Assessment of diphenhydramine toxicity – Is its mode of action conserved between human and zebrafish?

• Published in: Environment international 2022-06, Vol.164, p.107263-107263, Article 107263
• Main Authors: Barreto, Angela, Santos, Joana, Capitão, Ana, Eusébio, Rodrigo, Pinheiro Damasceno, Évila, Luísa Machado, Ana, Rocha, Luciana S., Calisto, Vânia, Amorim, Mónica J.B., Maria, Vera L.
• Format: Article
• Language: English
• Subjects: Freshwater fish; Mechanisms of toxicity; Multi-biomarkers; Pharmaceuticals; Risk evaluation
• ISSN: 0160-4120; 1873-6750
• DOI: 10.1016/j.envint.2022.107263

[Display omitted] •Diphenhydramine (DPH, 10 mg/L) reduced zebrafish embryos heartbeat rate (48 h);•DPH, 1 and 10 mg/L, induced larvae hypoactivity and erratic swimming, after 120 h;•DPH, 0.01 or 10 mg/L, reduced energy budgets and total glutathione content (96 h);•DPH affected cholinesterase/glutathione S-transferase activities and DNA integrity;•DPH target molecules are conserved in human and zebrafish. The main aim of the study is to evaluate the effects of the pharmaceutical diphenhydramine (DPH) on embryo-larvae Danio rerio across distinct levels of organization – individual and subcellular – and correlate those effects with the DPH mode of action (MoA) assessed by in silico analysis. An embryos heartbeat rate reduction was observed at 10 mg/L DPH, but 0.001 to 10 mg/L did not significantly affect the zebrafish survival, hatching and morphology. Larvae swimming distance decreased (hypoactivity) at 1 and 10 mg/L DPH. Moreover, the straightforward movements decrease and the increase in the zigzag movements or movements with direction changes, shown an erratic swimming behavior. Energy budgets decreased for lipid (0.01 mg/L DPH) and carbohydrate (10 mg/L DPH) contents. Cholinesterase (neural function) and glutathione S-transferase (Phase II biotransformation/antioxidant processes) increased their activities at 10 mg/L DPH, where a decrease in the total glutathione content (antioxidant system) was observed. DNA damage was found at 0.01 and 10 mg/L DPH. However, a DNA repair occurred after subsequent 72 h in clean media. The in silico study revealed a relevant conservation between human and zebrafish DPH target molecules. These data provide a valuable ecotoxicological information about the DPH effects and MoA to non-target organisms.