Transcriptomic Characterization of Inhalation Phosphine Toxicity in Adult Male Sprague–Dawley Rats

• Published in: Chemical research in toxicology 2021-09, Vol.34 (9), p.2032-2044
• Main Authors: Hartog, Matthew A, Lewandowski, Rebecca J, Hofmann, Christopher S, Melber, Ashley A, Rothwell, Cristin C, Sherman, Katherine, Andres, Jaclynn, Tressler, Justin A, Sciuto, Alfred M, Wong, Benjamin, Hoard-Fruchey, Heidi M
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Animals; Antihypertensive Agents - pharmacology; Apelin - metabolism; Cardiomegaly - chemically induced; Cardiotonic Agents - pharmacology; Cardiotoxicity - genetics; Cardiotoxicity - metabolism; Heart - drug effects; Male; Pesticides - toxicity; Phosphines - administration & dosage; Phosphines - toxicity; Rats; Rats, Sprague-Dawley; Rodenticides - administration & dosage; Rodenticides - toxicity; Signal Transduction - drug effects; Transcriptome - drug effects
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/acs.chemrestox.1c00108

Phosphine (PH3) is a highly toxic, corrosive, flammable, heavier-than-air gas that is a commonly used fumigant. When used as a fumigant, PH3 can be released from compressed gas tanks or produced from commercially available metal phosphide tablets. Although the mechanism of toxicity is unclear, PH3 is thought to be a metabolic poison. PH3 exposure induces multiorgan toxicity, and no effective antidotes or therapeutics have been identified. Current medical treatment consists largely of supportive care and maintenance of cardiovascular function. To better characterize the mechanism(s) driving PH3-induced toxicity, we have performed transcriptomic analysis on conscious adult male Sprague–Dawley rats following whole-body inhalation exposure to phosphine gas at various concentration–time products. PH3 exposure induced concentration- and time-dependent changes in gene expression across multiple tissues. These gene expression changes were mapped to pathophysiological responses using molecular pathway analysis. Toxicity pathways indicative of cardiac dysfunction, cardiac arteriopathy, and cardiac enlargement were identified. These cardiotoxic responses were linked to apelin-mediated cardiomyocyte and cardiac fibroblast signaling pathways. Evaluation of gene expression changes in blood revealed alterations in pathways associated with the uptake, transport, and utilization of iron. Altered erythropoietin signaling was also observed in the blood. Upstream regulator analysis identified several therapeutics predicted to counteract PH3-induced gene expression changes. These include antihypertensive drugs (losartan, candesartan, and prazosin) and therapeutics to reduce pathological cardiac remodeling (curcumin and TIMP3). This transcriptomics study has characterized molecular pathways involved in PH3-induced cardiotoxicity. These data will aid in elucidating a precise mechanism of toxicity for PH3 and guide the development of effective medical countermeasures for PH3-induced toxicity.