Glucocorticoid exposure disrupts vascular-immune interactions and impairs steroidogenesis in the fetal mouse testis†.

Abstract

Antenatal corticosteroid (ACS) therapy, typically using dexamethasone (Dex), is a cornerstone of improving preterm infant survival by accelerating lung maturation. However, its systemic effects on other developing organs remain poorly understood. Here, we reveal a previously unrecognized impact of prenatal Dex exposure on fetal testis development, with implications for male reproductive health. Analysis of fetal testes from a Dex-based ACS mouse model revealed that Dex suppressed androgen synthesis by reducing Leydig cell number and downregulating steroidogenic pathways. Dex also activated immune programs, induced CD163+ M2c macrophages and IL-10 signaling, and promoted endothelial expansion. In response to aberrant pro-angiogenic signals, vascular architecture was disrupted: capillary density and pericyte gene expression declined, while blood vessel diameter increased. Transcriptomic analyses revealed downregulation of androgen response and cholesterol metabolism pathways, alongside upregulation of immune and coagulation signatures. Analyses of fetal ovaries revealed a sexually dimorphic and organ-specific effect of ACS treatment, in which ovarian gene expression during this window of development remained unaffected. Our findings uncover an immune-vascular mechanism linking prenatal Dex to impaired steroidogenesis, providing new insight into potentially broad effects of glucocorticoid exposure.