title: Mutagenic activity of ethylene oxide and propylene oxide under XPG proficient and deficient conditions in relation to N-7-(2-hydroxyalkyl)guanine levels in Drosophila.
abstract: Ethylene oxide (EO) and propylene oxide (PO) are direct acting mutagens with high Swain-Scott s-values, which indicate that they react preferentially with ring nitrogens in the DNA. We have previously described that in the X-linked recessive lethal (RL) assay in Drosophila postmeiotic male germ cells EO is, per unit exposure dose, 5-10 times more mutagenic than PO. Furthermore, at the higher dose range of EO tested, 62.5-1000 ppm, up to 20-fold enhanced mutation rates were measured in the absence of maternal nucleotide excision repair (NER) compared to repair proficient conditions. The lower dose range of EO tested, 2-7.8 ppm, still produced a small increased mutation rate but without a significant elevated effect when the NER system is being suppressed. The lowest dose of PO tested, 15.6 ppm, produced only in NER- condition an increased mutation rate. The aim of the present study was to compare the mutagenic effect of EO and PO in the RL assay under XPG proficient and deficient conditions with the formation of N-7-(2-hydroxyethyl)guanine (7-HEG) and N-7-(2-hydroxypropyl)guanine (7-HPG), respectively, the major DNA adducts formed. The formation of 7-HEG and 7-HPG was investigated in Drosophila males exposed to EO and PO as a measure of internal dose for exposures ranging from 2 to 1000 or 2000 ppm, respectively, for 24h. Analysis of 7-HEG and 7-HPG, using a highly sensitive 32P-postlabelling assay, showed a linear increase of adduct levels over the entire dose range. The non-linear dose-response relationship for mutations could therefore not be explained by a reduced inhalation or increased detoxification at higher exposure levels. In analogy with the four times higher reactivity of EO the level of N-7-guanine alkylation per ppm was for EO 3.5-fold higher than that for PO. Per unit N-7-guanine alkylation EO was found to be slightly more mutagenic than PO, whereas PO was the more potent clastogenic agent. While this research has not identified the DNA lesions that cause the increase in repair deficient flies, it supports the hypothesis that efficient error-free repair of some N-alkylation products can explain why these agents tend to be weakly genotoxic or even inactive in repair-competent (premeiotic) germ cells of the mouse and the Drosophila fly.
authors.affiliation: Sylvius Laboratories, Department of Toxicogenetics, Medical Genetics Centre South-West Netherlands, Leiden University Medical Centre, Wassenaarseweg 72, 2300 RA Leiden, The Netherlands. m.j.m.nivard@lumc.nl
authors.forename: Madeleine J M
authors.initials: MJ
authors.lastname: Nivard
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.forename: Dan
authors.initials: D
authors.lastname: Segerbäck
authors.forename: Ekkehart W
authors.initials: EW
authors.lastname: Vogel
mesh_terms: D000818:Animals; D001711:Biotransformation; D004260:DNA Repair / Q000235:genetics; D004330:Drosophila / Q000187:drug effects / Q000235:genetics*; D004852:Epoxy Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D005027:Ethylene Oxide / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D005804:Genes, Lethal; D005808:Genes, Recessive; D006147:Guanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008297:Male; D009153:Mutagens / Q000494:pharmacology*; D013094:Spermatozoa / Q000166:cytology / Q000187:drug effects; D014960:X Chromosome
chemical_list: D004852:Epoxy Compounds; D009153:Mutagens; D006147:Guanine; D005027:Ethylene Oxide; C009068:propylene oxide