Unlike other chemicals, etoposide (a topoisomerase-II inhibitor) produces peak mutagenicity in primary spermatocytes of the mouse.
The cancer chemotherapy agent, and topoisomerase-II inhibitor, etoposide (VP-16) produced both recessive mutations at specific loci and dominants at other loci with peak frequencies in primary spermatocytes, a cell type in which the topo-II gene has been shown to be activated. Etoposide thus differs from all other chemicals whose germ-cell-stage specificity has been analyzed. No effects of etoposide exposure of spermatogonial stem cells ( approximately 15, 000 offspring scored) were detectable by either mutagenicity or productivity endpoints. The significant mutagenic response that followed exposure of poststem-cell stages ( approximately 25,000 offspring scored) showed a clear peak, with three of four specific-locus mutants, and three of four dominant mutants conceived during weeks 4 or 5 (days 22-35) post-injection, a period that also encompassed the dominant-lethal peak. For this period, the induced specific-locus rate (with 95% confidence limits) at a weighted-average exposure of 75.1 mg etop/kg was 59.5 (14.6, 170. 9)x10-6/locus. At least 3 of the 4 specific-locus mutations were deletions, paralleling findings with etoposide or analogs in other test systems where a recombinational origin of the deletions has been suggested. Because, unlike other chemicals that induce deletions in male germ cells, etoposide is effective in stages normally associated with recombinational events, it will be of interest to determine whether this chemical can affect meiotic recombination.
Russell
L B
LB
Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831-8077, USA. russellb@bioax1.bio.ornl.gov
Hunsicker
P R
PR
Johnson
D K
DK
Shelby
M D
MD
D000818:Animals; D003433:Crosses, Genetic; D005047:Etoposide / Q000633:toxicity*; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D016296:Mutagenesis / Q000187:drug effects; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation / Q000187:drug effects; D010088:Oxidoreductases; D011506:Proteins / Q000235:genetics; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics; D013090:Spermatocytes / Q000187:drug effects*; D013093:Spermatogonia / Q000187:drug effects; D015996:Survival Rate; D059005:Topoisomerase II Inhibitors
D008562:Membrane Glycoproteins; D009153:Mutagens; D011506:Proteins; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse; C064056:tyrosinase-related protein-1