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Thymol Preserves Spermatogenesis and Androgen Production in Cisplatin-Induced Testicular Toxicity by Modulating
Amira M Badr1,2, Sheka Aloyouni3, Yasmin Mahran4
1Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia.
Abstract:
Cisplatin (CDDP) is a widely used chemotherapeutic agent, but its off-target toxicity, including testicular damage, limits clinical use. Bioactive compounds may help mitigate chemotherapy-induced reproductive toxicity. This study investigates thymol's role in modulating ferritinophagy to preserve reproductive function and steroidogenesis. Male Wistar rats were randomized to control, CDDP, thymol, or CDDP + thymol groups. Thymol (60 mg/kg) was given orally for 14 days, and CDDP (8 mg/kg) was administered intraperitoneally on day 7. Testicular function was assessed through hormonal analysis, sperm evaluation, and histopathology. Ferritinophagy, oxidative stress, and inflammatory markers were assessed to elucidate thymol's chemoprotective mechanisms. Thymol co-administration preserved steroidogenesis, restored sperm quality, and maintained testicular architecture in CDDP-treated rats. Thymol suppressed ferritinophagy, reducing iron overload and mitigating reactive oxygen species (ROS)-induced cellular damage. Additionally, thymol activated the Keap1/Nrf2/HO-1 pathway, enhancing antioxidant defenses while downregulating inflammatory mediators (TNF-α, IL-6). Additionally, thymol enhanced CDDP's selectivity toward cancer cells while reducing its toxicity to normal cells. This study provides evidence that thymol modulates ferritinophagy to attenuate CDDP-induced testicular toxicity, helping preserve reproductive function via regulation of iron homeostasis. These findings highlight thymol's potential as an adjunct therapy to mitigate chemotherapy-associated reproductive damage while maintaining CDDP's anticancer efficacy.
Insights
Thymol protects against cisplatin-induced testicular damage by modulating ferritinophagy, preserving reproductive function and steroidogenesis. This natural compound enhances chemotherapy
Area of Science:
- Reproductive Toxicology
- Chemotherapy
- Natural Compounds
Background:
- Cisplatin (CDDP) chemotherapy causes testicular toxicity, limiting its clinical use.
- Chemotherapy-induced reproductive toxicity is a significant concern for patients.
- Bioactive compounds offer potential for mitigating chemotherapy side effects.
Purpose of the Study:
- To investigate thymol's protective effects against cisplatin-induced testicular damage.
- To elucidate the role of ferritinophagy modulation in thymol's chemoprotective mechanism.
- To assess thymol's impact on reproductive function, steroidogenesis, and oxidative stress.
Main Methods:
- Male Wistar rats were treated with cisplatin (CDDP) and/or thymol.
- Testicular function was evaluated via hormonal assays, sperm analysis, and histopathology.
- Ferritinophagy, oxidative stress, and inflammatory markers were assessed.
Main Results:
- Thymol preserved steroidogenesis, sperm quality, and testicular architecture in CDDP-treated rats.
- Thymol suppressed cisplatin-induced ferritinophagy, reducing iron overload and oxidative stress.
- Thymol activated the Keap1/Nrf2/HO-1 pathway and reduced inflammation.
Conclusions:
- Thymol attenuates cisplatin-induced testicular toxicity by modulating ferritinophagy and iron homeostasis.
- Thymol demonstrates potential as an adjunct therapy to preserve reproductive function during chemotherapy.
- Thymol may enhance cisplatin's anticancer efficacy while reducing its toxicity to normal cells.
