Hou_2026_Environ.Pollut__128582

In freshwater ecosystems, chronic exposure to anthropogenic pharmaceuticals represents an underappreciated functional pressure shaping organismal behavior and cellular fate. Using the freshwater clam Corbicula fluminea as a benthic model, we examined paracetamol (PAR) as a representative pharmaceutical stressor by integrating behavioral, histological, transcriptomic, and biochemical analyses following 28-day exposure at 0.02, 0.2, and 2 mg/L. Environmentally relevant concentration (0.02 mg/L) and pollution hotspot level (0.2 mg/L) induced dose-dependent effects: low-dose exposure altered escape responses with acetylcholinesterase inhibition and GABAergic pathway alterations, whereas medium-dose exposure impaired burrowing. Persistent tissue lesions, especially digestive gland vacuolation, were observed across doses. Chronic exposure elicited genotoxic stress, paradoxical COX-2 upregulation, and oxidative-detoxification imbalance, leading to apoptosis via the intrinsic caspase-9/3 pathways. High-dose exposure (2 mg/L) intensified behavioral, tissue, and cellular effects. Collectively, these findings show that chronic paracetamol exposure disrupts neuromodulation, metabolic homeostasis, and cell fate in benthic bivalves, revealing sublethal consequences overlooked in current assessment frameworks.