Acrylamide exposure promotes the progression of depression-like behavior in mice with CUMS via GSDMD-mediated pyroptosis
Aim: This study aimed to explore the mechanism by which the environmental toxin acrylamide (AM) contributes to the development of depression.
Methods: A depression mouse model was established using the chronic unpredictable mild stress (CUMS) method, with oral administration of AM to simulate environmental exposure. Depressive-like behaviors were assessed using the open field test, elevated plus maze test, swimming test, and sucrose preference test. Enzyme-linked immunosorbent assay (ELISA) was used to measure tissue inflammatory factor levels, while hematoxylin and eosin (H&E) and Nissl staining were performed to assess neuronal damage. Immunohistochemical staining was employed to detect IBA-1 expression, and Western blotting was used to quantify protein levels. GSDMD knockout (KO) mice and the GSDMD inhibitor LDC7559 were used to inhibit GSDMD activity. In vitro, primary microglial cells were treated with AM to evaluate inflammatory factor levels and GSDMD-NT expression, and propidium iodide (PI) staining was used to assess pyroptosis.
Results: AM exacerbated CUMS-induced depressive behavior in mice, elevated inflammatory factor levels in brain tissue, and worsened neuronal damage. This was accompanied by increased IBA-1 expression and upregulation of NLRP3, GSDMD, and GSDMD-NT. Intervention with GSDMD-KO or LDC7559 antagonized the effects of AM and alleviated CUMS-induced depression. In microglial cell experiments, AM promoted pyroptosis, increased inflammatory factor expression, and, when GSDMD-KO was applied, inhibited these effects.
Conclusion: AM promotes the progression of depression in CUMS-induced mice through GSDMD-mediated pyroptosis, which also increases tissue inflammation. GSDMD emerges as a key target in mediating the neurotoxic effects of AM.