Selenium protects mouse spermatogonia against ivermectin-induced apoptosis by alleviating endoplasmic reticulum stress in vitro

Abstract

Ivermectin (IVM) is a widely used anthelmintic in human and veterinary medicine. However, the increasing use of IVM raises concerns about its potential harm against non-targeted organisms. This study demonstrates a novel mechanism where IVM triggers apoptosis via endoplasmic reticulum (ER) stress in GC-1 spg in vitro. The inhibitory effects of selenium (Se) against the toxicological mechanism were also explored. IVM dose-dependently induces oxidative stress, dysregulated Ca2+ levels, and intracellular protein aggregation. Increased mitochondria-associated ER membrane (MAM) activity through Glucose-regulated Protein 75 (Grp75) overloads the mitochondria with Ca2+, causing mitochondrial dysfunction. These simultaneous stressors lead to unfolded protein response and apoptosis. Se reverses all these subcellular events by promoting the expression of selenoprotein-encoding genes to maintain the ER and redox homeostasis. The testis-enriched Glutathione Peroxidase 4 (Gpx4) and the testis-specific Selenoprotein V (Selenov) are only upregulated in the IVM and Se co-treatment group, suggesting their potential role in stress response. These findings confirm that toxic doses of IVM lead to programmed cell death in type B spermatogonia through redox imbalance-associated ER stress. This study provides valuable insights into refining male reproductive toxicity evaluation, targeting of ER stress to protect male germ cells, and maintaining male fertility from IVM-induced toxicity.

Keywords

• Ivermectin
• Selenium
• Redox Imbalance-associated Endoplasmic Reticulum (ER) Stress
• Male infertility