Mechanistic understanding of heat stress in cattle reproduction toward pharmacological strategies: review.

Heat stress is a major environmental challenge that compromises reproductive performance in cattle, particularly under the intensifying conditions of global climate change. This review provides a comprehensive overview of how heat stress impairs bovine reproduction at the physiological, cellular, and molecular levels and explores practical strategies for mitigation. In females, heat stress disrupts hormonal regulation, estrous behavior, and ovulation, and diminishes oocyte and embryo quality, resulting in reduced conception rates and increased pregnancy losses. In males, prolonged heat exposure impairs spermatogenesis and semen quality and delays post-stress recovery. Dairy cattle are especially vulnerable due to the elevated metabolic demands of lactation. Although beef cattle exhibit greater thermotolerance, they also experience reduced fertility under prolonged heat stress, particularly during breeding and early gestation. At the cellular level, heat stress triggers oxidative damage, mitochondrial dysfunction, immune dysregulation, and altered epigenetic and cytoskeletal dynamics. Integrative transcriptomic analyses across key reproductive tissues reveal both conserved and cell type-specific molecular responses. These include activation of inflammatory and apoptotic pathways, suppression of chaperone-mediated protein folding and hormone receptor signaling, and downregulation of uterine receptivity programs. To counter these effects, current strategies involve environmental modifications, genetic selection for thermotolerance, and supportive treatments such as antioxidants, methyl donors, and hormonal protocols. However, most interventions remain symptomatic and nonspecific. Future efforts must prioritize mechanistically grounded approaches that target the molecular drivers of heat-induced reproductive dysfunction. Continued research integrating multi-omics, network-based modeling, and pharmacological discovery will be critical to developing next-generation solutions that enhance reproductive resilience and sustainability in cattle production systems.