Chronic labetalol exposure induced dose-dependent testicular toxicity via disruptingt HPG-axis, spermatogenesis and steroidogenic pathways: A biochemical, molecular and histopathological evidence.

Labetalol (LBL) is a combined-alpha and non-selective β-adrenergic receptor antagonist commonly prescribed for high blood pressure patients. However, LBL intoxication showed severe toxicity including testicular impairments. This experimental study aimed to elucidate the dose-responsive reproductive perturbations of LBL in albino rats. Rats (n = 32) were categorized into control, LBL (200 mg/kg), LBL (250 mg/kg), and LBL (300 mg/kg) group. The cumulative data substantiated that LBL administration suppressed LHCGR, FSHR, AR, ESR1, ESR2, DAZL, STRA8, SYCP3, KIT, CREM, StAR, 3β-HSD, and 17β-HSD. Similarly, LBL exposure promoted pronounced accumulation of ROS & MDA while reducing GSR, CAT, SOD, HO-1, GST & GPx. Furthermore, LBL intoxication adversely diminished the concentrations of testosterone, LH, and FSH against all the tested doses. Testicular inflammation and apoptosis were confirmed by elevated IL-6, NF-κB, COX-2, Bax, IL-1β, Caspase-9, TNF-α, coupled with profoundly impaired Bcl-2 following LBL administration. Histo-morphological examination showed that LBL exposure produced profound architectural distortion of the testicular parenchyma, characterized by extensive seminiferous epithelial deterioration accompanied by marked depletion of spermatogenic cells, high mortality & low sperm viability. Furthermore, LBL administration altered semen parameters including abnormal head, tail, and mid-piece region of sperms thereby suggesting direct testicular toxicity. Collectively, these observations underscore the pronounced testiculotoxic capacity of LBL, highlighting the interplay of oxidative injury, inflammatory mediators, apoptotic processes, and severe histomorphological disruption as principal determinants of its pathogenic effects.