Analysis of hexamethylphosphoramide (HMPA)-induced genetic alterations in relation to DNA damage and DNA repair in Drosophila melanogaster.
This paper reports the results of a study on the mutagenic profile of HMPA in Drosophila melanogaster. HMPA produced all types of genetic damage tested for in post-meiotic cells of treated males; at the concentrations used, recessive lethals and ring-X losses were induced at significant rates while 2-3 translocations, entire and partial Y-chromosome losses only occurred at low rates. From a comparison with alkylation-induced mutational spectra, we note a number of peculiarities of HMPA mutagenesis: there is no storage effect on HMPA-induced translocations; the ratio of F2-lethals: F3-lethals varies from 6:1 to 9:1, indicating a low capacity of HMPA for delayed mutations; the use of the DNA-repair-deficient mei-9L1 females instead of an excision-proficient control strain has no influence on the recovery of mutations (recessive lethals) induced in males; the high frequencies of chromosome loss (CL) induced by HMPA, which are mostly due to ring-X loss, leads us to speculate that one (or more) of its metabolites acts as a DNA-crosslinking agent. In experiments on maternal effects with mei-9LI females, there is a 20-40% reduction in the rates of induced CL. Conversely, with mei-41D5 females, there is a weak increase in CL frequencies. HPLC analysis of DNA reacted with [14C]HMPA exhibits no methylation at the O6 or the N-7 of guanine. This finding, together with the observed inactivity of hexaethylphosphoramide (HEPA) in the recessive lethal assay, suggests that the formation of DNA-bound forms from HMPA may not be the result of simple methylation reactions. This conclusion is supported by the genetic data, i.e., the lack of a storage effect on HMPA-induced chromosome rearrangements. Consistent with a hypothesis by Brodberg et al. (1983) to explain the action of cisplatin in Drosophila, comparisons of the spectra of genetic alterations produced by HMPA, A 139 (bifunctional) and Thio-TEPA (trifunctional) in the assay for chromosome loss suggest the involvement of two distinct mechanisms in the formation of ring-X loss by crosslinking agents. One pathway concerns induction of chromosome loss as a consequence of sister-chromatid exchanges (SCEs). The second mechanism may be due to DNA adducts or a single adduct responsible for both a fraction of CL and for induced partial Y-loss (PL). Inactivation of the mei-9+ function has two consequences: SCE-mediated ring-X loss frequency is lowered in mei-9 females in comparison to the repair-proficient control strain, while the opposite effect is indicated for that fraction of ring-X loss generated by the second mutational pathway.(ABSTRACT TRUNCATED AT 400 WORDS)
D000477:Alkylating Agents / Q000633:toxicity*; D000782:Aneuploidy; D000818:Animals; D001711:Biotransformation; D004260:DNA Repair; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005804:Genes, Lethal; D005808:Genes, Recessive; D006492:Hempa / Q000633:toxicity*; D008297:Male; D008745:Methylation; D009943:Organophosphorus Compounds / Q000633:toxicity*; D013094:Spermatozoa / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors; D014178:Translocation, Genetic / Q000187:drug effects; D014960:X Chromosome
D000477:Alkylating Agents; D009943:Organophosphorus Compounds; D006492:Hempa