Toxic effects of gadolinium on spermatogenesis are associated with inflammation, oxidative stress, apoptosis and autophagy

Abstract

The widespread use of gadolinium (Gd) in industrial and medical applications has raised concerns about its environmental persistence, particularly in water and soil. Once ingested, Gd may exert toxic effects on various organs, but its impact on male reproductive health remains largely unexplored. This study investigated the effects of orally administered GdCl₃ or Gd₂O₃ on spermatogenesis and sperm quality in adult rats. To this purpose, male rats were allowed to drink GdCl₃ or Gd₂O₃ (10–20–40 mg/Kg bw) for 4 weeks. Gd exposure triggered a strong inflammatory response, evidenced by NF-κB activation and increased TNFα and IL-6 levels in serum and testis. This was accompanied by oxidative stress, as indicated by elevated TBARS levels, as well as apoptosis and autophagy processes activation. Notably, Gd-treated animals exhibited a downregulation of spermatogenesis-related proteins (PCNA, p-H3, SYCP3, PRM2). Histological analysis revealed morphological and morphometric alterations in the seminiferous tubules, along with compromised sperm quality. To explore the cellular mechanisms, in vitro experiments were carried out using mouse GC-1 spermatogonial cells treated with GdCl₃ or Gd₂O₃ for 24 h. Gd exposure resulted in cytotoxicity and reduced cell proliferation, with decreased levels of p-ERK1/2 and PCNA. Gd exposure also disrupted oxidative homeostasis and induced autophagy and apoptosis, likely through the inhibition of the AKT signaling pathway. This study provides the first evidence that oral Gd exposure adversely affects spermatogenesis through inflammation, oxidative stress, and impairment of key cellular pathways, highlighting Gd as a potential environmental threat to male reproductive health.