Effects of Chemotherapeutic Agents for Testicular Cancer on the Male Rat Reproductive System, Spermatozoa, and Fertility

Abstract

Testicular cancer is the most common cancer affecting men of reproductive age. Advances in treatment of the disease, which include the coadministration of bleomycin, etoposide, and cisplatinum (BEP), have brought the cure rate to over 90%. This high cure rate, coupled with the young age of patients, makes elucidation of the impact of the treatment on reproductive function, fertility, and progeny outcome increasingly important. The goal of this study was to determine the effects of BEP, in doses analogous to those given to humans, on the male reproductive system, spermatozoa, fertility, and progeny outcome in an animal model. Male Sprague-Dawley rats were treated daily with BEP for 3 cycles of 3 weeks each, for a total of 9 weeks. After 6 and 9 weeks, males were mated to 2 groups of untreated females. BEP treatment resulted in decreases in testicular and epididymal weights of 52% and 28%, respectively, when compared to control. Decreased testis and epididymis weights were accompanied by impairment of spermatogenesis and by a decrease in spermatozoal count of nearly 90% (11.9 ϫ 10 7 spermatozoa per caput epididymidis in control vs 1.65 ϫ 10 7 in BEP-treated rats). The percent of motile spermatozoa in the treated rats was more than 30% lower than in controls. Defects in the flagella of spermatozoa increased by more than twofold in the midpiece, and by more than sixfold in the principal piece. Paternal BEP treatment, for either 6 or 9 weeks, did not affect fertility, pre-or postimplantation loss, litter size, or sex ratio among progeny on gestation day 21. In contrast, among the pregnancies allowed to proceed to delivery, a significant number of pups sired by males treated with BEP for 9 weeks died between birth and postnatal day 2; this was not observed in pups sired by males treated for 6 weeks. Markers of postnatal development were not affected in the surviving offspring from either group. Thus, despite the dramatic effects of the testicular cancer drug regimen on spermatogenesis, the numbers of spermatozoa, and their motility and morphology, male rats were fertile. While fetal development was apparently normal, early postnatal mortality, which may be associated with a delay in parturition, was elevated among the progeny sired by males exposed to BEP for 9 weeks.

Impact of chemotherapeutics and advanced testicular cancer or Hodgkin lymphoma on sperm deoxyribonucleic acid integrity

“…These findings are in accordance with those of previous studies (6,7). The adverse effects of chemotherapeutics on testicular function have been demonstrated previously in animal models (8,9,28,29). The exposure of male rats to BEP caused the degeneration of germ cells, the formation of multinucleated giant cells, the shedding of immature germ cells within the lumen, Sertoli cell vacuolization, and increased apoptosis, especially of spermatogonia and spermatocytes (29).…”

“…Improved chemotherapeutic regimens for testicular cancer and HL have augmented survival (4,5). Unfortunately, these treatments are associated with a negative impact on reproductive health in men (6,7) and detrimental effects on testicular function, including a decrease in fertilization rate and pregnancy losses in animals (8)(9)(10)(11). Chemotherapy produces azoospermia or severe oligozoospermia in some patients with cancer (6,7) and may have a negative impact on sperm DNA integrity.…”

Editorial Commentary

“…Experimental use of the co-administration of bleomycin, etoposide, and cisplatinum (BEP) treatment in doses related to the ones used in testicular cancer patients induces DNA strand breaks and increments the susceptibility of sperm to DNA denaturation as studied by the acridine orange assay. It is noted that while these alterations do not compromise fertility in experimental animals, they might be responsible for early death of newborn pups sired by treated male rats, as demonstrated in a previous study (Bieber et al, 2006). These results coincide with similar reports of sperm aneuploidies, spontaneous abortions, and stillbirths in testicular cancer patients treated with CT (De Mas et al, 2001).…”

Involvement of TACE/ADAM17 and ADAM10 in etoposide‐induced apoptosis of germ cells in rat spermatogenesis

“…In the same way, modern life style and use of underwear has been proposed to produce an elevated scrotal temperature that may cause germ cell apoptosis, akin to transient (438C for 15 min) heat stress in testis (Hikim et al, 2003;Jung and Schuppe, 2007). Germ cells undergoing meiosis (named spermatocytes) are highly sensitive to DNA damage and other insults such as heat shock, ionizing radiation, growth factor deprivation, and impact of chemotherapeutic agents (Russell et al, 2004;Meachem et al, 2005;Bieber et al, 2006;Lizama et al, 2009). In this way, we have recently shown that etoposide, a topoisomerase-II inhibitor, which induces DNA damage, induces a massive apoptosis of spermatocytes in 21-day-old rats, 24 h after treatment (Ortiz et al, 2009).…”