J Hazard Mater. 2025 Jun 23;495:139049. doi: 10.1016/j.jhazmat.2025.139049. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic arsenic exposure is a global health concern linked to pulmonary diseases like fibrosis. However, its precise molecular mechanisms remain unclear. This study explored the effects of chronic arsenic exposure on a murine model (via diet) and BEAS-2B cells, focusing on oxidative stress, lipid peroxidation, mitochondrial dysfunction, and ferroptosis-mediated cell death.

METHODS: BEAS-2B cells were exposed to 1 μmol/L NaAsO₂ for 30 passages. Oxidative stress was assessed via ROS quantification, GSH depletion, and T-SOD activity. Lipid peroxidation was measured using BODIPY fluorescence and MDA levels. Mitochondrial dysfunction was determined by mtROS imaging and JC-1 staining. Ferroptosis was analyzed through GPX4 expression and TEM-based mitochondrial integrity. A 14-month murine model evaluated histopathology, metabolomic dysregulation, and gut-lung axis crosstalk.

RESULTS: Arsenic exposure significantly increased ROS, depleted GSH, and reduced T-SOD activity. Lipid peroxidation and mitochondrial dysfunction were evident, with more than 60 % decline in GPX4. Murine lung histology showed alveolar thickening, inflammatory infiltration, and elevated IL-6, TNF-α, and VEGF. Metabolomic analysis revealed disrupted lipid metabolism, correlating with ferroptosis markers (Acetyl-carnitine, L-Acetylcarnitine).

CONCLUSIONS: This was the first study to demonstrate ferroptosis as a key mechanism in arsenic-induced lung epithelial damage using a 14-month murine model and a 30-passage cellular model. We further demonstrated that ferroptosis induced by chronic exposure becomes functionally irreversible, as ferroptosis inhibition by Ferrostatin-1 failed to rescue GPX4 expression, unlike prior acute exposure models.

PMID:40614423 | DOI:10.1016/j.jhazmat.2025.139049