Sex and the Developmental Environment Shape Molecular Networks Underlying Bronchial Responsiveness in Mice

Epidemiological evidence supports sex-specific prevalence patterns of respiratory disease, yet the molecular basis of these dimorphic patterns under normal physiological conditions remains poorly understood. Using an isogenic murine model, we assessed bronchial responsiveness to methacholine in male and female adult offspring, with and without maternal exposure to air pollution particulates. We confirmed that males exhibit significantly greater bronchial responsiveness than females, independent of maternal exposure. RNA sequencing of lung tissue, coupled with gene co-expression analysis, revealed differentially expressed genes and sex-specific gene network modules associated with this physiological dimorphism. Interestingly, although maternal exposure did not alter the physiological response, it did interact with sex to affect which gene modules are associated with bronchial responsiveness. These findings provide new insight into the molecular architecture of sex-based differences in lung function and highlight the importance of incorporating both sex and developmental context in respiratory research.