The effect of trichlorfon and other organophosphates on prenatal brain development in the guinea pig


The organophosphates trichlorfon, dichlorvos, dimethoate, soman, triortho-cresyl phosphate (TOCP), and the diethoxy-analogue of trichlorfon (O,O-diethyl 2,2,2-trichloro-1-hydroxyethylphosphonate, ethyl-trichlorfon), were administrated to guinea pigs between day 42 and 46 of gestation. When the offsprings were examined at birth, there was a severe reduction in brain weight in the case of trichlorfon and dichlorvos, but not after treatment with the other organophosphates. The reduction in weight was most pronounced for cerebellum, medulla oblongata, thalamus/hypothalamus and quadrigemina. The effect was less marked for cerebral cortex and hippocampus. Since soman, a potent anticholinesterase, and TOCP, an inhibitor of neuropathy target esterase, did not show any effects, this excludes that the brain hypoplasia can be caused by inhibition of these two enzymes. Further, the lack of effect with ethyl-trichlorfon has shed some light on the part of the trichlorfon molecule which could be involved in the formation of the hypoplasia. It is suggested that alkylation of DNA may be involved in the development of the lesion. The possible consequences for a teratogenic effect of trichlorfon and dichlorvos on humans are discussed.

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  1. 1.

    Kronevi, T. 1977. Kan Neguvon®-behandling av dräktige suggor orsaka cerebellär hypoplasi hos gris? (Can Neguvon®-treatment of pregnant sows-cause cerebellar hypoplasia in piglets?) Svensk Veterinärtidning 29:931–932.

    Google Scholar 

  2. 2.

    Knox, B., Askaa, J., Basse, A., Bitsch, V., Eskildsen, M., Mandrup, M., Ottosen, H. E., Øverby, E., Pedersen, K. B., and Rasmussen, F. 1978. Congenital ataxia and tremor with cerebellar hypoplasia in piglets born by sows treated with Neguvon® vet. during pregnancy. Nord. Vet. Med. 30:538–545.

    Google Scholar 

  3. 3.

    Fatzer, R., Häni, H., and Scholl, E. 1981. Kongenital Tremor und zerebelläre Hypoplasie bei Ferkeln nach Behandlung der Mutterschweine mit Neguvon® während der Trächtigkeit. Schweiz Arch. Tierheilkd. 123:29–36.

    Google Scholar 

  4. 4.

    Gamlem, H. N., Lund, A., Moen, J. H., and Berge, G. N. 1983. Kongenital tremor og cerebellum-hypoplasi hos spedgriser som en mulig følge av Neguvon®-behandling av drektige purker. (Congenital tremor and cerebellar hypoplasia in piglets associated with trichlorfon-treatment of pregnant sows). Norsk Veternærtidsskrift 6:385–387.

    Google Scholar 

  5. 5.

    Pope, A. M., Heavner, J. E., Guarnieri, J.-A., and Knobloch, C. P. 1986. Trichlorfoninduced congenital cerebellar hypoplasia in neonatal pigs. J. Am. Vet. Med. Assoc. 189:781–783.

    Google Scholar 

  6. 6.

    Berge, G. N., Fonnum, F., and Brodal, P. 1987. Neurotoxic effects of prenatal trichlorfon administration in pigs. Acta Vet. Scand. 28:321–332.

    Google Scholar 

  7. 7.

    Berge, G. N., Fonnum, F., Søli, N. E., and Søgnen, E. 1987. Neurotoxicological examination of the piglet brain after prenatal and postnatal exposure to trichlorfon. Acta Vet. Scand. 28:313–320.

    Google Scholar 

  8. 8.

    Berge, G. N., Nafstad, I., and Fonnum, F. 1986. Prenatal effects of trichlorfon on the guinea-pig brain. Arch. Toxicol. 59:30–35.

    Google Scholar 

  9. 9.

    Hjelde, T., Mehl, A., Schanke, T. M., and Fonnum, F: Prenatal effects of trichlorfon on the development of different parts of the guinea-pig brain (in preparation).

  10. 10.

    Czeizel, A. E., Elek, C., Gundy, S., Métneki, J., Nemes, E., Reis, A., Sperling, K., Timár, L., Tusnády, G., and Virágh, Z. 1993. Environmental trichlorfon and cluster of congenital abnormalities. The Lancet. 341:539–542.

    Google Scholar 

  11. 11.

    Nordgren, I., Bergström, M., Holmstedt, B., and Sandoz, M. 1978. Transformation and action of metrifonat. Arch. Toxicol. 41:31–41.

    Google Scholar 

  12. 12.

    Barthel, W. F., Giang, P. A., and Hall, S. A. 1954. Dialkyl α-hydrocyphosphonates derived from chloral. J. Am. Chem. Soc. 76:4186–87.

    Google Scholar 

  13. 13.

    De Roos, A. M., and Toet, H. J. 1959. The preparation of some iso-propyl p-nitrophenyl alkylphosphonates. Rec. Trav. Chim. 78:59.

    Google Scholar 

  14. 14.

    Barrett, D. S., and Oehme, F. W. 1984. A review of organophosphoros ester-induced delayed neurotoxicity. Vet. Hum. Toxicol. 27:22–37.

    Google Scholar 

  15. 15.

    Blair, D., Hoadley, E. C., and Hutson, D. H. 1975. The distribution of dichlorvos in the tissues of mammals after it's inhalation or intravenous administration. Toxicol. Appl. Pharmacol. 31:243–253.

    Google Scholar 

  16. 16.

    Sterri, S. H., Lyngaas, S., and Fonnum, F. 1981. Toxicity of soman after repetitive injection of sublethal doses in guinea-pig and mouse. Acta Pharmacol. Toxicol. 49:8–13.

    Google Scholar 

  17. 17.

    Fonnum, F. 1975. A rapid radiochemical method for the determination of choline acetyltransferase. J. Neurochem. 25:407–409.

    Google Scholar 

  18. 18.

    Fonnum, F., Walaas, I., and Iverseh, E. G. 1977. Localization of GABAergic, cholinergic and aminergic structures on the mesolimbic system. J. Neurochem. 29:221–230.

    Google Scholar 

  19. 19.

    Ellman, G. L., Courtney, K. D., Andres, V. Jr., and Featherstone, R. M. 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 7:88–95.

    Google Scholar 

  20. 20.

    Harbison, R. D., Olubadewo, J., Dwivedi, C., and Sastry, B. V. R. 1975. Proposed role of the placental cholinergic system in the regulation of fetal growth and development, p.p 107–120 in P. L. Morselli, S. Garattini, and F. Sereni, eds. In: Basic and Therapeutic Aspects of Perinatal Pharmacology, Raven Press, New York.

    Google Scholar 

  21. 21.

    Coult, D. B., Marsh, D. J., and Read, G. 1966. Dealkylation studies on inhibited acetylcholinesterase. Biochem. J. 98:869–873.

    Google Scholar 

  22. 22.

    Abou-Donia, M. B. 1981. Organophosphorus ester-induced delayed neurotoxicity. Ann. Rev. Pharmacol. Toxicol. 21:511–548.

    Google Scholar 

  23. 23.

    Johnson, M. K. 1981. Delayed neurotoxicity-Do trichlorfon and/or dichlorvos cause delayed neuropathy in man or in test animals? Acta Pharmacol. Toxicol. 49, suppl. V, 87–98.

    Google Scholar 

  24. 24.

    Braun, R., Schöneich, J., Weissflog, L., and Dedek, W. 1982. Activity of organophosphorous insecticides in bacterial tests for mutagenicity and DNA repair-direct alkylation vs. metabolic activation and breakdown. I. Butonate, vinylbutonate, trichlorfon, dichlorvos, demethyl dichlorvos and demethyl vinylbutonate. Chem. Biol. Interactions. 39:339–350.

    Google Scholar 

  25. 25.

    Dedek, W. 1981. Guanine N7-alkylation in mice in vivo by metrifonate-discussion of possible genotoxic risk in mammals. Acta Pharmacol. Toxicol. 49, suppl. V, 7–14.

    Google Scholar 

  26. 26.

    Hofer, W. 1981. Chemistry of metrifonat and dichlorvos. Acta Pharmacol. Toxicol. 49, suppl. V, 7–14.

    Google Scholar 

  27. 27.

    Holmstedt, B., Nordgren, I., Sandoz, M., and Sundwall, A. 1978. Metrifonate. Summary of toxicological and pharmacological information available. Arch. Toxicol. 41:3–29.

    Google Scholar 

  28. 28.

    Bedford, C. T., and Robinson, J. 1972. The alkylating properties of organophosphates. Xenobiotica 2:307–337.

    Google Scholar 

  29. 29.

    Wooder, M. F., and Wright, A. S. 1981. Alkylation of DNA by organophosphorous pesticides. Acta Pharmacol. Toxicol. 49: suppl. V, 51–55.

    Google Scholar 

  30. 30.

    Wild, D. 1975. Mutagenicity studies on organophosphorous insecticides. Mutat. Res. 32:133–150.

    Google Scholar 

  31. 31.

    Krueger, H. R., O'Brien, R. D., and Dauterman, W. C. 1960. Relationship between metabolism and differential toxicity in insects and mice of diazinon, dimethoate, parathion and acethion. J. Econ. Entomol. 53:25–31.

    Google Scholar 

  32. 32.

    Khera, K. S., Whalen, C., Trivett, G., and Angers, G. 1979. Teratogenicity studies on pesticidal formulations of dimethoate, diuran and lindane in rats. Bull. Environ. Contam. Toxicol. 22:522–529.

    Google Scholar 

  33. 33.

    Courtney, K. D., Andrews, J. E., Springer, J., and Dalley, L. 1985. Teratogenic evaluation of the pesticides Baygon, carbofuran, dimethoate and EPN. J. Environ. Sci. Health 20:373–406.

    Google Scholar 

  34. 34.

    Crebelli, R., Conti, G., Conti, L., and Carete, A. 1985. Mutagenicity of trichloroethylene, trichloroethanol and chloral hydrate inAspergillus nidulans. Mutat. Res. 155:105–111.

    Google Scholar 

  35. 35.

    Russo, A., Pacchierotti, F., and Metalli, P. 1984. Nondisjunction induced in mouse spermatogenesis by chloral hydrate, a metabolite of trichloroethylene. Environ. Mutagen. 6:695–703.

    Google Scholar 

  36. 36.

    Lee, G. M., Diguiseppi, J., Gawdi, G. M., and Herman, B. 1987. Chloral hydrate disrupts mitosis by increasing intracellular free calcium. J. Cell Science 88:603–612.

    Google Scholar 

  37. 37.

    Löfroth, G. 1978. The mutagenicity of dichloroacetaldehyde. Z. Natufrosch. 33c:783–785.

    Google Scholar 

  38. 38.

    Dobbing, J., and Sands, J. 1970. Growth and development of the brain and spinal cord of the guinea pig. Brain Res. 17:115–123.

    Google Scholar 

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Correspondence to Anna Mehl.

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Special issue dedicated to Dr. Bernard W. Agranoff.

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Mehl, A., Schanke, T.M., Johnsen, B.A. et al. The effect of trichlorfon and other organophosphates on prenatal brain development in the guinea pig. Neurochem Res 19, 569–574 (1994).

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Key Words

  • Brain development
  • dichlorvos
  • dimethoate
  • guinea pig
  • organophosphates
  • soman
  • teratogen
  • trichlorfon
  • tri-o-cresyl phosphate
  • Acetylcholinesterase