Neurodevelopmental Protective Effects of Maternal Urolithin a Supplementation against Perinatal Glyphosate Exposure: Long-Term Cognitive and Behavioral Outcomes in Offspring

Background and Objective: Perinatal exposure to environmental toxins such as glyphosate, a widely used herbicide, poses significant risks to neurodevelopment and may result in persistent cognitive and behavioral impairments in offspring. Glyphosate-induced neurotoxicity has been linked to oxidative stress, mitochondrial dysfunction, neuroinflammation, and gut microbiome disruption. Urolithin A (UA), a gut microbiota-derived postbiotic produced from ellagitannins, exhibits antioxidant, anti-inflammatory, and mitophagy-enhancing properties, suggesting potential neuroprotective effects. This study aimed to investigate whether maternal UA supplementation could attenuate neurodevelopmental toxicity induced by perinatal glyphosate exposure and improve long-term cognitive and behavioral outcomes in offspring. Materials and Methods: Pregnant mice were exposed to glyphosate via drinking water during gestation and lactation, with or without concurrent UA supplementation. Adult offspring were assessed for cognitive function using the Morris Water Maze, Novel Object Recognition, and Y-Maze tests, and for anxiety-like behavior using the Elevated Plus Maze and Open Field Test. Neurobiological evaluations included brain oxidative stress markers, mitochondrial function, inflammatory cytokine levels, and gut microbiome composition. Data were analyzed using appropriate one-way and two-way ANOVA models, with PERMANOVA applied for microbiome beta diversity analyses, and statistical significance set at p<0.05. Results: Perinatal glyphosate exposure resulted in marked impairments in spatial learning, memory retention, and recognition memory, along with increased anxiety-like behaviors. These deficits were accompanied by elevated oxidative stress, mitochondrial dysfunction, heightened neuroinflammatory responses, and gut microbiome dysbiosis. Maternal UA supplementation significantly mitigated these adverse effects, restoring cognitive and behavioral performance toward control levels and improving neurobiological and microbiome parameters. Conclusion: Maternal Urolithin A supplementation effectively protects against glyphosate-induced neurodevelopmental impairments by modulating oxidative stress, mitochondrial function, neuroinflammation, and gut microbiome balance, highlighting its potential as a preventive strategy against environmental neurotoxicity.