Cisplatin Induces Apoptosis in Mouse Neonatal Testes Organ Culture

Abstract

Chemotherapy is used for childhood cancer but may lead to infertility in patients. Spermatogonia stem cells are present in the testes of prepubertal boys, although they do not produce sperm at this age. Herein, we evaluated the toxicity of cisplatin, a known medicine for cancer treatment, in neonatal mouse testes using in vitro organ culture. Mouse testicular fragments (MTFs) derived from 5.5-d postpartum mouse testes were exposed to 1–10 μg/mL cisplatin. The results showed that cisplatin significantly downregulated the expression of germ cell marker genes, including differentiated and undifferentiated, in a dose-dependent manner. In particular, a high dose of cisplatin (10 μg/mL) led to germ cell depletion. In addition, the expression levels of the Sertoli cell marker gene, the number of SOX9+ Sertoli cells, and the levels of SOX9 protein were markedly decreased in cisplatin-treated MTFs compared to controls. The mRNA expression of steroidogenic enzyme-related genes significantly increased in cisplatin-treated MTFs, except for estrogen receptor 1 (Esr1). Consistently, 3β-hydroxysteroid dehydrogenase protein was also observed in the interstitial regions of cisplatin-treated MTFs. Altogether, our findings showed a significant impairment in germ cell development, Sertoli cell survival, and steroidogenesis in the MTFs of cisplatin-treated mice.

Anti-oxidative effects of broccoli (Brassica oleracea var. italica) sprout extract in RAW 264.7 cell and cisplatin-induced testicular damage

“…Therefore, in this study, cisplatin-induced oxidative stress was studied in testicular organ cultures in vitro. This model was reported in our previous study (Park et al, 2022).…”

“…MTFs were cultured as described previously (Park et al, 2020b). Further, ROS generation was induced in the testes by cisplatin, and the cisplatin concentration was determined according to our previous study (Park et al, 2022). In brief, MTFs were cultured with 5 μg/mL cisplatin and 1 mg/mL BSE for five days.…”

Circulating microRNAs as promising testicular translatable safety biomarkers: current state and future perspectives

“…One of the challenges for difficulty in preclinical to clinical translation of testicular toxicity can be attributed to the physiological and metabolic differences between the species. With the cutting-edge technologies such as 'organs-on-chips' (Zommiti et al 2022) that can emulate the human organ's physiological environment and function, there is potential to enhance our understanding of the translatability of biomarker miRNAs from nonclinical to clinical settings (Akinjo et al 2018;Park et al 2022). Leveraging such emerging tools will enable biomarker discovery, validation and clinical translation for regulatory qualification and implementation for a specific context of use in drug development.…”

Alkylating agents‐induced gonadotoxicity in prepubertal males: Insights on the clinical and preclinical front

“…In addition, Park et al. have further demonstrated that 1–10 μg/mL of cisplatin increases the expression of pro‐apoptotic genes ( BAX , BAD , FAS , and TRAF3 ), leading the authors to hypothesize that damage was mediated by ROS accumulation 118 . Recently, a study has shown that only high cisplatin concentrations of 12–40 μg/mL can induce persistent germ cell loss and impair the in vitro spermatogenesis process 119…”