Zinc Oxide Nanoparticles Mitigate Nonylphenol-Induced Testicular Toxicity by Modulating Blood-Testis Barrier Proteins and JAK2/STAT3 Signaling.

Nonylphenol (NP), a widely used environmental endocrine disruptor, is known to impair male reproductive health by disrupting spermatogenesis, testicular structure, and inflammatory-apoptotic signaling pathways. This study investigated the extent of NP-induced testicular toxicity and evaluated the modulatory effects of zinc oxide (ZnO) nanoparticles using spermatological, histopathological, biochemical, and molecular approaches. Thirty-five male Sprague Dawley rats were randomly allocated into five groups: control, NP (40 mg/kg), ZnO (30 mg/kg), NP + ZnO (15 mg/kg), and NP + ZnO (30 mg/kg), and treated orally for 28 days. NP exposure resulted in a significant reduction in sperm motility, increased proportions of abnormal and dead spermatozoa, and elevated serum testosterone levels. Histopathological examination revealed marked degeneration of the seminiferous epithelium and germ cell desquamation, accompanied by decreased expression of key blood-testis barrier proteins, including claudin-11, occludin, N-cadherin, and connexin-43. At the molecular level, NP significantly upgraded the expression of apoptosis and inflammation related genes, such as BAX, IL-1β, TNF-α, JAK2, and STAT3. Co-administration of ZnO nanoparticles partially attenuated NP-induced alterations by improving sperm functional parameters, preserving seminiferous tubule architecture, and enhancing junctional protein expression in a dose-dependent manner. ZnO nanoparticles administration also modulated apoptotic signaling, as reflected by increased BCL-2 expression, while differentially regulating inflammatory and JAK2/STAT3-associated responses. Overall, these findings indicate that ZnO nanoparticles partially mitigate NP-induced testicular toxicity through dose sensitive cytoprotective and barrier-preserving mechanisms, with the 15 mg/kg dose providing more consistent functional benefits.