomas, 2004)

An agent which is capable of satisfying the first two conditions is categorized as a teratogenic agent. It is revealed that teratogenic agents in the human do fill all the three criteria. Some of these agents are rubella virus, radiation and androgens are known to masculinize the female fetus. The most widely discussed and universally accepted teratogenic agent is Thalidomide inspite of the fact that it doesn’t fulfill the third criterion as the compound does not affect conceptus in its unaltered form (Bishop, 1997). It is also discussed that agents that are known to cause embryonic or fetal death in experimental animals often prove to be teratogenic in humans also but they cannot be categorized as teratogenic unless they produce physical or functional defects (Kalter, 1968).

It is also reported that the time window of the exposure is also imperative to cause birth defects. This is called as concept or a “termination period”. It is the time period which if crossed cannot cause malformation (Warkany, 1971). The best example of this is occurrence of meningomyelocele; the caudal neuropore closes at 27 days, drug administered on 35th day would not be able to cause any kind of malformation (Warkany, 1971). In the similar manner diethylstilbesterol if taken during pregnancy, cause vaginal carcinomas in girls.

Mechanism of Action of Teratogens

Teratogens are known to affect the development at the embryonic stage. They do so by altering the genetic function of the organism. For the normal development of the fetus, it is essential that genes are expressed in a normal sequential manner, at this stage if any kind of external and internal variations are induced then it results in malformation (embryonic alteration in morphogenesis, due to abnormal developmental process), deformation (abnormal form, shape or position of a body part due to extrinsic mechanical forces) or disruption (caused by external force that alters previously normal tissue causing teratogenic defects or amputation of fetal part by an amniotic band). These agents either directly binds with the gene or its product or their presence induce changes in the gene(s) so the genes make an altered product resulting in the wrong signaling pathways causing disturbance in normal development (Lewin, Genes IX, Birth Defects and Genetics).

Drugs administered during pregnancy affect the development of the fetus in a different ways, from no effect to a major structural and functional deficit and therefore any substance can act as teratogen including infectious agents, ionizing radiation, pesticides, metals (mercury or lead), organic solvents, effects of maternal chronic disorders, herbal drugs with potential to act as abortifacients and uterine stimulants (Thomas, 2004). Agents known to be teratogenic in humans:

1. Radiation: encompassing atomic weapons, Radioiodine
2. Maternal and Metabolic Imbalance: Alcoholism, Amniocentesis (early), Chorionic villus sampling (before 60th day), Cretinism, endemic, Diabetes, Folic acid deficiency, Hyperthermia, Myasthenia gravis, Phenylketonuria, Rheumatic disease and congenital heart block, Sjogren’s syndrome, Virilizing tumors.
3. Infections: Cytomegalovirus (CMV), Herpes Simplex virus 1 and 2, Lymphocytic choriomeningitis, Parvovirus B-19, Rubella virus, Syphilis, Toxoplasmosis, Varicella virus, Venezuelan equine encephalitis virus.
4. Drugs and Environmental Chemicals: Aminopterin and methylaminopterin, Androgenic hormones, Busulfan, Carbamazepine, Corticosteroids, Cyclophosphamide, Diethylstilbestrol, Enalapril (renal failure), Fluconazole (high dose), Lithium, Mercury (organic), Methylene blue (via- intra-amniotic injection), Phenobarbitol, 1,2-cis-Retinoic acid (Isotretinoin and Axxutane), Tetracyclines, Thalidomide, Toluene abuse, Triethadione, Valproic acid. (Defects are discussed in Appendix).

Principles of Teratogenesis:

1. Susceptibility to a teratogenic agent is dependent upon the genotype of the embryo and the manner in which the agent interacts with environmental factors.
2. Susceptibility to teratogenic agents is dependent on the timing of the exposure and the developmental stage of the embryo.
3. Teratogenic agents act in specific ways on cells or tissues to cause pathogenesis.
4. The final manifestations of abnormal development are death, malformation, growth restriction and functional disorders.
5. Access to the embryo by environmental teratogens depends on the nature of the agent.
6. As the dosage increases, manifestation of deviant development increases (Blackburn, 2007)

Conclusion

There are no absolute teratogens; however, many agents can exhibit teratogenic effects under certain circumstances. The dose and the time of exposure to a particular agent often determine the severity of the damage and the type of defect that occurs. The dose response is obvious: the greater the dose, the greater the effect. The time of exposure is another important concept, as certain stages of embryonic and fetal development are more vulnerable than others. In general, the embryonic stage (first trimester) is more vulnerable than the fetal period (second and third trimesters). Thalidomide provides a classic example. The critical period of exposure is during organogenesis (the formation of the organs) from the 35th-48th day after the last menstrual period. The specificity of the malformations is linked to the time of exposure: 35-37 days, no ears; 39-41 days, no arms; 41-43 days, no uterus; 45-47 days, no tibia; and 47-49 days, triphalangeal thumbs. The types or severity of abnormalities caused by a teratogenic agent is also dependent on the genotype of the pregnant woman and the genotype of the fetus (genetic susceptibility). For example, variation in maternal metabolism of a particular drug will determine what metabolites the fetus is exposed to and the duration of exposure. Differences in placental membranes, placental transport and biotransformation all affect fetal exposure. The genetic susceptibility of the fetus to a particular teratogenic agent will also have an effect on the final outcome. It is therefore advised to go for the genetic counseling before conceiving the baby (King, 1986)

References

1. Blackburn, S. T. (2007). Chapter 7, Maternal, Fetal & Neonatal Physiology- A clinical Perspective. 3rd  Edn.  Saunders
2. Bishop, J. B., Witt, K. L., Sloane, R. A., (1997). Genetic toxicities of human teratogens.Mutat. Res396. 9-43.
3. Dicke, J. M. (1989). Teratology: principles and practice.Med. Clin. North Am73 (3). 567- 82
4. Jones, K. L. (2004). Smith’s Recognizable Patterns of Human Development, 6th ed. Philadelphia: w. b. Saunders Company.
5. Kalter, H. (1968). Teratology of Central nervous System Chicago: University of Chicago Press.
6. King, C. R. (1986). Genetic Counseling for teratogen exposure.Obstertrics and Gynecology.67(6). 843-6
7. Lewin, B. Genes IX
8. Thomas, H. S., Ronald, J. L. (2004). Developmental Gene Mutations as Teratogenic Agents
9. Warkany, J. (1971). Congenital Malformations: Notes and Comments. Chicago: Year Book Medical Publishers.
10. Birth Defects & Genetics: Birth Defects Accessed on 12th June 2009

Appendix

Maternal Conditions

Teratogen

Adverse Effects

Critical Period

Diabetes

Holoprosencephaly, porencephalic cysts, cardiac defects, sacral agenesis, caudal regression, laterality defects, facial clefts, renal defects

I trimester

Hypo/Hyperthyroidism

Mental retardation (MR), growth restriction

Entire pregnancy

Phenylketonuria (PKU)

MR, microcephaly, craniofacial defects

Hyperthermia

Anencephaly/ other neural tube defects (NTDs)

2- 4 wks

Systemic lupus erythematosus (SLE)

Transient neonatal SLE, intrauterine growth restriction, prematurity, congenital heart block

2- 4 wks

Non-prescription substance use:

Teratogen

Adverse Effects

Critical Period

Alcohol

Short palpebral fissures, altered facies, prenatal and postnatal growth deficiency, mild to moderate MR, microcephaly

Entire pregnancy

Tobacco

LBW, miscarriage

Toluene(PKU)

CNS (developmental delay, microcephaly, IUGR)

Medications

Teratogen

Adverse Effects

Critical Period

Aminopetrin/ Methotrexate

CNS, limb and skeletal defects

14-60 days

ACE inhibitors

Oligohydramnios, renal dysplasia/ failure, IUGR, joint contractures, prenatal death

II & III trimester

Carbamazepine

Spina bifida, hypoplasia of the phalanges, IUGR

14-60 days

Cyclophosphamide

CNS defects, skeletal defects (especially cranial and digits), IUGR, cleft palate, neonatal death

14-60 days

Fluconazole

(high dose)

Brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, cardiac defects, skeletal defects (thinning)

I trimester

Indomethacin

Oligohydramnios, anuria, necrotizing enterocolitis, premature ductus arteriosus closure

II- III trimester

Lithium

Cardiac defects (Ebstein anomaly)

14- 60 days

Methylene blue

Jejuna atresia

II trimester

Penicillamine

Connective tissue abnormality

14- 60 days

Retinoids (isotrtinoin)

CNS, ocular, cardiac, great vessel and limb defects, microtia, micrognathia, clet lip/ palate, thymic deficiency

Tetracycline

Staining of primary dentition

II – III trimester

Thalidomide

Cranial nerve abnormalities, limb shortening defects (phocomelia), ocular and cardiac defects, oral/ facial anomalies, renal and urogenital defects

27-40 days

Valproic acid

CNS defects (including developmental delay), brachycephaly, craniosynostosis, microcephaly, ocular hypertelorism, midface hypoplasia, limb anomalies, spina bifida

14- 60 days

Warferin

CNS and ocular defects, IUGR, neonatal hemorrhage, nasal hypoplasia, vertebral anomalies, stippled epiphysis

6- 9 wks