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Published on: May 15, 2021
Cisplatin-induced pulse of germ cell apoptosis precedes long-term elevated apoptotic rates in C57/BL/6 mouse testis
F Seaman1, P Sawhney, C J Giammona
1Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712-1074, USA.
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.
Insights
Cisplatin chemotherapy causes significant germ cell death in mice, leading to infertility. This study reveals a massive early apoptotic wave and a subsequent rise in apoptosis, indicating potential long-term testicular damage.
Area of Science:
- Reproductive Biology
- Toxicology
- Cancer Research
Background:
- Cisplatin is a chemotherapy drug known to impair male fertility.
- The precise mechanisms of cisplatin-induced testicular germ cell damage remain unclear.
- Cisplatin's effects include DNA cross-linking followed by delayed testicular damage.
Purpose of the Study:
- To investigate the early cellular events following cisplatin exposure in male mice.
- To characterize the dose-dependent effects of cisplatin on germ cell apoptosis.
- To identify potential long-term consequences of cisplatin on testicular health.
Main Methods:
- Administration of single intraperitoneal injections of cisplatin (5 or 10 mg/kg) to 11-week-old male mice.
- Quantification of germ cell apoptosis using the apoptotic index at various time points post-injection.
- Comparison of apoptotic rates between different cisplatin doses and control groups.
Main Results:
- A rapid and substantial increase in germ cell apoptosis was observed within 24-36 hours after cisplatin injection.
- The higher cisplatin dose (10 mg/kg) induced a faster and larger peak in apoptosis compared to the lower dose (5 mg/kg).
- Elevated apoptotic rates persisted at 12 days post-injection, particularly in the lower dose group, suggesting lasting damage.
Conclusions:
- Acute cisplatin exposure triggers a massive, early wave of germ cell apoptosis in mice.
- A secondary, sustained elevation in germ cell apoptosis indicates potential long-term or permanent damage to the seminiferous tubules.
- These findings highlight the critical need for understanding and mitigating cisplatin's reproductive toxicity.
