Mutation spectra of 1,2-dibromoethane, 1,2-dichloroethane and 1-bromo-2-chloroethane in excision repair proficient and repair deficient strains of Drosophila melanogaster

Abstract

DNA sequence changes produced by 1,2-dibromoethane (DBE), 1,2-dichloroethane (DCE) and 1-bromo-2-chloroethane (BCE) were analyzed using the vermilion locus of Drosophila melanogaster. Under excision repair proficient (exr+) conditions (mutagenized exr+ males mated with exr+ females) all mutants isolated from the first generation (F1) after DBE and DCE exposure represented DNA rearrangements (multi-locus deletions, small deletions with tandem repeats, duplicate insertions). By contrast, mutants expressing a vermilion phenotype only in the F2 (F1 mosaics) all carried single bp changes. When exr+ males, after exposure to DBE, were mated to excision repair deficient (exr-) mus 201 females 11 of 14 mutational events isolated from either F1 or F2 progeny were single bp changes. In general the mutation spectra for the three dihaloalkanes were similar to the spectrum obtained at the same locus for the direct-acting monofunctional agent methylmethanesulfonate (MMS). The data lend support to the conclusions that these 1,2-dihaloalkanes are genotoxic through modification at ring nitrogens in DNA, primarily at the N7 of guanine and, to a lesser extent, at the N1 of adenine. These N-adducts could be directly miscoding. However, more important for the mutagenic action of the chemicals seems to be the formation of non-coding lesions and/or misrepair.

S-(2-Chloroethyl)glutathione-generated p53 Mutation Spectra Are Influenced by Differential Repair Rates More than Sites of Initial DNA Damage

“…as shown in the upper part of this figure. A repair time course was established for each position, and the time at which 50% of the initial damage was removed was then determined from a semilogarithmic plot (log 10 [adduct] versus t). C, mutations (from Table III).…”

“…Adduct t1 ⁄2 (the time at which 50% of the initial damage was removed was then determined from a semi-logarithmic plot, i.e. log 10 [adduct] versus t) was determined for every damaged G in both strands in exons 5-8.…”

Conjugation of Haloalkanes by Bacterial and Mammalian Glutathione Transferases: Mono- and Vicinal Dihaloethanes

“…In previous work, we have studied the DNA adducts derived from the episulfonium ion pathway (16,20,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). S-[2-(N 7 -Guanyl)ethyl]GSH is the major adduct (20,26,27) but the N 2 -and O 6 -guanyl adducts (35)(36)(37) may also contribute to explain the predominance of GC:AT transitions in several organisms (35,(38)(39)(40). An unexpected and yet unexplained observation is the increased bacterial mutagenicity seen with expression of O 6 -alkyguanine transferase (41)(42)(43), which does not appear to be related to the GSH conjugates.…”

Synthesis of Oligonucleotides Containing the Ethylene Dibromide-Derived DNA Adducts S-[2-(N7-Guanyl)ethyl]glutathione, S-[2-(N2-Guanyl)ethyl]glutathione, and S-[2-(O6-Guanyl)ethyl]glutathione at a Single Site

“…A forward mutation assay using bacteriophage M13mp18 with the reactive GSH conjugate S- (2-chloroethyl)GSH revealed that base-pair substitution muta-tions occurred in the lacZ region and GC to AT transitions dominated (7). The same mutational changes were dominant in widely different biological systems such as Drosophila melanogaster, Chinese hamster ovary cells, and Escherichia coli after treatment with EDB (8)(9)(10).…”