Bisphenol A (BPA) is a high–production volume chemical classified as an environmental estrogen and used primarily in the plastics industry. BPA’s increased usage correlates with rising BPA levels in people and a corresponding increase in the incidence of asthma. Due to limited studies, the contribution of maternal BPA exposure to allergic asthma pathogenesis is unclear. Using two established mouse models of allergic asthma, we examined whether developmental exposure to BPA alters hallmarks of allergic lung inflammation in adult offspring. Pregnant C57BL/6 dams were gavaged with 0, 0.5, 5, 50, or 500 μg BPA/kg/day from gestational day 6 until postnatal day 21. To induce allergic inflammation, adult offspring were mucosally sensitized with inhaled ovalbumin containing low-dose lipopolysaccharide or ip sensitized using ovalbumin with alum followed by ovalbumin aerosol challenge. In the mucosal sensitization model, female offspring that were maternally exposed to ≥ 50 μg BPA/kg/day displayed enhanced airway lymphocytic and lung inflammation, compared with offspring of control dams. Peritoneally sensitized, female offspring exposed to ≤ 50 μg BPA/kg/day presented dampened lung eosinophilia, compared with vehicle controls. Male offspring did not exhibit these differences in either sensitization model. Our data demonstrate that maternal exposure to BPA has subtle and qualitatively different effects on allergic inflammation, which are critically dependent upon route of allergen sensitization and sex. However, these subtle, yet persistent changes due to developmental exposure to BPA did not lead to significant differences in overall airway responsiveness, suggesting that early life exposure to BPA does not exacerbate allergic inflammation into adulthood.

The response of CD8⁺ T cells to influenza virus is very sensitive to modulation by aryl hydrocarbon receptor (AhR) agonists; however, the mechanism underlying AhR-mediated alterations in CD8⁺ T cell function remains unclear. Moreover, very little is known regarding how AhR activation affects anamnestic CD8⁺ T cell responses. In this study, we analyzed how AhR activation by the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the in vivo distribution and frequency of CD8⁺ T cells specific for three different influenza A virus epitopes during and after the resolution of a primary infection. We then determined the effects of TCDD on the expansion of virus-specific memory CD8⁺ T cells during recall challenge. Adoptive transfer of AhR-null CD8⁺ T cells into congenic AhR^+/+ recipients, and the generation of CD45.2AhR^−/−→CD45.1AhR^+/+ chimeric mice demonstrate that AhR-regulated events within hemopoietic cells, but not directly within CD8⁺ T cells, underlie suppressed expansion of virus-specific CD8⁺ T cells during primary infection. Using a dual-adoptive transfer approach, we directly compared the responsiveness of virus-specific memory CD8⁺ T cells created in the presence or absence of TCDD, which revealed that despite profound suppression of the primary response to influenza virus, the recall response of virus-specific CD8⁺ T cells that form in the presence of TCDD is only mildly impaired. Thus, the delayed kinetics of the recall response in TCDD-treated mice reflects the fact that there are fewer memory cells at the time of reinfection rather than an inherent defect in the responsive capacity of virus-specific memory CD8⁺ cells.

It has long been known that activation of the aryl hydrocarbon receptor (AhR) by ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses T cell–dependent immune responses; however, the underlying cellular targets and mechanism remain unclear. We have previously shown that AhR activation by TCDD reduces the proliferation and differentiation of influenza virus–specific CD8⁺ T cells through an indirect mechanism; suggesting that accessory cells are critical AhR targets during infection. Respiratory dendritic cells (DCs) capture antigen, migrate to lymph nodes, and play a key role in activating naive CD8⁺ T cells during respiratory virus infection. Herein, we report an examination of how AhR activation alters DCs in the lung and affects their trafficking to and function in the mediastinal lymph nodes (MLN) during infection with influenza virus. We show that AhR activation impairs lung DC migration and reduces the ability of DCs isolated from the MLN to activate naive CD8⁺ T cells. Using novel AhR mutant mice, in which the AhR protein lacks its DNA-binding domain, we show that the suppressive effects of TCDD require that the activated AhR complex binds to DNA. These new findings suggest that AhR activation by chemicals from our environment impacts DC function to stimulate naive CD8⁺ T cells and that immunoregulatory genes within DCs are critical targets of AhR. Moreover, our results reinforce the idea that environmental signals and AhR ligands may contribute to differential susceptibilities and responses to respiratory infection.