Adverse health effects of humidifier disinfectants in Korea: toxic mechanism of polyhexamethylene guanidine phosphate

抄録

Polyhexamethylene guanidine phosphate (PHMG-p) was used as a disinfectant for the prevention of microorganism growth in humidifiers, without recognizing that a change of exposure route might cause significant health effects. Epidemiological and toxicological studies indicated that PHMG-p is strongly associated with interstitial lung diseases. Herein, we have outlined the cellular and molecular mechanisms underlying pulmonary fibrosis induced by PHMG-p. The leakage of zwitterionic liposomes, induced by PHMG-p, was more extensive than that of negative liposomes, indicating that PHMG-p adsorption onto lipid head groups via electrostatic interaction cannot fully explain the induced lipid membrane damage. Using PHMG-p-FITC conjugate, we identified that PHMG-p is rapidly located in the endoplasmic reticulum (ER) and causes ER-stress-mediated apoptosis. PHMG-p triggered G1/S arrest and apoptosis through p53 pathway in lung epithelial cells. We assumed that G1/S arrest induced by PHMG-p may precondition cells undergoing EMT, contributing to the expansion of fibroblasts. Epithelial cells at other phases may result in apoptosis. PHMG-p activated the Akt/β-catenin and Notch signaling pathways, resulting in increased ZEB2 expression. The interplay between these pathways induced EMT, resulting in PHMG-p-induced lung fibrogenesis.