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Volume 40 Issue 10
Oct.  2024
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Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(10): 2062-2069

Protective effect of folic acid against cholestatic liver injury in mice caused by bis（2-ethylhexyl） phthalate exposure

DOI: 10.12449/JCH241021
  • 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);

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: 2024-01-26
  • Accepted Date: 2024-03-12
  • Published Date: 2024-10-25
    Abstract
  •   Objective  To investigate the protective effect of folic acid against cholestatic liver injury in mice induced by bis（2-ethylhexyl） phthalate （DEHP） exposure and its mechanism.  Methods  ICR mice were randomly divided into control group， high-dose folic acid （H-FA） group， DEHP group， DEHP+low-dose folic acid （DEHP+L-FA） group， and DEHP+high-dose folic acid （DEHP+H-FA） group， with 6 mice in each group. The mice in the H-FA group， the DEHP+L-FA group， and the DEHP+H-FA group were given folic acid by gavage at the corresponding dose， and those in the control group and the DEHP group were given an equal volume of PBS solution by gavage. After 2 hours， the mice in the DEHP group， the DEHP+L-FA group， and the DEHP+H-FA group were given corn oil containing 200 mg/kg DEHP， and those in the control group and the H-FA group were given an equal volume of pure corn oil， by gavage for 4 weeks. Body weight and food intake were recorded every day， and blood and liver tissue samples were collected. A biochemical analyzer was used to measure the serum levels of total bile acid （TBA） and alkaline phosphatase（ALP）； HE staining was used to observe the histopathological changes of liver tissue； kits were used to measure the content of malondialdehyde （MDA） and superoxide dismutase （SOD） in the liver； LC-MS/MS was used to measure serum bile acid profiles； Western blot was used to measure the expression levels of proteins associated with hepatic bile acid metabolism. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups.  Results  Compared with the control group， the daily food intake of the mice in the DEHP group decreased significantly， and the body weight decreased significantly from day 10 （P<0.05）， and compared with the DEHP group， the DEHP+L-FA group and the DEHP+H-FA group had basically unchanged body weight and daily food intake （P>0.05）. Compared with the control group， the DEHP group had significant increases in liver weight index and the serum levels of TBA and ALP （all P<0.05）， with enlarged portal area， bile duct deformity and hyperplasia， and a small amount of inflammatory cell infiltration in liver tissue； compared with the DEHP group， the DEHP+L-FA group and the DEHP+H-FA group had a significant reduction in liver weight index （P<0.01）， and the DEHP+H-FA group had significant reductions in the serum levels of TBA and ALP （P<0.05）， with a significant improvement in liver histomorphology and structure after folic acid intervention. Compared with the control group， the DEHP group had a significant reduction in the content of SOD （P<0.05） and a significant increase in the content of MDA in the liver （P<0.01）， and compared with the DEHP group， the DEHP+H-FA group had significant reductions in the content of MDA and SOD （P<0.05）. Compared with the control group， the DEHP group had significant increases in the serum levels of α-muricholic acid （α-MCA），β- muricholic acid （β-MCA），deoxycholic acid （DCA）， lithocholic acid （LCA）， taurocholic acid （TCA）， taurodeoxycholic acid （TDCA）， tauroursodeoxycholic acid （TUDCA）， tauro-β-muricholic acid （T-β-MCA）， tauro-α-muricholic acid （T-α-MCA）， taurohyodeoxycholic acid （THDCA）， and taurolithocholic acid （TLCA）（P<0.05） and a significant reduction in ursodeoxycholic acid （UDCA）（P<0.05）； compared with the DEHP group， the DEHP+H-FA group had significant reductions in the serum levels of DCA， LCA， TCA， TDCA， TUDCA， T-β-MCA， T-α-MCA， THDCA， and TLCA （P<0.05）. Compared with the control group， the DEHP group had significant increases in the protein expression levels of FXR and CYP3A11 in the liver （P<0.01） and significant reductions in the protein expression levels of CYP7A1 and MRP2 （P<0.01）； compared with the DEHP group， the DEHP+L-FA group and the DEHP+H-FA group had significant reductions in the protein expression levels of FXR and CYP3A11 in the liver （P<0.05） and a significant increase in the protein expression level of MRP2 （P<0.05）， and the DEHP+H-FA group had a significant increase in the protein expression level of CYP7A1 （P<0.05）.  Conclusion  Folic acid has a protective effect against cholestatic liver injury in mice induced by DEHP exposure， possibly by regulating bile acid synthesis， catabolism， and transport and maintaining bile acid homeostasis.

     

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