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Induction of Drug-Induced, Autoimmune Hepatitis in BALB/c Mice for the Study of Its Pathogenic Mechanisms
Published on: May 29, 2020
The toxicity of perfluorodecanoic acid is mainly manifested as a deflected immune function
Keming Li1,2, Qian Zhao1, Ziyan Fan3
1Department of Medical Microbiology, School of Basic Medical Science & Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
Background:
Perfluorodecanoic acid (PFDA) is a type of perfluoroalkyl acid (PFAA). PFDA has toxicity similar to dioxin; its effect on the body is not through a single target or a single pathway. However, the mechanism at the global level is still unclear.
Methods And Results:
We treated mice with PFDA and characterized the global changes in gene expression in the liver using microarray analyses. The enriched KEGG pathways and GO analyses revealed that PFDA greatly affected the immune response, which was different from the response of gastric cells previously studied. As a proof of principle, the expressions of IL-1β and IL-18 were both decreased after PFDA treatment, and qRT-PCR and ELISAs verified the reduction of IL-1β and IL-18 in liver tissues. Mechanistic investigations indicated that PFDA inhibited caspase-1 activation, and decreased the mRNA levels of NLRP1, NLRP3, and NLRC4; thus, suggesting that inflammasome assemblies were suppressed. Further microarray data revealed that cIAP2 and its binding proteins, which are critical for regulating inflammasome assembly, were also repressed by PFDA. In addition, flow cytometry results revealed a significant inhibition of Th1 cell differentiation in the livers of PFDA-treated mice.
Conclusions:
The results of this study suggested that one of the main toxic effects of PFDA on livers was the inhibition of immune response.
Insights
Perfluorodecanoic acid (PFDA) exposure suppresses immune responses in mouse livers. This study reveals PFDA inhibits inflammasome activation and Th1 cell differentiation, impacting overall immune function.
Area of Science:
- Toxicology
- Immunology
- Molecular Biology
Background:
- Perfluorodecanoic acid (PFDA) is a perfluoroalkyl acid (PFAA) with complex toxicity.
- The precise mechanisms underlying PFDA's global toxic effects remain largely unknown.
Purpose of the Study:
- To investigate the global gene expression changes in the liver following PFDA treatment in mice.
- To elucidate the molecular mechanisms by which PFDA exerts its toxic effects on the immune system.
Main Methods:
- Mice were treated with PFDA, and liver gene expression was analyzed using microarray.
- Quantitative reverse transcription PCR (qRT-PCR) and ELISAs were employed to validate gene and protein expression.
- Flow cytometry was used to assess immune cell differentiation.
Main Results:
- PFDA treatment significantly altered immune response pathways in the liver.
- PFDA inhibited caspase-1 activation and decreased mRNA levels of NLRP1, NLRP3, and NLRC4, suppressing inflammasome assembly.
- PFDA repressed cIAP2 and its binding proteins, and inhibited Th1 cell differentiation.
Conclusions:
- PFDA's toxic effects on the liver are significantly mediated by the inhibition of immune responses.
- PFDA disrupts key components of the innate and adaptive immune systems, including inflammasome pathways and T-cell differentiation.
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