The blood-testis barrier (BTB) is a specialized structure that maintains the testicular microenvironment and supports normal spermatogenesis. Preserving its structural integrity is critical for male reproductive function. In recent years, growing attention has been directed toward the adverse effects of exogenous toxicants, including environmental pollutants, nanomaterials, endocrine-disrupting chemicals (EDCs), and microplastics, on BTB integrity. Increasing evidence indicates that these toxicants impair the BTB through four major, interconnected mechanisms: (i) oxidative stress and disruption of antioxidant defenses; (ii) cytoskeletal remodeling and programmed cell death; (iii) endocrine disruption and hormonal imbalance; and (iv) metabolic dysfunction and abnormalities of the gut-testis axis. Moreover, simultaneous exposure to multiple pollutants often produces synergistic toxic effects, leading to more severe BTB damage. Despite substantial progress, the molecular regulatory networks underlying BTB injury remain incompletely understood, and targeted therapeutic strategies are still largely in the preclinical stage. This review systematically summarizes the structural organization and physiological functions of the BTB, comprehensively examines the mechanisms of toxicant-induced injury and their downstream reproductive consequences, and highlights recent advances in the field. We further discuss emerging BTB repair strategies, including antioxidant-based therapies, signaling pathway modulators, and targeted drug delivery systems. Finally, by critically evaluating current knowledge gaps and research challenges, this review establishes a comprehensive framework to advance fundamental research in male reproductive toxicology, facilitate the development of therapeutic interventions for BTB-related reproductive disorders, and ultimately support the protection and restoration of male reproductive health.
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