Maternal Exposure of BALB/c Mice to Indoor NO2 and Allergic Asthma Syndrome in Offspring at Adulthood with Evaluation of DNA Methylation Associated Th2 Polarization

Fetal stress has been proposed to be associated with diseases in both children and adults. Epidemiological studies suggest that maternal exposure to nitrogen dioxide (NO2) contributes to increased morbidity and mortality of offspring with allergic asthma later in life. Objectives: We aimed to test whether maternal NO2 exposure causes allergic asthma-related consequences in offspring absent any subsequent lung provocation and whether this exposure enhances the likelihood of developing allergic asthma or the intensity of developed allergic airway disease following postnatal allergic sensitization and challenge. In addition, if such consequences and enhancements occurred, we sought to determine the mechanism(s) of these responses.

Maternal exposure to indoor environmental NO2 causes allergic asthma-related consequences in offspring absent any subsequent lung provocation and potentiates the symptoms of allergic asthma in adult offspring following postnatal allergic sensitization and challenge; this response is associated with the Th2-based immune response and DNA methylation of the IL4 gene. https://doi.org/10.1289/EHP685.

Pregnant BALB/c mice were exposed to either NO2 (2.5 ppm, 5 h/day) or air daily throughout the gestation period. Offspring were sacrificed on postnatal days (PNDs) 1, 7, 14, 21, and 42, and remaining offspring were sensitized by ovalbumin (OVA) injection followed by OVA aerosol challenge during postnatal wk 7-9. We analyzed the lung histopathology, inflammatory cell infiltration, airway hyper-responsiveness (AHR), immune responses, and gene methylation under different treatment conditions.

Maternal exposure to NO2 caused a striking increase in inflammatory cell infiltration and the release of type 2 cytokines in the lungs of offspring at PNDs 1 and 7; however, these alterations were reversed during postnatal development. Following OVA sensitization and challenge, the exposure enhanced the levels of allergic asthma-characterized OVA-immunoglobulin (Ig) E, AHR, and airway inflammation in adult offspring. Importantly, differentiation of T-helper (Th) 2 cells and demethylation of the interleukin-4 (IL4) gene occurred during the process. Conclusions: Maternal exposure to indoor environmental NO2 causes allergic asthma-related consequences in offspring absent any subsequent lung provocation and potentiates the symptoms of allergic asthma in adult offspring following postnatal allergic sensitization and challenge; this response is associated with the Th2-based immune response and DNA methylation of the IL4 gene. https://doi.org/10.1289/EHP685.