Gadolinium induces Sertoli cell damage: cellular and molecular mechanisms

The widespread use of gadolinium (Gd) in industrial and medical applications has raised concerns about its environmental persistence, particularly in water and soil, thereby reaching the human food chain. Once ingested, Gd may have toxic effects on all body tissues, but its impact on male reproductive health remains largely unexplored. In rats, oral exposure to Gd impairs both steroidogenesis and spermatogenesis, exerting direct toxic effects on Leydig and germ cells. However, its impact on Sertoli cells, crucial for providing metabolic support and structural guidance to developing germ cells, remains unexplored. To address this gap, we exposed mouse TM4 Sertoli cells to increasing concentrations of GdCl₃ or Gd₂O₃ for 24 h and evaluated their cellular and molecular responses. Our results showed that exposure to Gd induces oxidative stress, leading to decreased cell viability and inhibiting proliferation in TM4 cells. Notably, Gd suppressed both the expression of the androgen receptor protein and the activity of LDH. Furthermore, Gd decreased the expression of junctional proteins, with the most severe effect observed with Gd₂O₃. Activation of autophagic and apoptotic processes in Gd-treated TM4 cells was also observed. These processes appeared to originate from significant molecular impairment of the mitochondrial compartment, along with functional alterations of the Mitochondria-Associated Membranes, the crucial interface between mitochondria and the endoplasmic reticulum. Therefore, the study highlights the Sertoli cells as targets of the toxic action of Gd, providing a new framework for understanding the risks Gd poses to male reproductive health.