期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/ijms23105429
关键词
fluconazole; prochloraz; miconazole and ketoconazole; mouse Sertoli TM4 cells; synergistic effects; oxidative stress; ROS generation and apoptosis; mitochondrial activity; SOD; enzymatic activity; GSH homeostasis
资金
- intramural DISCAB GRANT 2021 - Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila [07-RIA 2021 IORIO ROBERTO]
- MIUR (Ministero dell'Istruzione, dell'Universita e della Ricerca, Italy) [CUP E11I18000300005]
Triazole and imidazole fungicides, as emerging pollutants with endocrine-disrupting properties, have been found to have adverse effects on male reproductive cells. This study specifically demonstrates that ketoconazole and miconazole, alone or in combination with prochloraz, significantly impair the functions of Sertoli cells and cause oxidative stress. However, fluconazole shows no cytotoxic effects.
Triazole and imidazole fungicides represent an emerging class of pollutants with endocrine-disrupting properties. Concerning mammalian reproduction, a possible causative role of antifungal compounds in inducing toxicity has been reported, although currently, there is little evidence about potential cooperative toxic effects. Toxicant-induced oxidative stress (OS) may be an important mechanism potentially involved in male reproductive dysfunction. Thus, to clarify the molecular mechanism underlying the effects of azoles on male reproduction, the individual and combined potential of fluconazole (FCZ), prochloraz (PCZ), miconazole (MCZ), and ketoconazole (KCZ) in triggering in vitro toxicity, redox status alterations, and OS in mouse TM4 Sertoli cells (SCs) was investigated. In the present study, we demonstrate that KCZ and MCZ, alone or in synergistic combination with PCZ, strongly impair SC functions, and this event is, at least in part, ascribed to OS. In particular, azoles-induced cytotoxicity is associated with growth inhibitory effects, G0/G1 cell cycle arrest, mitochondrial dysfunction, reactive oxygen species (ROS) generation, imbalance of the superoxide dismutase (SOD) specific activity, glutathione (GSH) depletion, and apoptosis. N-acetylcysteine (NAC) inhibits ROS accumulation and rescues SCs from azole-induced apoptosis. PCZ alone exhibits only cytostatic and pro-oxidant properties, while FCZ, either individually or in combination, shows no cytotoxic effects up to 320 mu M.
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