The rare-earth yttrium induces cell apoptosis and autophagy in the male reproductive system through ROS-Ca-CamkII/Ampk axis.

China has the world's largest reserves of rare earth elements (REEs), but widespread mining and application of REEs has led to an increased risk of potential pollution. Yttrium (Y), the first heavy REEs to be discovered, poses a substantial threat to human health. Unfortunately, little attention has been given to the impact of Y on human reproductive health. In this study, we investigated the toxic effects of YCl on mouse testes and four types of testicular cells, including Sertoli, Leydig, spermatogonial and spermatocyte cells. The results showed that YCl exposure causes substantial damage to mouse testes and induces apoptosis and autophagy, but not pyroptosis or necrosis, in testicular cells. Genome-wide gene expression analysis revealed that YCl induced significant changes in gene expression, with Ca and mitochondria-related genes being the most significantly altered. Mechanistically, YCl exposure induced mitochondrial dysfunction in testicular cells, triggering the overproduction of reactive oxygen species (ROS) by impairing the Nrf2 pathway, regulating downstream Ho-1 target protein expression, and increasing Ca levels to activate the CamkII/Ampk signaling pathway. Blocking ROS production or Ca signaling significantly attenuates apoptosis and autophagy, while supplementation with Ca reverses the suppression of apoptosis and autophagy by ROS blockade in testicular cells. Notably, apoptosis and autophagy induced by YCl treatment are independent of each other. Thus, our study suggests that YCl may impair the antioxidant stress signaling pathway and activate the calcium pathway through the ROS-Ca axis, which promotes testicular cell apoptosis and autophagy independently, thus inducing testicular damage and impairing male reproductive function.