Early-life exposure to F-53B remodels the pulmonary immune microenvironment and enhances susceptibility to neutrophil-predominant asthma via dysregulation of arachidonic acid metabolism.

Abstract

The novel per- and polyfluoroalkyl substance (PFAS) alternative, 6:2 chlorinated polyfluorinated ether sulfonic acid (F-53B), has emerged as a major replacement for perfluorooctane sulfonate (PFOS) in China. Its widespread detection in the environment and human matrices, including umbilical cord blood, poses a potential public health threat. This study investigated how early-life F-53B exposure affects offspring lung development and asthma susceptibility using an ovalbumin (OVA)-sensitized mouse model. Pregnant dams were exposed to environmentally relevant concentrations of F-53B (0, 0.015, 0.15, and 1.5 mg/kg/day) in drinking water starting from gestation day 7. An OVA-induced asthma was initiated in the offspring mice at postnatal day 22. RNA sequencing and bioinformatics analysis were used to identify the potential targets and pathogenic mechanisms of F-53B. Our results demonstrated that early-life F-53B exposure not only directly impaired the pulmonary epithelial barrier and pulmonary surfactant homeostasis but also reprogrammed the lung immune microenvironment. Following a subsequent allergen challenge, this reprogramming induced a more severe asthma phenotype characterized by prominent neutrophilic infiltration. Transcriptomic analysis highlighted the upregulation of Alox12e and the downregulation of Hpgd, suggesting their potential roles in F-53B-induced asthma susceptibility and phenotype switching. Furthermore, pathways enrichment analysis revealed the activation of the arachidonic acid metabolism signaling pathway as a key driver of the altered asthma susceptibility. These findings provide crucial toxicological evidence for the risk assessment of F-53B and offer a scientific basis for developing public health protection strategies concerning childhood asthma.