TeratogenIntroduction 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:
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:
Principles of Teratogenesis:
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
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 |