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bioRxiv · 10.1101/2025.02.11.637631

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

Junnila, A.·Rytkonen, K. T.·Martinez-Nieto, G.·Perk, M.·Li, H.·Airaksinen, J.·Hyotylainen, I.·Mehtovuori, O.·Laiho, A.·Ohlsson, C.·Elo, L. L.·Kuure, S.·Poutanen, M.·Sipila, P.
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Abstract

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.

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Junnila, A., Rytkonen, K. T., Martinez-Nieto, G., Perk, M., Li, H., Airaksinen, J., Hyotylainen, I., Mehtovuori, O., Laiho, A., Ohlsson, C., Elo, L. L., Kuure, S., Poutanen, M., Sipila, P.. 2025-02-11. Testosterone exposure during fetal masculinization programming window determines the kidney size in adult mice.. https://doi.org/10.1101/2025.02.11.637631

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