ER Stress Links HSP90/NLRP3-Mediated Pyroptosis in Grass Carp Brain under Synergistic Exposure to Cypermethrin and Sulfamethoxazole.

With the aggravation of pesticide and antibiotic pollution, drug residues in water increasingly threaten the stability of aquatic ecosystems, which has aroused widespread social concern. The nervous system plays a leading role in the organism, but the mechanism of brain damage induced by cypermethrin (CMN) and sulfamethoxazole (SMZ) is still unclear. In this study, the effects of CMN (0.65μg/L) and SMZ (0.30μg/L) alone and combined exposure for 42 days on the brain tissue of grass carp (Ctenopharyngodon idella) were investigated. We noted that co-exposure to CMN and SMZ resulted in more pronounced pathological damage and ultrastructural disruptions in brain tissue, accompanied by endoplasmic reticulum stress (ERS), heat shock response (HSR), and pyroptosis. A detailed mechanistic investigation indicated that the ERS pathway (PERK) was activated, which may trigger cell protection against the damage caused by CMN and SMZ exposure. Excessive ERS was also accompanied by the HSR and the pyroptosis response, which were supported by increased expression levels of heat shock proteins (HSP60, HSP70, and HSP90) and related molecular mechanisms of pyroptosis (NLRP3, ASC, IL-18, Caspase-1) from mRNA and protein levels. This study suggested that CMN and SMZ induced neurotoxicity in grass carp through activating the HSP90/NLRP3 signaling pathway, providing valuable data for the ecological risk assessment of SMZ and CMN to aquatic organisms and theoretical support for the conservation of aquatic organisms.