Preferential pericentric lesions and aneuploidy induced in mouse oocytes by the topoisomerase II inhibitor etoposide

Abstract

Etoposide (VP-16) is used as an antineoplastic drug in humans. It inhibits topoisomerase II(topoII) activity by forming a ternary complex (DNA-etoposide-topoII). This complex prevents the DNA-strand rejoining activity of topo II, which results in DNA-strand breaks and the formation of structural chromosome aberrations. Topo II activity is also required for removing regions of DNA catenation prior to chromosome segregation. The possibility exists that patients undergoing etoposide chemotherapy may incur genetic damage and, consequently, may be at a greater risk for developing secondary tumors and having genetically abnormal offspring. We studied the ability of etoposide for inducing both structural chromosome aberrations and aneuploidy in mouse oocytes. Different dosages of etoposide were given to female mice at various times before and after human chronic gonadotrophin injection, and ovulated oocytes were collected 17 h later. The proportions of chromatid acentric fragments and of hyperploid metaphase II oocytes were significantly higher (P < 0.01) in the etoposide groups than in concurrent controls. These results indicate that both structural and numerical aberrations can be induced without direct interaction with DNA or with the various organelles associated with chromosome segregation. Additionally, unlike other compounds (vinblastine, colchicine, benomyl, and griseofulvin) that induce both meiotic delay (ovulated metaphase I oocytes and polyploidy) and aneuploidy, etoposide did not cause meiotic delay in oocyte maturation.

Etoposide induces heritable chromosomal aberrations and aneuploidy during male meiosis in the mouse

“…The frequency of hyperhaploidy found in MII spermatocytes after treatment of pachytene spermatocytes is the highest ever reported for an aneugen in male germ cells (41,42). Also, unlike model aneugens, such as colchicine and vinblastine, for which male germ cells seem to be less sensitive than female germ cells (47), the frequency of hyperhaploidy found in MII spermatocytes in this study was similar to that found in MII oocytes (20).…”

“…It has been reported that exposure of germ cells to ET results in a preferential localization of the aberrations near the centromere (20,23,24). We have observed a similar phenomenon in both MI and MII spermatocytes.…”

“…It is also a germ-cell mutagen with unique properties in both maternal and paternal gametes of mice. ET induced both aneuploidy and chromosomal structural aberrations in female germ cells (20,21) and, unlike any other chemical shown to induce aneuploidy in female germ cells (22), ET did so without causing a delay in meiotic progression (20). In male germ cells, ET induced fragmentation of centromeric DNA and micronuclei after exposure of primary spermatocytes (23,24).…”

Abnormal chromosome migration and chromosome aberrations in mouse oocytes during meiosis II in the presence of topoisomerase II inhibitor ICRF-193

“…Therefore, topoisomerase II interactive agents have potential clastogenic and aneugenic actions on meiotic cells. Etoposide, a specific topoisomerase II inhibitor, caused both structural chromosome aberrations and aneuploidy in primary oocytes of the mouse [3,4] and the Chinese hamster [5]. Similar chromosomal effects of the inhibitor were found in mouse primary spermatocytes [6,7].…”

The DNA Damage Response in Mammalian Oocytes.

“…Past studies hinted at the possibility of a limited DDR in fully grown oocytes (Mailhes et al, 1994;Bradshaw et al, 1995). More specifically, it has been shown that a significant delay in the duration of MI is not observed following injection into female mice of etoposide, a topoisomerase II inhibitor and DSB inducer (Mailhes et al, 1994;Bradshaw et al, 1995).…”