Teratogen
Introduction
Teratogen is a substance or body, or physical agent present deficient state during pregnancy that is able to induce abnormalities in the structure or function after childbirth (biochemical, physiological or behavioral) to interfere with embryonic or fetal development and, therefore, disrupts fetal development if fetal exposure to these agents occurs during pregnancy. A child born with some form of malformation or birth defects can create social problems and therefore this issue should concern (Blackburn, 2007). This study shows that approximately 3% of all human newborns have a congenital abnormality that requires medical attention and about 1 / 3 rd of these conditions can be regarded as a threat to life. Of the hospitalized children 40% are due to prenatal malformations (Thomas, 2004). We are only at the tip of the iceberg to explore all the reasons 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 clear that large gaps exist between our understanding and the role these agents play cause human malformations (Thomas, 2004).
Any agent can be classified as a teratogenic agent if it is capable of creating defect. A congenital defect or anomaly is a kind of deviation more or less 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 anomalies such as cleft palate or myelomeningocele are defects that alter the function. A change in the functions also is attributed to molecular mechanisms. Altered function of the nervous system and endocrine apparatus or function after childbirth is the main concern for both experimental and human teratology (Thomas, 2004).
Koch's postulates are used in the definition of an agent to be teratogenic:
- The agent must be present during critical periods of development.
- The agent must produce birth defects in an experimental animal. The defect rate must be significantly greater in the treated group than in the control animals received the same vehicle or procedure.
- We must get the proof that the agent acts in a natural state in the embryo-fetus, directly or indirectly through the placenta. Biochemistry and cultured in vitro are used to evaluate (Thomas, 2004)
An agent is able to satisfy the first two conditions is classified as a teratogenic agent. It is revealed that the teratogenic agents in humans must fill in all the three criteria. Some of these agents are rubella, radiation and androgens are known for masculinizing the female fetus. The most widely discussed and universally accepted teratogenic agent is thalidomide, despite the fact that does not meet the third criterion that the compound does not affect unaltered concept form (Bishop, 1997). It also analyzes the agents known to cause embryonic or fetal death in experimental animals have often proved to be teratogenic in humans as well, but can not be categorized as teratogens that produce less physical or functional defects (Kalter, 1968).
Also reported that the time window of exposure is also essential to cause birth defects. This is known as a concept or a period of termination. " It is the period of time than if crossed can not cause malformations (Warkany, 1971). The best example is the occurrence of myelomeningocele, the caudal neuropore closes at the 27 days, drug administered on day 35 would not be able to cause any type of malformations (Warkany, 1971). In similar diethylstilbestrol if taken during pregnancy, cause vaginal cancers in girls.
Mechanism of action of Teratogens
Known to be teratogenic affect development in the embryonic stage. They do this by altering gene function in the body. For normal fetal development, it is essential that the genes are expressed in a way normal sequence at this stage whether any form of external and internal changes are induced then leads to malformations (abnormal morphogenesis embryo due to abnormal development process), deformation (abnormal form, shape or position of a body part due to mechanical forces extrinsic) or alteration (caused by an external force that changes the previously normal tissue defects or teratogenic causing the amputation of part of the fetus, amniotic band). These agents directly binds to the gene or its product or their presence induce changes in the gene (s) so that the altered genes to make a product resulting in signaling pathways wrong causing disturbances in normal development (Lewin, Genes IX, Birth Defects and Genetics).
The drugs administered during pregnancy affect fetal development in different ways, from no effect to significant structural and functional deficits and therefore any substance can act as a teratogen including infectious agents, ionizing radiation, pesticides, metals (mercury, lead), organic solvents, the effects of maternal chronic conditions, medications Herbal potential to act as abortifacients and stimulating the uterus (Thomas, 2004). Agents known to be teratogenic in humans:
- Radiation: including atomic weapons, radioiodine
- The mother and metabolic imbalance: alcoholism, amniocentesis (early) Chorionic villus sampling (Before the 60th day), endemic cretinism, diabetes, folic acid deficiency, hyperthermia, myasthenia gravis, phenylketonuria, rheumatic disease and congenital heart block, Sjogren's syndrome, virilizing tumors.
- Infections: Cytomegalovirus (CMV), herpes simplex virus 1 and 2, the lymphocytic choriomeningitis virus, Parvovirus B-19, rubella virus, syphilis, toxoplasmosis, varicella virus, Venezuelan equine encephalitis.
- Drugs and environmental chemicals: aminopterin and methylaminopterin, androgenic hormones, busulfan, carbamazepine, corticosteroids, cyclophosphamide, diethylstilbestrol, enalapril (kidney failure), fluconazole (high dose), lithium, mercury (organic), methylene blue (injection via intra-amniotic) phenobarbital acid, 1,2-cis-retinoic acid (isotretinoin and Axxutane), tetracyclines, thalidomide, toluene abuse, Triethadione, valproic acid. (The defects are discussed in the Appendix).
Principles of Teratogenesis:
- Susceptibility to a teratogenic agent depends on genotype of the embryo and the manner in which the agent interacts with environmental factors.
- Susceptibility to teratogenic agents depends on the time of exposure and stage of embryo development.
- Teratogenic agents act specifically in cells or tissues because of the pathogenesis.
- The final manifestations of abnormal development are death, malformation, growth retardation and functional disorders.
- Access to the embryo by environmental teratogens depends on the nature of the agent.
- As you increase the dose, the event will go to develop the diverted (Blackburn, 2007)
Conclusion
There are no absolute teratogenic, however, many agents may have teratogenic effects in certain circumstances. The dose and duration of exposure to a particular agent often determine the severity of the damage and the defect to occur. The dose and the answer is obvious: the higher the dose, the greater the effect. The exposure time is another important concept, as certain stages of embryonic and fetal development are more vulnerable than others. In general, the embryonic stage (first quarter) is more vulnerable than in the fetal period (second and third quarter). Thalidomide provides a classic example. The period exposure is critical during organogenesis (organ formation) from 35th to 48th day after the last menstruation. Specificity of malformations is related to exposure time: 35-37 days, ears 39-41 days, without arms, 41-43 days, without a uterus, 45-47 days not warm, and days 47-49, with thumbs Triphalangeal. The types or severity of abnormalities caused by a teratogenic agent also depends on the genotype of women pregnant and fetal genotype (genetic predisposition). For example, the variation in the metabolism of the mother of a particular drug will determine which metabolites the fetus is exposed and the duration of exposure. The differences in the membranes of the placenta, the transport of the placenta and affect all fetal biotransformation exposure. Genetic susceptibility of the fetus to a particular teratogenic agent will also have an effect on the outcome. Therefore, it was advised to genetic counseling before conceiving the baby (King, 1986)
References
- Blackburn, ST (2007). Chapter 7, maternal, fetal and neonatal physiology-A clinical perspective. 3rd ed. Saunders
- Bishop JB, Witt KL, Sloane, RA (1997). genetic toxicity of human teratogens. Mutat. Res 396. 9-43.
- Dicke, JM (1989). Teratology: principles and practice. Med Clin. North Am 73 (3). 567-82
- Jones, KL (2004). Smith's recognizable patterns of Human Development, 6th ed. Philadelphia: WB Saunders Company.
- Kalter, H. (1968). Teratology of the central nervous system Chicago: University of Chicago Press.
- King, CR (1986). Genetic counseling for teratogen exposure. Obstertrics and Gynecology. 67 (6). 843-6
- Lewin, B. IX genes
- Thomas, SA, Ronald, JL (2004). The developmental gene mutations teratogenic agents
- Warkany, J. (1971). Congenital Malformations: Notes and Comments. Chicago: Year Book Medical Publishers.
- Defects Birth and Genetics: Birth Defects http://www.marchofdimes.com/pnhec/4439 1206.asp Retrieved on June 12, 2009
Appendix
Maternal Conditions
Teratogen
Adverse effects
Critical Period
Diabetes
Holoprosencephaly, porencephalic cysts, heart defects, sacral agenesis, caudal regression, laterality defects, facial clefts, renal defects
I quarter
Hypo / hyperthyroidism
Mental retardation (MR) growth restriction
Throughout pregnancy
Phenylketonuria (PKU)
MR, microcephaly, craniofacial defects
Hyperthermia
Anencephaly / other neural tube defects (NTD)
2 to 4 weeks
Systemic erythematosus (SLE)
Transient neonatal SLE, intrauterine growth restriction, prematurity, congenital heart block
2 to 4 weeks
counter substance use:
Teratogen
Adverse Effects
Critical Period
Alcohol
Short palpebral fissures, altered facies, prenatal growth deficiency postnatal mild to moderate MR, microcephaly
Throughout pregnancy
Snuff
Low birth weight, miscarriage
Toluene (PKU)
CNS (developmental delay, microcephaly, intrauterine growth retardation)
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, stillbirth
II and III quarter
Carbamazepine
Spina bifida, hypoplastic of the phalanges, IUGR
14-60 days
Cyclophosphamide
CNS defects, skeletal defects (especially the skull and fingers) IUGR, cleft palate, newborn death
14-60 days
Fluconazole
(High dose)
Brachycephaly, abnormal facies, abnormal development of the ordeal, cleft palate, heart defects, skeletal defects (thinning)
I quarter
Indomethacin
Oligohydramnios, anuria, necrotizing enterocolitis, premature closure of ductus arteriosus
II-III quarter
Lithium
Heart Defects (abnormality Ebstein)
14 – 60 days
Methylene blue
Jejunal Atresia
II quarter
Penicillamine
connective tissue disorder
14 – 60 days
Retinoids (isotrtinoin)
Central nervous system, eye, heart, large vessels and limb defects, microtia, micrognathia, Clet lip / palate, thymic deficiency
Tetracycline
Stains in primary teeth
II – III quarter
Thalidomide
cranial abnormalities, shortened limb defects (phocomelia) ocular and cardiac defects, oral / facial abnormalities, kidney 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 eye defects, intrauterine growth retardation, neonatal hemorrhage, nasal hypoplasia, vertebral anomalies, dotted epiphysis
6 to 9 weeks
About the Author
Cowgirl Express Performs at the North Carolina Equine Extravaganza 2008
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