Zhang_2025_Front.Pharmacol_16_1657527

INTRODUCTION: Phoxim (chemical name O-alpha-cyanophenylamino-O, O-diethyl phosphorothioate, molecular formula C(12)H(15)N(2)O(3)PS) is classified as a high-efficiency, low-toxicity organophosphorus insecticide. Its primary mechanism of action involves inhibition of cholinesterase activity in insects, which disrupts nerve conduction, ultimately leading to paralysis and death. METHODS: The effects of phoxim exposure (0.5, 1, and 2.5 microg/mL) on survival, neurological function, and intestinal integrity in Caenorhabditis elegans (C.elegans) were investigated. RESULTS: Phoxim at all concentrations significantly increased the mortality rate of C. elegans. Fluorescence microscopy revealed that 2.5 microg/mL phoxim reduced dopaminergic neural processes in the BZ555 transgenic strain of C. elegans from 4 to 2, and 0.5 and 1 microg/mL phoxim accelerated amyloid beta (Abeta)-induced paralysis in the CL4176 strain, with complete paralysis observed at 32 and 36 h, respectively. FD&C Blue #1 staining demonstrated intestinal damage in 46.7% and 68.3% of C. elegans exposed to phoxim at 1 and 2.5 microg/mL, respectively. Exposure to 1 microg/mL phoxim decreased enterocyte numbers and reduced autophagic vesicles in the lgg-1::GFP strain of C. elegans from 1.8 to 1.3. qPCR analysis revealed downregulation of autophagy-related genes (vps-34, atg-13, and unc-51) by 0.53-, 0.43-, and 0.36-fold of the control levels, respectively. RNAi targeting the eat-2 gene further confirmed the impact of phoxim on cell survival through the autophagy pathway. DISCUSSION: Our results indicate that phoxim exposure reduces dopaminergic neuron integrity, accelerates Abeta-induced paralysis, and damages intestinal cells through inhibition of autophagy in C. elegans.