Teratogenesis

James Wilson (in 1959) proposed six principles of teratology. A simplified version of these is as follows  

Susceptibility to teratogenesis depends on the embryo s genotype that interacts with adverse environmental factors (G x E interaction). 

The developmental stage of exposure to the conceptus determines the outcome. 

Teratogenic agents have specific mechanisms through which they exert there pathogenic effects. 

The nature of the teratogenic compound or factor determines its access to the developing conceptus/tissue. 

Underlying causes of birth defects are shown in Table 22.3. It should be appreciated that approximately 90% of birth defects have a genetic component. Birth defects caused by drugs represent the one group of anomalies that can potentially be prevented. However/ it is a small list of drugs that have been proved to cause human anomalies (Table 22.4). Potential effects of drugs on the developing fetus 

Carbamazepine Facial dysmorpho genes is, neural tube defect 

Phenytoin Facial dysmorphogenesis, mental retardation, growth retardation, distal digital hypoplasia 

Valproate Lumbosacral spina bifida, facial dysmorphogenesis 

Trinaetliadione Facial dysmorphogenesis, intrauterine growth retardation, intrauterine fetal demise, neonatal demise 

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M. R. Juchau, ed.. The Biochemical Basis of Chemical Teratogenesis, Elsevier/North Holland, New York, 1981. 

F. Reproductive toxins Chemicals which affect the reproductive capabilities including chromosomal damage (mutations) and effects on fetuses (teratogenesis) ... 

In addition to direct effects of chemical compounds on the fetus, metabolic disturbances in the mother, such as diabetes or hyperthermia, or deficiencies of calories or specific nutrients such as vitamin A, zinc, and folic acid may lead to teratogenesis. Compounds that inhibit placental functions may also induce malformations, e.g., by inhibiting placental circulation. For example, hydroxyurea disrupts the placental circulation and induces malformations. In addition, it also induces DNA damage. 

Farr CH, Reinisch K, Helsen JF, Neubert D (2001) Petential teratogenicity of di-n-butyltin dichloride and ether dibutyltin compounds. Teratogenesis, Carcinogenesis, and Mutagenesis, 21(6) 405-415. 

Noda T, Nakamura T, Shimizu M, Yamano T, Merita S (1992b) Critical gestational day of teratogenesis by di-normal-butyltin diacetate in rats. Bulletin of Environmental Contamination and Toxicology. 49(5) 715-722. 

Developmental effects of trichloroethylene exposure have been demonstrated with the FETAX (Frog Embryo Teratogenesis Assay Xenopus) bioassay, an in vitro method using whole frog embryos (Fort et al. 1991, 1993 Rayburn et al. 1991). Observed defects included gut miscoding, skeletal kinking, and heart malformations heart malformations have also been observed in rat developmental assays (Dawson et al. 1993). 

Dawson BV, Johnson PD, Goldberg SJ, et al. 1990. Cardiac teratogenesis of trichloroethylene and dichloroethylene in a mammalian model. J Am Coll Cardiol 16 1304-1309. 

Fort DJ, Stover EL, Rayburn JR, et al. 1993. Evaluation of the developmental toxicity of trichloroethylene and detoxification metabolites usingXenopus. Teratogenesis Carcinog Mutagen 13 35-45. 

Arnhold, T, Ehnazar, M.M.A., and Nau, H., Prevention of vitamin A teratogenesis by phytol or phytanic acid results from reduced metabolism of retinol to the teratogenic metabolite, all frara-retinoic acid, Toxicol. Sci., 66, 274, 2002. 

Ocular teratogenesis Optic organs CD-I mouse No Increased Nemeth et al. 

Anthelmintic agents have been utilized to treat a multimde of nematode infections. These include roundworms, tapeworms, and lungworms in cattle and swine. Two classes of compounds included as anthelmintic agents will be discussed here, lev-amisole and thiabendazoles (thiabendazoles can also act as pesticides). Thiabendazoles can cause nephrotoxicity, teratogenesis, and immunosuppression and can disrupt endocrine balance. Because of these toxicides, residues of these compounds in food animals are of food safety concern. 

Intake can be expressed either as a pollutant mass per unit time, as discussed above, or as a mass per kg of body weight per unit time. The latter expression facilitates comparison to health effects data, especially laboratory animal data, which are commonly reported in equivalent units. Similarly, depending on the route of exposure, intake may be estimated on an annual basis to address chronic effects, or on a smaller time scale for addressing acute effects including lethality, teratogenesis, reproductive and neurotoxic effects. 

Frog embryo teratogenesis assay - Xenopus Not sufficiently... 

Schrader T J, Cherry W, Soper K, Langlois I and Vijay H M (2001), Examination of Altemaria altemata mutagenicity and effects of nitrosylation using the Ames Salmonella Test , Teratogenesis, Carcinogenesis, and Mutagenesis, 21, 261-274. 

Lijinsky W, Andrews AW. 1980. Mutagenicity of vinyl compounds in Salmonella typhimurium. Teratogenesis Carcinog Mutagen 1 259-267. 

Fort, D.J., B.L. James, and J.A. Bantle. 1989. Evaluation of the developmental toxicity of five compounds with the frog embryo teratogenesis assay Xenopus (FETAX) and a metabolic activation system. Jour. Appl. Toxicol. 9 377-388. 

No teratogenesis observed in 7 generations at dietary level of 17.5 mg/kg positive effect on litter size and survival... 

Hanlon, D.P. and V.H. Ferm. 1986a. Teratogen concentration changes as the basis of the heat stress enhancement of arsenate teratogenesis in hamsters. Teratology 34 189-193. 

Bruggeman, D.J., J.A. Bantle, and C. Goad. 1998. Linking teratogenesis, growth, and DNA photodamage to artificial ultraviolet B radiation in Xenopus laevis larvae. Environ. Toxicol. Chem. 17 2114-2121. 

Bronzetti G, Morichetti E, Del Carratore R, et al. 1989. Tetrachloroethane, pentachloroethane, and hexachloroethane genetic and biochemical studies. Teratogenesis Carcinog Mutagen 9 349-357. 

Ellison, A.C. and Maren, T.H. (1972). The effect of potassium metabolism on acetazolamide-induced teratogenesis. Johns Hopkins Med. J. 130 105-115. 

Watkinson, W.P. and Millicovsky, G. (1983). Effect of phenytoin on maternal heart rate in A/J mice Possible role in teratogenesis. Teratology 28 1-8. 

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