Metabolic reprogramming and organelle quality control: The "silent" drivers of Sertoli cell dysfunction under environmental stressors.

Sertoli cells (SCs) are the metabolic and structural "nurse" cells of the seminiferous epithelium. Classical testicular toxicology has largely focused on endpoints such as germ cell apoptosis, testicular atrophy and overt Sertoli cell death. These outcomes undoubtedly capture severe injury, but they are the last step in a longer pathogenic sequence. A growing body of work indicates that environmental toxicants and systemic metabolic stress reprogram SC energy metabolism and disrupt organelle quality control at sub-lethal levels long before cell death becomes evident. In this early phase, SCs lose their ability to sustain glycolysis-lactate shuttling, to recycle and oxidize lipids efficiently, and to maintain a healthy mitochondrial and lysosomal network, with important consequences for blood-testis barrier integrity and germ cell development. Here, we synthesize current evidence on SC-centered metabolic and organelle mechanisms in male reproductive toxicology. We first summarize the physiological roles of SCs in glycolysis and lactate export, lipid handling, mitochondrial dynamics, autophagy and LC3-associated phagocytosis, emphasizing how these pathways are coordinated to support spermatogenesis. We then discuss how selected environmental and systemic stressors-including atrazine, phthalates, cadmium, fine particulate matter (PM₂.₅), thermal stress and obesity-converge on these pathways to reprogram SC function. Building on these observations, we propose a two-phase model of SC injury in which sub-lethal metabolic and organelle misregulation represents an early, potentially reversible phase that precedes overt regulated cell death and structural collapse of the seminiferous epithelium. Finally, we highlight emerging therapeutic opportunities targeting SC metabolism and organelle quality control, and outline how incorporating SC-centered biomarkers into experimental designs could improve the sensitivity and mechanistic depth of reproductive risk assessment.