Sex-specific in utero reprogramming of lung immunity

Abstract

Lung mucosal immunity must balance effective antimicrobial defense with tightly controlled inflammatory responses to maintain pulmonary homeostasis. Although sex differences in respiratory disease susceptibility are well documented, the developmental origins of these differences and their modulation by prenatal environmental exposures remain poorly defined. Here, we tested the hypothesis that prenatal benzene exposure establishes sex-specific reprogramming of lung mucosal immunity during fetal development. Using a controlled inhalation exposure model in pregnant C57BL/6 mice, we characterized immune responses in fetal and postnatal lungs under baseline conditions and following viral challenge. We found that female offspring displayed heightened type I interferon signaling and enhanced viral clearance, accompanied by exaggerated inflammatory pathology and altered expressions of DREAM and A20. In contrast, male offspring exhibited augmented proinflammatory cytokine production following lipopolysaccharide challenge. Alveolar macrophages from prenatally benzene exposed offspring demonstrated persistent inflammatory priming, indicating durable alteration of innate immune populations. These findings demonstrate that lung mucosal immune development is intrinsically sex-dependent and that prenatal environmental pollutants interact with fetal sex to durably reprogram respiratory immunity. Together, our results identify in utero environmental exposure as a critical determinant of sex-specific mucosal immune trajectories that shape postnatal responses to infection.