Rytkonen, K. T. | Search bioRxiv

bioRxiv2025

Testosterone exposure during fetal masculinization programming window determines the kidney size in adult mice.

Kidney size is sex-dimorphic and regulated by androgens in adult humans and mice. However, the effects of developmental androgen deficiency on kidneys remain elusive. We hypothesized that androgens program future kidney growth during a fetal development. Male mice lacking main testosterone-producing enzyme HSD17B3 had reduced testosterone at embryonic day 15.5, but the concentrations increased by E18.5, creating a short time window of androgen deficiency resulting in reduced kidney size in adult males. In male Hsd17b3-/-kidneys, nephron development was qualitatively normal, but number of glomeruli and proliferation of proximal tubules was reduced. Testosterone supplementation at E14.5-17.5 normalized the renal size in adult Hsd17b3-/-males. Our data suggests that androgen receptor and Hnf4a jointly regulate Igfbp5, FOXO1 and mTOR signaling to convey male-specific kidney growth. In conclusion, we have identified a novel developmental programming effect on male kidneys, where fetal androgen deficiency reduces kidney growth and androgen responsiveness in adult males.

developmental biology↗

bioRxiv2019

Transcriptomic responses to hypoxia in endometrial and decidual stromal cells

Human reproductive success depends on a properly decidualized uterine endometrium that allows implantation and the formation of the placenta. At the core of the decidualization process are endometrial stromal fibroblasts (ESF) that differentiate to decidual stromal cells (DSC). As variations in oxygen levels are functionally relevant in endometrium both upon menstruation and during placentation, we assessed the transcriptomic responses to hypoxia in ESF and DSC. In both cell types hypoxia upregulated genes in classical hypoxia pathways such as glycolysis and the epithelial mesenchymal transition. In DSC hypoxia restored an ESF like transcriptional state for a subset of transcription factors that are known targets of the progesterone receptor, suggesting that hypoxia partially interferes with progesterone signaling. In both cell types hypoxia modified transcription of several inflammatory transcription factors that are known regulators of decidualization, including decreased transcription of STATs and increased transcription of CEBPs. We observed that hypoxia upregulated genes had a significant overlap with genes previously detected to be upregulated in endometriotic stromal cells. Promoter analysis of the genes in this overlap suggested the hypoxia upregulated Jun/Fos and CEBP transcription factors as potential drivers of endometriosis-associated transcription. Using immunohistochemistry we observed increased expression of JUND and CEBPD in endometriosis lesions compared to healthy endometria. Overall the findings suggest that hypoxic stress establishes distinct transcriptional states in ESF and DSC, and that hypoxia influences the expression of genes that contribute to the core gene regulation of endometriotic stromal cells.

physiology↗