No abstract

Chemotherapeutic doses of cisplatin impair spermatogenesis and ultimately cause azoospermia and infertility in some men. The mechanism by which cisplatin damages testicular germ cells is poorly understood. Cisplatin's impact is first detected hours after exposure in the formation of DNA cross-links followed by weeks of testicular damage. Here, we report in 11-week-old male mice an early and massive rise of germ cell apoptosis after a single intraperitoneal (i.p.) injection of either 5 or 10 mg/kg cisplatin. For the lower dose, a roughly 9-fold peak increase in the apoptotic index over the control level is observed at 36 h, and for the higher dose, a 24-fold rise is seen at 24 h. At these peak levels, the lower dose produced a higher ratio of apoptotic early spermatocytes to apoptotic spermatogonia than did the higher dose. In addition to this early wave of germ cell die-off, our data show that while the post-wave apoptotic rates for both dose regimes diminish, at 12 days the apoptotic rates appear significantly higher (5 mg/kg) than controls. In summary, our findings show two events set in motion by acute cisplatin exposure: (1) a previously unreported massive apoptotic die-off of germ cells followed by (2) an elevated apoptotic rate possibly reflecting long-term or permanent damage to the seminiferous tubule.

: Exposure to cisplatin results in impaired spermatogenesis, azoospermia, and, sometimes, permanent infertility in male patients. The mechanism(s) by which cisplatin induces damage to testicular cells is poorly understood. We previously reported that acute exposure to cisplatin results in elevated germ cell apoptotic rates and that this indicates long‐term damage to the seminiferous epithelium. Here, we present data that implicate an injury to Sertoli cells as a possible mechanism to explain an elevated rate of germ cell apoptosis and consequent infertility. Normal adult C57/Bl/6J mice were exposed to 1, 2, or 4 rounds of 1, 2.5, or 5 mg/kg cisplatin in a regimen designed to resemble clinical chemotherapeutic exposure (1 injection daily for 5 days with a recovery phase of 16 days between cycles). A dose‐dependent reduction in testicular weight due to germ cell loss was observed. While exposure to 1 mg/kg caused only temporary germ cell depletion, higher doses (2.5 and 5 mg/kg) revealed widespread testicular atrophy as evidenced by gaps in the epithelium due to cytoplasmic vacuolization and loss of differentiating germ cells. Although the acute loss of germ cells by apoptosis can result in temporary infertility, the testis has the ability to repopulate itself with mature cells, provided the stem germ cell population remains unharmed. Here, we demonstrate that a sustained disruption of spermatogenesis occurs despite the continued presence of stem spermatogonia in the seminiferous epithelium. These results suggest that cisplatin‐induced germ cell loss may occur, in part, as a result of Sertoli cell injury‐dependent alterations in germ cell microenvironment.