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 complex prevents the DNA-strand-rejoining activity of topo II and may result in structural chromosome aberrations. Inhibition of topo II activity may also predispose cells to aneuploidy because this enzyme is needed for removing regions of DNA catenation prior to chromosome segregation. Our objectives were to study the dose response for ET-induced numerical and structural chromosomal aberrations in mouse one-cell zygotes, to compare these data with those obtained from a contemporary metaphase II (MII) oocyte study and to evaluate the sensitivity of dictyate oocytes to ET-induced aneuploidy. ICR female mice were superovulated and injected i.p. with either 6% dimethylsulphoxide (controls) or 20, 40 or 60 mg/kg ET 2 h after human chorionic gonadotrophin (HCG). ICR males 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 cytogenetic analysis 17 h after colchicine. The percentages of hyperploid zygotes were 1.1, 5.7, 13.8 and 20.7 and of zygotes with structural aberrations 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 both structural and numerical aberrations were statistically significant (P < 0.01). When the ET dose response aneuploidy data from zygotes were compared with similar data from a contemporary study involving metaphase II oocytes, the frequencies of hyperploidy were greater in zygotes than in oocytes. We conclude that when ET is administered during the preovulatory phase of meiosis, it is both an aneugen and a clastogen in mouse one-cell zygotes.
Mailhes
J B
JB
Department of Obstetrics and Gynecology, Louisiana State University Medical Center, PO Box 33932, Shreveport, LA 71130, USA.
Marchetti
F
F
Young
D
D
London
S N
SN
D000782:Aneuploidy; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002869:Chromosome Aberrations; D005047:Etoposide / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009153:Mutagens / Q000633:toxicity*; D009865:Oocytes / Q000187:drug effects* / Q000254:growth & development; D015053:Zygote / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D009153:Mutagens; D005047:Etoposide