Functional disorder of primary immunity responding to respiratory syncytial virus infection in offspring mice exposed to a flame retardant, decabrominated diphenyl ether, perinatally.

Perinatal exposure to a representative flame retardant, decabrominated diphenyl ether (DBDE), was shown previously to increase viral titers in the lungs of respiratory syncytial virus (RSV)-infected offspring on day 5 post-infection, resulting in exacerbation of pneumonia. In this study, the significant increase of pulmonary viral titers was confirmed even on day 1 post-infection and the effect on the primary immune response to RSV infection were examined to assess a mode of DBDE action on developmental immunotoxicity. On day 1 after infection, the secretion of both TNF-alpha and IL-6 decreased significantly in the bronchoalveolar lavage fluid prepared from RSV-infected offspring exposed to DBDE perinatally, but IL-1beta increased. However, in ex vivo lipopolysaccharide stimulation test, the productivity of TNF-alpha in the bronchoalveolar lavage cells, which are mainly primary immune cells responding to RSV infection, prepared from offspring mice exposed to DBDE perinatally was not lower than that in the control. The primary immune cells retained normally the ability of cytokine production after the DBDE exposure. Gene expressions of innate pattern recognition receptors (Toll-like receptor 3 and 4, melanoma differentiation-associated gene-5, and retinoic acid-inducible gene I) in lung tissues were not affected by DBDE exposure. Because the levels of TNF-alpha, IL-6, and IL-1beta are known to be elevated in the lungs of RSV-infected mice, these irregular productions due to perinatal DBDE exposure indicate a disorder of the primary immune response to RSV infection. Thus, perinatal exposure to DBDE was suggested to cause a functional disorder of primary immunity responding to RSV infection.

Effects of tetrabromobisphenol A, a brominated flame retardant, on the immune response to respiratory syncytial virus infection in mice.

Effects of the brominated flame retardants (BFRs), decabrominated diphenyl ether (DBDE), hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA), on host immunity of mice were evaluated using respiratory syncytial virus (RSV) infection. Five-week-old female mice were fed a diet containing 1% BFRs for 28days, and subsequently infected with RSV. No toxicological sign was observed in BFR-treated mice before infection. TBBPA significantly increased the pulmonary viral titer in the infected mice on day 5 post-infection, but DBDE and HBCD did not. Slight histological changes were observed in lung tissues of TBBPA-treated mice with mock infection. These changes due to TBBPA were much exacerbated by RSV infection. Cytokine analysis of bronchoalveolar lavage fluid (BALF) from RSV-infected mice treated with or without TBBPA revealed that TBBPA significantly increased the levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and interferon (IFN)-gamma at each time point after virus infection, but no change was observed for IL-1beta and IL-12. The levels of IL-4 and IL-10, Th2 cytokines, significantly decreased. Thus, TBBPA caused unusual production of the various cytokines in RSV-infected mice. Flow cytometry revealed that the percentage of double-positive CD4+CD8+ cells, immature T lymphocytes, in the cell populations in BALF from RSV-infected mice increased due to TBBPA treatment. The change was not observed in spleen cells of TBBPA-treated mice. The response to RSV infection verified that TBBPA treatment affected the host immunity of mice. Irregular changes in cytokine production and immune cell populations due to TBBPA treatment were suggested to cause exacerbation of pneumonia in RSV-infected mice.

Anti-influenza virus activity of propolis in vitro and its efficacy against influenza infection in mice.

BACKGROUND: Propolis has been used worldwide as a dietary supplement to maintain and improve human health. We examined whether ethanol extracts of Brazilian propolis exhibit antiviral activity against influenza virus in vitro and in vivo. METHODS: Among 13 ethanol extracts screened in a plaque reduction assay, four showed anti-influenza virus activity. The anti-influenza efficacy of the four extracts was further examined in a murine influenza virus infection model. The mice were infected intranasally with influenza virus, and the four extracts were orally administered at 10 mg/kg three times daily for seven successive days after infection. RESULTS: In this infection model, only one extract, AF-08, was significantly effective at 10 mg/kg in reducing the body weight loss of infected mice. The doses of 2 and 10 mg/kg were also effective in prolonging the survival times of infected mice significantly, but 0.4 mg/kg was not. The anti-influenza efficacy of AF-08 at 10 mg/kg was confirmed in a dose-dependent manner in mice. AF-08 at 10 mg/kg significantly reduced virus yields in the bronchoalveolar lavage fluids of lungs in infected mice as compared with the control. The reduction of virus yields by AF-08 at 10 mg/kg significantly corresponded to those induced by oseltamivir at 1 mg/kg twice daily from day 1 to day 4 after infection. CONCLUSION: The Brazilian propolis AF-08 was indicated to possess anti-influenza virus activity and to ameliorate influenza symptoms in mice. AF-08 may be a possible candidate for an anti-influenza dietary supplement for humans.

A new assay system for evaluation of developmental immunotoxicity of chemical compounds using respiratory syncytial virus infection to offspring mice.

We evaluated the effect of 6-propyl-2-thiouracil (PTU), an anti-thyroid agent, on developmental immunity using respiratory syncytial virus (RSV) infection to offspring mice as a new risk assessment for brominated flame retardants (BFRs), because some BFRs are suspected of affecting the thyroid system. Pregnant mice were exposed to PTU in drinking water from gestation day 10 to weaning on postnatal day 21. Their offspring mice were infected intranasally with RSV. Exposure of 100ppm PTU significantly increased virus titers in the lungs of RSV-infected offspring compared with the control, and the 10ppm also elevated levels of interferon-γ, a marker of pneumonia, in the bronchoalveolar lavage fluids of offspring. Histopathological analysis revealed that PTU-exposure exacerbated pneumonia in RSV-infected offspring. Thus, exacerbation of RSV infection suggested PTU-exposure of dams elicited developmental immune disorder in the offspring. The murine RSV infection model may be useful to evaluate the developmental immunotoxicity of BFRs.

Effects of decabrominated diphenyl ether (DBDE) on developmental immunotoxicity in offspring mice.

Decabrominated diphenyl ether (DBDE), a representative brominated flame retardant ubiquitous in the environment, is suspected of being hazardous to humans. We evaluated the developmental immunotoxicity of DBDE by an assay system using respiratory syncytial virus (RSV) infection in offspring mice. Pregnant mice were continuously exposed to DBDE (10, 100, 1000, or 10,000ppm) in the diet from gestation day 10 to weaning on postnatal day 21. Offspring mice born to these dams were intranasally infected with RSV. Virus titers in the lungs of RSV-infected offspring exposed perinatally to DBDE increased dose-dependently compared with the control. The level of interferon-γ in the bronchoalveolar lavage fluids and gene expression of the chemokine RANTES in the lungs were also significantly elevated in offspring mice exposed to DBDE. Histopathological analysis revealed that pneumonia in the lungs of offspring mice exposed to 10,000ppm of DBDE was exacerbated compared with the control. These results indicate that DBDE is a developmental immunotoxic agent.