Adolescent chronic unpredictable mild stress impairs adult adrenal steroidogenesis in mice via glucocorticoid-mediated downregulation of SHH promoter H3K4me3 and hedgehog signaling.

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is a hallmark of major depressive disorder in adults. However, the long-term impact of adolescent depression on adult HPA axis function and adrenal steroidogenesis remains unclear. To address this, we exposed male mice to chronic unpredictable mild stress (CUMS) during postnatal weeks (PW) 4-8 to model adolescent depression. At PW8, CUMS mice exhibited elevated HPA axis activity and enhanced adrenal steroidogenesis, confirming successful model induction. By PW16 (adulthood), HPA axis activity had normalized, whereas adrenal steroidogenesis was markedly suppressed. Transcriptomic analysis followed by validation revealed downregulation of Hedgehog signaling components in the adrenal glands of CUMS mice at PW16. Furthermore, a persistent reduction in H3K4me3 enrichment at the SHH promoter was observed from PW8 to PW16. In vitro, corticosterone treatment reduced SHH promoter H3K4me3 levels and inhibited Hedgehog signaling in adrenocortical cells. Collectively, these findings indicate that adolescent CUMS impairs adult adrenal steroidogenesis via glucocorticoid-mediated epigenetic repression of the SHH/Hedgehog signaling pathway. This study provides novel mechanistic insights into the persistent endocrine consequences of adolescent depression.