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The effects of BDE-99 on the gene expression of MCP-1, IFN-γ, NF-κB and the metabolising enzyme CYP3A, during coxsackievirus B3 infection
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. (Infektionssjukdomar)
Livsmedelsverket. (Toxikologiska enheten)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. (Infektionssjukdomar)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

It has been shown that coxsackievirus B3 (CVB3), a common virus with a similar disease development in mice and humans, affects CYP-enzymes and the metabolism of environmental pollutants, such as 2,2’,4,4’,5-penta-BDE (BDE-99). The transcription factor nuclear factor-κB (NF-κB) regulates several genes, including the proinflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) and the cytokine interferon-γ (IFN-γ). These immune mediators are produced during infection and are involved in the antiviral defence as well as in the regulation of genes for CYP enzyme synthesis. The aim of the study was to investigate how interactions between infection and concomitant BDE-99 exposure affects virus levels, gene expression of MCP-1, IFN-γ, NF-κB, CYP3A11 and subsequent CYP3A enzyme activity. Female Balb/c mice were infected with CVB3 on day 0, orally exposed to BDE-99 (20 mg/kg bw) on day 1 and put to death on day 3. The gene expression of MCP-1, IFN-γ, NF-κB, CYP3A11 and the levels of CVB3 were measured with RT-PCR in the liver. The present study suggests that CYP3A is involved in the metabolism of PBDE. In general, infection decreased the expression and CYP3A enzyme activity, increased the gene expression of MCP-1 and NF-κB, but did not affect gene expression of IFN-γ. BDE-99 exposure in non-infected mice increased CYP3A enzyme activity but not the gene expression of MCP-1, IFN-γ, NF-κB and CYP3A11. Although, CVB3 induced gene expression of NF-κB and of MCP-1, as well as concomitant down-regulation of CYP3A11 gene expression and enzyme activity, no clear interaction effects had yet developed at this early stage of disease.

National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-108848OAI: oai:DiVA.org:uu-108848DiVA: diva2:240983
Available from: 2009-09-30 Created: 2009-09-30 Last updated: 2010-01-14
In thesis
1. Coxsackievirus B3 Infection and Host Defence Responses Change the Metabolism of PBDE
Open this publication in new window or tab >>Coxsackievirus B3 Infection and Host Defence Responses Change the Metabolism of PBDE
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

It has been suggested that the rising amounts of chemicals in the environment may affect host resistance and increase susceptibility to infections. Studies have also shown that infections can change the toxicity of pollutants. The aim of this thesis was to study interactions between environmental pollutant exposure in terms of polybrominated diphenyl ethers (PBDE) and a common human coxsackievirus B3 (CVB3) infection adapted to Balb/c mice. The studies focused on virus levels, cytokines, metabolising cytochrome P450 (CYP) enzymes and tissue distribution of PBDE.

A novel finding was an organ-specific effect of CVB3 infection on the metabolising capacity of PBDE. The PBDE metabolising enzyme CYP2B10 was down-regulated by the CVB3 infection in the liver, up-regulated in the lungs, but not affected in the pancreas. Accordingly, CVB3 infection increased the concentration of PBDE in the livers of infected mice. However, serum levels of PBDE were not affected by the infection, indicating that serum does not reflect the actual organ exposure of PBDE in infected individuals. The change in metabolising capacity was likely mediated by infection-induced cytokines and associated effects on the nuclear factor-κB (NF-κB) pathway.

PBDE drastically decreased serum levels of several cytokines and chemokines, an event that may create a slot for viruses to replicate. Accordingly, some results show that infected mice exposed to a high dose of PBDE had higher virus levels than mice exposed to a low dose.

In conclusion, infected individuals showed organ-specific changes in metabolism and tissue levels of PBDE, which potentially could change the toxicity of PBDE. PBDE also seems to affect the fate of the infection. NF-κB activated pathways may mediate one possible mechanism underlying these effects. Thus, further investigations of this pathway are warranted. In addition, future studies should address how PBDE exposure affects viral replication.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 487
Keyword
Coxsackievirus, environmental pollutants, PBDE, cytokines, chemokines, metabolism, infection, tissue distribution, toxicology, virology, immunology
National Category
Pharmacology and Toxicology Microbiology in the medical area
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-108849 (URN)978-91-554-7619-9 (ISBN)
Public defence
2009-11-13, Universitetshuset, sal IV, Universitetsparken, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2009-10-27 Created: 2009-09-30 Last updated: 2009-10-27Bibliographically approved

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