Etoposide-induced cytogenotoxicity in mouse spermatogonia and its potential transmission

As cancer chemotherapeutic agents are cytogenotoxic but not target-specific during systemic treatment, they affect all the encountered cells including the non-cancerous ones and consequently lead to the recurrence of second malignancy in post-chemotherapeutic cancer survivors. The effects would be persistent if the stem cells were affected. These drugs also may affect germline cells during therapeutic treatments. There is every chance that the effects are transmitted through the germline cells to the gametes and to the next generation if the gonadal mother cells are affected. Such transmission of effects from the post-chemotherapeutic childhood cancer survivors is of serious concern but very little attention has been given so far to such studies. Etoposide (VP-16)--a semi-synthetic epipodophyllotoxin derivative, a DNA non-intercalating agent and a topoisomerase II inhibitor--is prescribed frequently for the treatment of various types of cancers. It is a potent clastogen inducing chromosomal damage both in vitro and in vivo. Its clastogenic effect is indirect through inhibition of the catalytic activity of topoisomerase II enzymes, which maintain the topology of DNA during replication, recombination, transcription, etc. by forming a 'cleavable complex' and facilitate the cleaving and re-ligation of the cleaved DNA to relieve the torsional stress during such events. Transient stabilization of the cleavable complex by etoposide leads to illegitimate ligation of the cleaved DNA. Consequently, single- and double-strand breaks occur. In the present study, the clastogenic potential of three different doses of etoposide (10, 15 and 20 mg kg(-1)) in the male germline of mice was assessed from the dividing spermatogonia after a single exposure for one cell cycle duration at 24 h post-treatment. Transmission of such effects was assessed from the frequency of aberrant primary spermatocytes at week 4 post-treatment and of abnormal sperm at week 8 post-treatment. All three doses of etoposide were found to be clastogenic to the dividing spermatogonia of mice, and mostly chromatid breaks were induced. The effects also were transmitted through the male germline of mice, which was evident from the prevalence of statistically significant increased percentages of aberrant primary spermatocytes at week 4 posttreatment and the higher percentages of abnormal sperm at week 8 post-treatment. Thus, there is every chance that the cytogenotoxic effects of etoposide are transmitted to the next generation through the male germline of post-chemotherapeutic cancer survivors, therefore it is essential to make etoposide target-specific or modulate its effects.