Cadmium‐Induced Mitochondrial and <scp>MAMs</scp> Dysregulation in Rat Testis: The Protective Role of D‐Aspartate

Cadmium (Cd), a heavy metal, disrupts the structure of seminiferous tubules and induces cell death at multiple stages of sperm development. Cd also impairs Leydig cells (LCs), resulting in reduced serum testosterone (T) levels. This study primarily examined the impact of Cd on the mitochondrial compartment and mitochondrial-associated endoplasmic reticulum membranes (MAMs) in rat testis. Additionally, the potential of D-aspartate (D-Asp) to mitigate Cd-induced effects on steroidogenesis and spermatogenesis was assessed by administering D-Asp simultaneously or preventively with Cd. The findings demonstrated that Cd exerts reprotoxicity by affecting the mitochondrial compartment and MAMs, evidenced by an imbalance in mitochondrial dynamics, impaired mitophagy pathway, and downregulated mitochondrial biogenesis. Cd exposure also reduced lipid transfer-related factor expression and increased ER stress. Moreover, elevated levels of Ca²⁺ transfer-related proteins, indicative of perturbed Ca²⁺ homeostasis, may be associated with enhanced oxidative stress and apoptosis, which are known effects of Cd. Immunofluorescent analysis revealed that the Cd-induced mitochondrial and MAMs damage was prominent in LCs, spermatocytes, and spermatids, confirming the metal's adverse effects on steroidogenesis and spermatogenesis. Conversely, co-administration or preventive administration of D-Asp with Cd preserved mitochondrial homeostasis and functional ER-mitochondria interactions. In conclusion, the study offers novel insights into the cellular mechanisms underlying Cd-induced reprotoxicity. Importantly, it highlights the efficacy of D-Asp in preventing or counteracting testicular damage caused by Cd by enhancing mitochondrial and MAMs functionality.