Teratogenesis mechanism

There is evidence that phenytoin is teratogenic in humans, but the mechanism is not clear. However, it is known that phenytoin can produce a folate deficiency, and folate deficiency is associated with teratogenesis. 

Teratogenesis involves interference with the normal development of either the embryo or fetus in utero, giving rise to abnormalities in the neonate. This interference may take many forms, and there is therefore no general mechanism underlying this type of response. Many of the toxic effects described elsewhere in this book may be teratogenic in the appropriate circumstances. 

The mechanism underlying thalidomide teratogenesis has been the subject of considerable research. Thalidomide exists as two isomers, one intriguing finding is that there is a difference in the toxicity of the two isomers of thalidomide, with only the S- enantiomer being teratogenic and not the R+ enantiomer (Fig. 7.74). 

In 1977, the NAS Safe Drinking Water Committee outlined four principles that it said should be useful in dealing with the assessment of hazards that involve chronic irreversible toxicity or the effects of longterm exposure (20). These principles (paraphrased as follows) were intended to apply primarily to cancer risks from substances whose mechanisms involve somatic mutations and may also be applicable to mutagenesis and teratogenesis ... 

Mirkes PE. 1987. Molecular mechanisms of cyclophosphamide teratogenesis (rats, humans). Crisp Data Base National Institutes of Health. 

A syndrome resembling that of the fetal alcohol syndrome has been described in infants who had been exposed to toluene in utero (54). Of all toluene-exposed infants, 39% were born prematurely and 9% died during the perinatal period 54% were small for gestational age and 52% had continued postnatal growth deficiency 33% had prenatal microcephaly, 67% postnatal microcephaly, and 80% developmental delay. In 83% there were craniofacial features similar to the fetal alcohol syndrome, and 89% of these children had other minor anomalies. The authors suggested that toluene and alcohol have a common mechanism of craniofacial teratogenesis, namely deficiency of craniofacial neuroepithelium and mesodermal components owing to increased embryonic cell death. 

The potential ability of fluconazole to modulate pheny-toin teratogenesis has been studied in Swiss mice (59). Pretreatment with a non-embryotoxic dosage of fluconazole (10 mg) potentiated phenytoin teratogenesis combined treatment of fluconazole 50 mg with phenytoin resulted in a significant increase in embryo deaths. The mechanism of this teratological interaction remains to be established. 

Beckmau DA, Breut RL. Mechanisms of teratogenesis. Annu Rev Pharmacol Toxicol 1984 24 483-500. 

Trosko JE, Chang CC, and Upham B (2002) Modulation of gap junctional communication by epigenetic toxicants A shared mechanism in teratogenesis, carcinogenesis, at-herogenesis, immunomodulation, reproductive- and ne-uro-toxicities. In Wilson SH and Suk WA (eds.) Biomarkers of Environmentally Associated Diseases, pp. 445—454. Boca Raton, FL Lewis Publishers. 

Diphenylhydantoin. An anticonvulsant drug causing orofacial (cleft palate) and skeletal malformations, especially on days 11-12 in mice. Teratogenesis shows a steep dose-response. The mechanism may involve metabolism (epoxidation) and covalent binding to protein. 

Teratogens are chemical species that canse birth defects. These usually arise from damage to embryonic or fetal cells. However, mntations in germ cells (egg or sperm cells) may canse birth defects, snch as Down s syndrome. The biochemical mechanisms of teratogenesis are varied. These include enzyme inhibition by xenobiotics deprivation of the fetus of essential substrates, such as vitamins interference with energy supply or alteration of the permeability of the placental membrane. 

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