PMID- 36306612
OWN - NLM
STAT- MEDLINE
DCOM- 20221122
LR  - 20221122
IS  - 1090-2414 (Electronic)
IS  - 0147-6513 (Linking)
VI  - 247
DP  - 2022 Dec 1
TI  - Intratracheal exposure to polyhexamethylene guanidine phosphate disrupts 
      coordinate regulation of FXR-SHP-mediated cholesterol and bile acid homeostasis 
      in mouse liver.
PG  - 114213
LID - S0147-6513(22)01053-3 [pii]
LID - 10.1016/j.ecoenv.2022.114213 [doi]
AB  - 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.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Choi, You-Jin
AU  - Choi YJ
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea.
FAU - Yang, Hyo-Seon
AU  - Yang HS
AD  - Inhalation Toxicology Center for Airborne Risk Factors, Korea Institute of 
      Toxicology, Jeongeup, Republic of Korea; College of Veterinary Medicine, Jeonbuk 
      University, Iksan, Republic of Korea.
FAU - Zhang, Yunfan
AU  - Zhang Y
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea.
FAU - Lee, Wonseok
AU  - Lee W
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea.
FAU - Yun, Sung Ho
AU  - Yun SH
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea.
FAU - Nam, Yoon Ah
AU  - Nam YA
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea.
FAU - Lee, Gakyung
AU  - Lee G
AD  - Department of Integrative Biological Sciences and Industry, Sejong University, 
      Seoul, Republic of Korea; Center for Advanced Biomolecular Recognition, Korea 
      Institute of Science and Technology (KIST), Seoul, Republic of Korea.
FAU - Jung, Byung Hwa
AU  - Jung BH
AD  - Center for Advanced Biomolecular Recognition, Korea Institute of Science and 
      Technology (KIST), Seoul, Republic of Korea; Division of Bio-Medical Science and 
      Technology, KIST School, Korea University of Science and Technology (UST), Seoul, 
      Republic of Korea.
FAU - Chang, Tong-Shin
AU  - Chang TS
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea.
FAU - Lee, Kyuhong
AU  - Lee K
AD  - Inhalation Toxicology Center for Airborne Risk Factors, Korea Institute of 
      Toxicology, Jeongeup, Republic of Korea; Human and Environmental Toxicology, 
      University of Science and Technology, Daejeon, Republic of Korea. Electronic 
      address: khleekit@gmail.com.
FAU - Lee, Byung-Hoon
AU  - Lee BH
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea. Electronic address: lee@snu.ac.kr.
LA  - eng
PT  - Journal Article
DEP - 20221025
PL  - Netherlands
TA  - Ecotoxicol Environ Saf
JT  - Ecotoxicology and environmental safety
JID - 7805381
RN  - 0 (Bile Acids and Salts)
RN  - 31961-54-3 (polyhexamethyleneguanidine)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Bile Acids and Salts/metabolism
MH  - *Cholesterol/metabolism
MH  - Liver/metabolism
MH  - Homeostasis
OTO - NOTNLM
OT  - Bile acid homeostasis
OT  - Cholesterol synthesis
OT  - Distant-organ effect
OT  - Farnesoid X receptor (FXR)
OT  - Polyhexamethylene guanidine phosphate (PHMG)
OT  - Small heterodimer partner (SHP)
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2022/10/29 06:00
MHDA- 2022/11/23 06:00
CRDT- 2022/10/28 18:19
PHST- 2022/07/27 00:00 [received]
PHST- 2022/10/14 00:00 [revised]
PHST- 2022/10/18 00:00 [accepted]
PHST- 2022/10/29 06:00 [pubmed]
PHST- 2022/11/23 06:00 [medline]
PHST- 2022/10/28 18:19 [entrez]
AID - S0147-6513(22)01053-3 [pii]
AID - 10.1016/j.ecoenv.2022.114213 [doi]
PST - ppublish
SO  - Ecotoxicol Environ Saf. 2022 Dec 1;247:114213. doi: 10.1016/j.ecoenv.2022.114213. 
      Epub 2022 Oct 25.