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Volume 40 Issue 5
May  2024
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Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(5): 1003-1008

Mechanism of bis（2-ethylhexyl） phthalate in inducing cholestasis and liver injury in mice

DOI: 10.12449/JCH240521
  • 1.

    Department of Pharmacy，Anhui Medical University，Hefei 230032，China

  • 2.

    Department of Pharmacy，The First Affiliated Hospital of Anhui Medical University，Hefei 230012，China

  • 3.

    Anhui Public Health Clinical Center，Hefei 230012，China

Research funding:

National Natural Science Foundation of China (82073566);

The Program of Excellent Young Talents in Universities of Anhui Province (gxyq2019014);

Clinical Pharmacy and Pharmacology (2020);

Anhui Public Health Clinical Center Supported by North District Scientific Research and Cultivation Foundation of the First Affiliated Hospital of Anhui Medical University (2023YKJ14);

Anhui Public Health Clinical Center Supported by North District Scientific Research and Cultivation Foundation of the First Affiliated Hospital of Anhui Medical University (2023YKJ06);

Anhui Public Health Clinical Center Supported by North District Scientific Research and Cultivation Foundation of the First Affiliated Hospital of Anhui Medical University (2023YKJ11)

More Information
  • Corresponding author: WANG Jianqing， jianqingwang81@126.com （ORCID： 0000-0002-7935-9520）
  • Received Date: 2023-08-09
  • Accepted Date: 2023-09-11
  • Published Date: 2024-05-25
    Abstract
  •   Objective  To investigate the mechanism of bis（2-ethylhexyl） phthalate （DEHP） in inducing cholestasis and liver injury in mice.  Methods  In the in vivo experiment， adult female ICR mice were randomly divided into control group （corn oil） and DEHP group （200 mg/kg/d）， and a model of cholestasis was established by intragastric administration for 4 weeks. After blood and liver tissue samples were collected from all mice， a biochemical analyzer was used to measure the level of total bile acid （TBA） in serum and the liver， and a microplate reader was used to measure alkaline phosphatase （ALP） and gamma-glutamyl transpeptidase （GGT）； HE staining was used to observe the pathological changes of the liver； RT-PCR was used to measure the mRNA expression levels of the inflammatory factors interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α） in the liver； liquid chromatography/triple quadrupole mass spectrometry was used to measure the bile acid profile in the liver of mice. In the invitro experiment， AML-12 mouse hepatocytes were cultured and treated with DEHP （250 µmol/L）， DCA （125 µmol/L）， and CDCA （125 µmol/L） for 24 hours， and RT-PCR was used to measure the mRNA expression levels of the inflammatory cytokines IL-1β， IL-6， and TNF-α. The independent-samples t test was used for comparison of continuous data between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the LSD-t test was used for further comparison between two groups.  Results  The invivo experiment showed that compared with the control group， the DEHP group had significant increases in the serum levels of TBA， ALP， and GGT and the level of TBA in the liver （the t values are respectively -4.396， -5.109， -8.504， -3.792 and -7.974， all P<0.05，）. Compared with the control group， the DEHP group had significant increases in cholic acid， chenodeoxycholic acid， taurocholic acid， deoxycholic acid， and ursodeoxycholic acid （the t values are respectively -2.802， -3.177， -2.633， -2.874 and -2.311， all P<0.05）. HE staining of the liver showed that the mice in the DEHP group had enlargement of the portal area， bile duct deformation， inflammatory cell infiltration around the bile duct， and significant increases in the mRNA expression levels of the inflammatory factors IL-1β， IL-6， and TNF-α in the liver （the t values are respectively -2.539， -2.823 and -4.636， all P<0.05）. The invitro experiment showed that the actual difference in hepatocyte viability after 0-1 000 µmol/L DEHP treatment does not exceed 15%， but there were significant increases in the mRNA expression levels of the inflammatory cytokines IL-1β， IL-6， and TNF-α after treatment with DEHP at different concentrations of 125 µmol/L， 250 µmol/L， and 500 µmol/L （all P<0.05）. Compared with DEHP stimulation alone， the combined stimulation of CDCA and DEHP upregulates the cytokine in hepatocyte IL-1β mRNA levels （P<0.01）； the combined stimulation of DCA and DEHP can significantly increase the cytokine in hepatocyte IL-1β and IL-6 mRNA levels （all P<0.01）.  Conclusion  DEHP exposure can cause cholestasis and induce liver inflammation in mice， possibly by promoting the production of toxic bile acids and the secretion of inflammatory factors.

     

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