Pulmonary Injury, Functional Impairment, and Transcriptomic Responses Following Phosphine Inhalation in Mice: Implications for Therapeutic Development

Abstract

Phosphine (PH₃) is a highly lethal gas that is widely used as an agricultural fumigant. Human exposure occurs through inhalation of accidentally released gas or phosphide-containing pesticides. Its high lethality, combined with its ready accessibility, makes it a chemical threat agent. Although its toxic mechanism remains unclear, PH₃ is known to induce oxidative stress, leading to cell death. With no available antidote, this study examines the pulmonary effects of acute PH₃ inhalation exposure in order to support future treatment strategies and identifies key biological pathways affected in the lungs and hearts. Female mice were exposed acutely to one of three PH₃ doses in a dynamic whole-body exposure chamber. Following exposure, respiratory function, total protein levels in bronchoalveolar lavage fluid (BALF), and lung pathology were evaluated. Bulk RNA sequencing of PH₃-exposed lungs and hearts was performed, and differentially expressed genes (DEGs) in tissues from exposed versus nonexposed mice were analyzed. Animals exposed to high PH₃ doses experienced a significant decrease in respiratory rate and had to be euthanized within 5 h postexposure. There was a significant increase in total protein and cell counts in BALF of PH₃-exposed mice at the medium and high doses, and histopathological evaluation of lungs showed foci of hypercellularity and scattered vessels filled with platelet aggregates and neutrophils, indicative of early pulmonary thrombi formation. Gene expression analysis revealed upregulation of genes involved in protein synthesis, inflammation, cell cycle, and apoptosis. The MAPK, IL-17, and atherosclerosis pathways were among the most impacted pathways in lung and heart tissues. Fos, Fosb, Jun, and Junb were significantly upregulated following exposure; all of them are components of the AP-1 protein complex, a potentially key element in inducing injuries subsequent to PH₃ exposure and therefore a promising therapeutic target.