27 | CELLULAR AND MOLECULAR MECHANISMS OF GADOLINIUM TOXICITY IN SERTOLI CELLS

Sara Falvo¹, Giulia Grillo¹, Gabriella Chieffi Baccari¹, Giuseppe Petito¹, Massimo Venditti², Maria Maddalena Di Fiore¹, Tiziana Cappello³, Maria Maisano³, Alessandra Santillo¹ | ¹Dept of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania L. Vanvitelli, Caserta, Italy; ²Dept of Experimental Medicine, University of Campania L. Vanvitelli, Napoli, Italy; ³Dept of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Italy

The increasing environmental release of gadolinium (Gd), due to both industrial and clinical applications, has raised concerns about human health. Following ingestion/absorption, Gd exerts toxic effects across various tissues, but its consequences for male reproductive health are still poorly understood. Our previous studies demonstrated that oral Gd administration to adult rats adversely affects steroidogenesis and spermatogenesis, with direct effects on Leydig and germ cells. However, the impact of Gd on Sertoli cells, which provide vital support and energy (e.g., lactate) to germ cells, remains unreported. Therefore, in the present study we exposed mouse Sertoli (TM4) cells to increasing concentrations (5-1000 µM) of GdCl3 or Gd2O3 for 24h. Our results showed a dose-dependent decrease in TM4 cell viability and proliferation. Gd cytotoxic effects reflect a significant impairment of Sertoli cell functions. Specifically, Gd inhibited both the expression of the AR protein and the activity of LDH, as such as Blood-Testis Barrier integrity was also compromised. Gd induced oxidative stress and activated autophagic and apoptotic processes, mediated by the inhibition of the Akt pathway. Finally, we documented mitochondrial dysfunction and alteration in Mitochondrial-Associated Endoplasmic Reticulum Membranes (MAM) integrity. In conclusion, our findings highlight novel cellular and molecular mechanisms underlying Gd-induced testicular damage, specifically implicating that Gd-induced impairment to spermatogenesis may also result from compromised Sertoli cell function.
Acknowledgments: This work was supported by PRIN PNRR 2022 CUP B53D23024710001: “GADOlinium (Gd), an emergent contaminant, is a new threat to the living beings: a comparative study to assess its biological TOXicity in animal models (GADOTOX)”