title: Brain hypoplasia caused by exposure to trichlorfon and dichlorvos during development can be ascribed to DNA alkylation damage and inhibition of DNA alkyltransferase repair.
abstract: Treatment of pregnant guinea pigs with trichlorfon causes cerebellar hypoplasia in offspring. The most sensitive period for treatment is days 42-47 of gestation, which coincides with the rapid brain growth spurt and with the development of cerebellar granule cells. When rat granule cells were exposed in vitro to trichlorfon and dichlorvos for 24 hours they died, whereas trichloroethanol had no effect. When the cells were exposed to trichlorfon and dichlorvos for 3 hours, only dichlorvos was lethal indicating that the metabolite dichlorvos was more potent than trichlorfon itself. Cultured cerebellar granule cells were also found to be quite sensitive to other DNA-alkylating agents such as methylazoxymethanol and methylmethane sulphonate and to O6-benzylguanine; a potent and specific inhibitor of the DNA alkyltransferase involved in the repair of DNA alkylation damage. The organophosphorous compounds were also found to cause inhibition of the alkyltransferase and the lethal effects of the tested compounds on granule cell culture correlated well with the potency of inhibition. In a bacterial test system for monitoring alkylation effects on the DNA, dichlorvos was demonstrated to have a strong DNA alkylation effect. These results suggest that alkylation of DNA and inhibition of its repair can contribute to the brain hypoplasia observed after exposure to trichlorfon and dichlorvos during brain development.
authors.affiliation: Norwegian Defence Research Establishment, Division for Environmental Toxicology, Kjeller.
authors.forename: A
authors.initials: A
authors.lastname: Mehl
authors.forename: V
authors.initials: V
authors.lastname: Rolseth
authors.forename: S
authors.initials: S
authors.lastname: Gordon
authors.forename: M
authors.initials: M
authors.lastname: Bjøraas
authors.forename: E
authors.initials: E
authors.lastname: Seeberg
authors.forename: F
authors.initials: F
authors.lastname: Fonnum
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000477:Alkylating Agents / Q000494:pharmacology; D000478:Alkylation; D000818:Animals; D001419:Bacteria / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D001923:Brain Chemistry / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004006:Dichlorvos / Q000633:toxicity*; D005260:Female; D006168:Guinea Pigs; D007306:Insecticides / Q000633:toxicity*; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D014236:Trichlorfon / Q000633:toxicity*
chemical_list: D000477:Alkylating Agents; D007306:Insecticides; D008746:Methylazoxymethanol Acetate; D004006:Dichlorvos; D004247:DNA; D008741:Methyl Methanesulfonate; D014236:Trichlorfon; D019883:Alkyl and Aryl Transferases; C030667:methylazoxymethanol