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Freshwater snails are used as sensitive biomarkers of aquatic ecosystem pollution. The potential impacts of zinc oxide nanoparticles (ZnONPs) on aquatic ecosystems have attracted special attention due to their unique properties. The present investigation was designed to evaluate the possible mechanisms of ecotoxicological effects of ZnONPs on freshwater snail Biomphalaria alexandrina. ZnONPs showed molluscicidal activity against B. alexandrina snails, and the LC50 was 145 ug/ml.Exposure to ZnONPs (7 and 35 ug/ml) for three consecutive weeks significantly induced malondialdehyde and nitric oxide with concomitant decreases in glutathione and glutathione- S-transferase levels in hemolymph and soft tissues of treated snails. Moreover, ZnONPs elicited a significant decrease in total protein and albumin contents coinciding with enhancement of total lipids and cholesterol levels as well as activities of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase hemolymph and soft tissues of treated snails.