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

Etoposide, a topoisomerase II inhibitor widely used in cancer therapy, is s uspected of inducing secondary tumors and affecting the genetic constitutio n of germ cells. A better understanding of the potential heritable risk of etoposide is needed to provide sound genetic counseling to cancer patients treated with this drug in their reproductive years. We used a mouse model t o investigate the effects of clinical doses of etoposide on the induction o f chromosomal abnormalities in spermatocytes and their transmission to zygo tes by using a combination of chromosome painting and 4 ' ,6-diamidino-2-ph enylindole staining. High frequencies of chromosomal aberrations were detec ted in spermatocytes within 64 h after treatment when over 30% of the metap hases analyzed had structural aberrations (P < 0.01), Significant increases in the percentages of zygotic metaphases with structural aberrations were found only for matings that sampled treated pachytene (28-fold, P < 0.0001) and preleptotene spermatocytes (13-fold, P < 0.001). Etoposide induced mos tly acentric fragments and deletions, types of aberrations expected to resu lt in embryonic lethality, because they represent loss of genetic material. Chromosomal exchanges were rare. Etoposide treatment of pachytene cells in duced aneuploidy in both spermatocytes (18-fold, P < 0.01) and zygotes (8-f old, P < 0.05). We know of no other report of an agent for which paternal e xposure leads to an increased incidence of aneuploidy in the offspring. Thu s, we found that therapeutic doses of etoposide affect primarily meiotic ge rm cells, producing unstable structural aberrations and aneuploidy, effects that are transmitted to the progeny. This finding suggests that individual s who undergo chemotherapy with etoposide may be at a higher risk for abnor mal reproductive outcomes especially within the 2 months after chemotherapy .