Choi, You-Jin Yang, Hyo-Seon Zhang, Yunfan Lee, Wonseok Yun, Sung Ho Nam, Yoon Ah Lee, Gakyung Jung, Byung Hwa Chang, Tong-Shin Lee, Kyuhong Lee, Byung-Hoon 2024-01-19T10:32:49Z 2024-01-19T10:32:49Z 2022-12-22 2022-12 0147-6513 https://pubs.kist.re.kr/handle/201004/114232 A public health crisis in the form of a significant incidence of fatal pulmonary disease caused by repeated use of humidifier disinfectants containing polyhexamethylene guanidine phosphate (PHMG) recently arose in Korea. Although the mechanisms of pulmonary fibrosis following respiratory exposure to PHMG are well described, distant-organ effect has not been reported. In this study, we investigated whether intratracheal administration of PHMG affects liver pathophysiology and metabolism. Our PHMG mouse model showed a significant decrease in liver cholesterol level. An mRNA-seq analysis of liver samples revealed an alteration in the gene expression associated with cholesterol biosynthesis and metabolism to bile acids. The expression of genes involved in cholesterol synthesis was decreased in a real-time PCR analysis. To our surprise, we found that the coordinate regulation of cholesterol and bile acid homeostasis was completely disrupted. Despite the decreased cholesterol synthesis and low bile acid levels, the farnesoid X receptor/small heterodimer partner pathway, which controls negative feedback of bile acid synthesis, was activated in PHMG mice. As a consequence, gene expression of Cyp7a1 and Cyp7b1, the rate-limiting enzymes of the classical and alternative pathways of bile acid synthesis, was significantly downregulated. Notably, the changes in gene expression were corroborated by the hepatic concentrations of the bile acids. These results suggest that respiratory exposure to PHMG could cause cholestatic liver injury by disrupting the physiological regulation of hepatic cholesterol and bile acid homeostasis. English Academic Press Intratracheal exposure to polyhexamethylene guanidine phosphate disrupts coordinate regulation of FXR-SHP-mediated cholesterol and bile acid homeostasis in mouse liver Article 10.1016/j.ecoenv.2022.114213 1 Ecotoxicology and Environmental Safety, v.247 Ecotoxicology and Environmental Safety 247 Y scie scopus 000891793300002 2-s2.0-85140309264 Environmental Sciences Toxicology Environmental Sciences & Ecology Toxicology Article NUCLEAR RECEPTOR SHP HUMIDIFIER DISINFECTANT LUNG INFLAMMATION FIBROSIS METABOLISM PATHWAYS KIDNEY Polyhexamethylene guanidine phosphate (PHMG) Distant -organ effect Cholesterol synthesis Bile acid homeostasis Farnesoid X receptor (FXR) Small heterodimer partner (SHP)