PMID- 35019730
OWN - NLM
STAT- MEDLINE
DCOM- 20220316
LR  - 20220316
IS  - 1552-9924 (Electronic)
IS  - 0091-6765 (Print)
IS  - 0091-6765 (Linking)
VI  - 130
IP  - 1
DP  - 2022 Jan
TI  - Role of Hepatocyte- and Macrophage-Specific PPARgamma in Hepatotoxicity Induced by 
      Diethylhexyl Phthalate in Mice.
PG  - 17005
LID - 10.1289/EHP9373 [doi]
LID - 017005
AB  - BACKGROUND: Phthalates may disturb metabolic homeostasis in the liver by 
      interfering with the peroxisome proliferator-activated receptors (PPARs). 
      However, the role of hepatic macrophages in the lipid metabolic dysregulation 
      induced by diethylhexyl phthalate (DEHP) remains unclear. OBJECTIVES: We aimed to 
      evaluate the respective role of hepatocyte- and macrophage-specific PPARgamma in the 
      hepatotoxicity induced by DEHP. METHODS: Wild-type (WT), hepatocyte-specific 
      PPARgamma knockout (Hep-KO), and macrophage-specific PPAR knockout (Mac-KO) mice were 
      administered DEHP (625 mg/kg body weight) by daily gavage for 28 d, followed by 
      hepatotoxicity examination and macrophage analysis. RNA sequencing and lipid 
      metabolomic analysis were used to characterize the molecular changes in mouse 
      liver. Mouse bone marrow-derived macrophages (BMDMs) and human monocytic THP-1 
      cell-derived macrophages were used to investigate the mechanistic regulation of 
      macrophages' polarization by DEHP and mono(2-ethylhexyl) phthalate (MEHP). 
      RESULTS: The levels of hepatic steatosis and triglyceride were significantly 
      higher in the mice treated with DEHP compared with the control mice in the WT and 
      Hep-KO model. Lipid accumulation induced by DEHP was notably attenuated in the 
      Mac-KO mice, but M2-polarization of hepatic macrophages in the Mac-KO mice was 
      significantly higher compared with the WT mice under DEHP treatment. The 
      M2-polarization of BMDMs and human macrophages was suppressed by DEHP and MEHP. 
      Transcriptomic and lipidomic data suggested lower levels of lipid biosynthesis, 
      fatty acid oxidation, and oxidative phosphorylation in the Mac-KO mice compared 
      with the WT and Hep-KO mice under DEHP treatment. CONCLUSIONS: Our data suggested 
      that the orchestrated activation of PPARalpha and PPARgamma by MEHP may reprogram hepatic 
      macrophages' polarization, thereby affecting lipid homeostasis in the mouse 
      liver. Although this conclusion was based on studies conducted in mice and in 
      vitro, these findings may aid in elucidating the health effect of environmental 
      phthalate exposure. https://doi.org/10.1289/EHP9373.
FAU - Xu, Miao
AU  - Xu M
AD  - National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, 
      Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National 
      Center for Food Safety Risk Assessment, Beijing, China.
AD  - West China School of Public Health, Sichuan University, Chengdu, China.
FAU - Li, Yongning
AU  - Li Y
AUID- ORCID: 0000-0002-1099-2782
AD  - National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, 
      Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National 
      Center for Food Safety Risk Assessment, Beijing, China.
FAU - Wang, Xiaohong
AU  - Wang X
AD  - National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, 
      Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National 
      Center for Food Safety Risk Assessment, Beijing, China.
FAU - Zhang, Qiannan
AU  - Zhang Q
AD  - National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, 
      Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National 
      Center for Food Safety Risk Assessment, Beijing, China.
FAU - Wang, Lei
AU  - Wang L
AUID- ORCID: 0000-0001-8810-5197
AD  - Affiliated Hospital of Jining Medical University, Jining, China.
FAU - Zhang, Xin
AU  - Zhang X
AD  - National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, 
      Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National 
      Center for Food Safety Risk Assessment, Beijing, China.
FAU - Cui, Wenming
AU  - Cui W
AD  - National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, 
      Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National 
      Center for Food Safety Risk Assessment, Beijing, China.
FAU - Han, Xiaomin
AU  - Han X
AD  - National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, 
      Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National 
      Center for Food Safety Risk Assessment, Beijing, China.
FAU - Ma, Ning
AU  - Ma N
AD  - National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, 
      Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National 
      Center for Food Safety Risk Assessment, Beijing, China.
FAU - Li, Haishan
AU  - Li H
AD  - Institute of Chemicals Safety, Chinese Academy of Inspection and Quarantine, 
      Beijing, China.
FAU - Fang, Hongyun
AU  - Fang H
AD  - National Institute for Nutrition and Health, Chinese Center for Disease Control 
      and Prevention, Beijing, China.
FAU - Tang, Song
AU  - Tang S
AD  - China CDC Key Laboratory of Environment and Population Health, National Institute 
      of Environmental Health, Chinese Center for Disease Control and Prevention, 
      Beijing, China.
AD  - Center for Global Health, School of Public Health, Nanjing Medical University, 
      Nanjing, Jiangsu, China.
FAU - Li, Jingguang
AU  - Li J
AD  - National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, 
      Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National 
      Center for Food Safety Risk Assessment, Beijing, China.
FAU - Liu, Zhaoping
AU  - Liu Z
AD  - National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, 
      Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National 
      Center for Food Safety Risk Assessment, Beijing, China.
FAU - Yang, Hui
AU  - Yang H
AUID- ORCID: 0000-0002-6025-338X
AD  - National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, 
      Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National 
      Center for Food Safety Risk Assessment, Beijing, China.
FAU - Jia, Xudong
AU  - Jia X
AD  - National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, 
      Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National 
      Center for Food Safety Risk Assessment, Beijing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220112
PL  - United States
TA  - Environ Health Perspect
JT  - Environmental health perspectives
JID - 0330411
RN  - C42K0PH13C (Diethylhexyl Phthalate)
SB  - IM
MH  - Animals
MH  - *Chemical and Drug Induced Liver Injury
MH  - *Diethylhexyl Phthalate/toxicity
MH  - Hepatocytes
MH  - Macrophages
MH  - Mice
PMC - PMC8754100
EDAT- 2022/01/13 06:00
MHDA- 2022/03/17 06:00
PMCR- 2022/01/12
CRDT- 2022/01/12 12:19
PHST- 2022/01/12 12:19 [entrez]
PHST- 2022/01/13 06:00 [pubmed]
PHST- 2022/03/17 06:00 [medline]
PHST- 2022/01/12 00:00 [pmc-release]
AID - EHP9373 [pii]
AID - 10.1289/EHP9373 [doi]
PST - ppublish
SO  - Environ Health Perspect. 2022 Jan;130(1):17005. doi: 10.1289/EHP9373. Epub 2022 
      Jan 12.