Prenatal corticosteroid exposure disrupts vascular-immune interactions and impairs steroidogenesis in the fetal 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 long-term 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, inducing CD163⁺ M2 macrophages and IL10 signaling, which promoted endothelial expansion. Despite these pro-angiogenic signals, vascular architecture was disrupted: capillary density and pericyte coverage 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 therapy, in which ovarian gene expression remained unaffected. Our findings uncover an immune-vascular mechanism linking prenatal Dex exposure to impaired steroidogenesis, providing new insight into potentially broad effects of ACS therapy. One Sentence Summary Prenatal corticosteroid exposure disturbs immune-vascular interactions and suppresses androgen synthesis in the fetal testis, revealing potentially widespread effects of a commonly used therapy.