Adrenal injury induced by real-ambient PM2.5: Mechanisms of disrupted Shh/Wnt signaling crosstalk

Fine particulate matter (PM_2.5) exposure is known to induce systemic endocrine disruption, yet the specific mechanisms underlying adrenal injury remain elusive. This study investigates the hypothesis that PM_2.5 impairs adrenal homeostasis by disrupting key paracrine signaling pathways, Sonic hedgehog (Shh) and Wnt/β-catenin, which are vital for adrenal cortical differentiation and function. Utilizing a novel real-ambient exposure system that closely mimics human inhalation exposure, as opposed to traditional instillation models, we assessed the pathological and endocrine-disrupting effects of PM_2.5 on murine adrenal glands. Our results demonstrate that PM_2.5 exposure triggered hypothalamic-pituitary-adrenal (HPA) axis activation and caused significant adrenal structural damage, including cortical architecture disruption and enhanced inflammation. Crucially, we found that these effects were associated with the dysregulation of both Shh and Wnt signaling pathways. The data suggest that PM_2.5 may hinder adrenal self-renewal and repair by impairing these critical pathways. Collectively, our findings indicate that PM_2.5-induced adrenal dysfunction involves inflammatory responses and the disruption of Shh and Wnt signaling, highlighting their potential key role in preserving adrenal endocrine health.