NUMERICAL AND STRUCTURAL CHROMOSOME-ABERRATIONS INDUCED BY ETOPOSIDE (VP16) DURING OOCYTE MATURATION OF MICE - TRANSMISSION TO ONE-CELL ZYGOTES AND DAMAGE TO DICTYATE OOCYTES

The antineoplastic drug etoposide (ET) inhibits topoisomerase II (topo II) activity by forming a ternary complex (DNA-ET-topo II), This comp lex prevents the DNA-strand-rejoining activity of topo II and may resu lt in structural chromosome aberrations, Inhibition of topo II activit y may also predispose cells to aneuploidy because this enzyme is neede d for removing regions of DNA catenation prior to chromosome segregati on, Our objectives were to study the dose response for ET-induced nume rical and structural chromosomal aberrations in mouse one-cell zygotes , to compare these data with those obtained from a contemporary metaph ase II (MII) oocyte study and to evaluate the sensitivity of dictyate oocytes to ET-induced aneuploidy, ICR female mice were superovulated a nd injected i.p, with either 6% dimethylsulphoxide (controls) or 20, 4 0 or 60 mg/kg ET 2 h after human chorionic gonadotrophin (HCG), ICR ma les were paired (1:1) with females immediately after treatment, After 17 h the males were removed, and after 24 h the females with a vaginal plug were given colchicine, One-cell zygotes were harvested for cytog enetic analysis 17 h after colchicine, The percentages of hyperploid z ygotes were 1.1, 5.7, 13.8 and 20.7 and of zygotes with structural abe rrations were 2.5, 16.3, 37.7 and 64.7, for control, 20, 40 and 60 mg/ kg ET respectively, The differences between each succeeding dose for b oth structural and numerical aberrations were statistically significan t (P < 0.01), When the ET dose response aneuploidy data from zygotes w ere compared with similar data from a contemporary study involving met aphase II oocytes, the frequencies of hyperploidy were greater in zygo tes than in oocytes, We conclude that when ET is administered during t he preovulatory phase of meiosis, it is both an aneugen and a clastoge n in mouse one-cell zygotes.