Sodium valproate at concentrations bracketing estimated seminal plasma levels impairs human sperm function in vitro...

Sodium valproate (VPA), a first-line broad-spectrum antiseizure medication, has been associated with altered semen quality in clinical settings, but its direct effects on human sperm remain incompletely defined. In this in vitro study, sperm from normozoospermic donors were exposed to VPA concentrations bracketing an estimated seminal exposure range (10, 20, 50, and 100µM). Sperm motility was evaluated at 1, 2, and 4h of incubation, whereas other functional parameters and intracellular oxidative/mitochondrial markers were assessed after a 4-h exposure. VPA induced concentration-dependent reductions in progressive and total motility as well as sperm penetration capacity, without affecting viability or spontaneous acrosome reaction. These functional impairments were accompanied by elevated intracellular oxidative stress and lipid peroxidation, decreased ATP content, depolarization of mitochondrial membrane potential, and ultrastructural mitochondrial abnormalities. Notably, co-incubation with 10µM resveratrol partially attenuated the oxidative stress-related changes and motility impairment induced by VPA. Taken together, acute in vitro exposure of mature ejaculated human sperm to VPA at concentrations covering the estimated seminal exposure range is associated with impaired sperm function, increased oxidative stress markers and lipid peroxidation, as well as mitochondrial dysfunction-associated changes. Resveratrol co-incubation partially attenuates selected VPA-associated reproductive impairments. These findings provide mechanistic, hypothesis-generating evidence at the level of mature ejaculated sperm; however, they do not establish the mechanisms of chronic VPA-associated reproductive toxicity in men with epilepsy or support clinical antioxidant supplementation. Further in vivo and translational clinical studies are warranted to verify the reproductive relevance of these findings in patients receiving long-term VPA therapy.