Dissecting the Impact of Maternal Androgen Exposure on Developmental Programming through Targeting the Androgen Receptor.

Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE

Original Publication: Weinheim : WILEY-VCH, [2014]-

Androgens*/metabolism ; Androgens*/pharmacology ; Receptors, Androgen*/metabolism ; Receptors, Androgen*/genetics ; Polycystic Ovary Syndrome*/metabolism ; Polycystic Ovary Syndrome*/genetics ; Polycystic Ovary Syndrome*/chemically induced ; Disease Models, Animal*; Female ; Animals ; Mice ; Pregnancy ; Placenta/metabolism ; Placenta/drug effects ; Humans ; Embryonic Development/drug effects ; Maternal Exposure/adverse effects

Women with polycystic ovary syndrome (PCOS) exhibit sustained elevation in circulating androgens during pregnancy, an independent risk factor linked to pregnancy complications and adverse outcomes in offspring. Yet, further studies are required to understand the effects of elevated androgens on cell type-specific placental dysfunction and fetal development. Therefore, a PCOS-like mouse model induced by continuous androgen exposure is examined. The PCOS-mice exhibited impaired placental and embryonic development, resulting in mid-gestation lethality. Co-treatment with the androgen receptor blocker, flutamide, prevents these phenotypes including germ cell specification. Comprehensive profiling of the placenta by whole-genome bisulfite and RNA sequencing shows a reduced proportion of trophoblast precursors, possibly due to the downregulation of Cdx2 expression. Reduced expression of Gcm1, Synb, and Prl3b1 is associated with reduced syncytiotrophoblasts and sinusoidal trophoblast giant cells, impairs placental labyrinth formation. Importantly, human trophoblast organoids exposed to androgens exhibit analogous changes, showing impaired trophoblast differentiation as a key feature in PCOS-related pregnancy complications. These findings provide new insights into the potential cellular targets for future treatments.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

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2022-00550 Swedish Medical Research Council; 2020-00253 Swedish Medical Research Council; 2019.0211 Knut and Alice Wallenberg Foundation; NNF22OC0072904 Novo Nordisk Foundation; NNF18OC0033992 Novo Nordisk Foundation; NNF19OC0056647 Novo Nordisk Foundation; DIA2021-633 Diabetes Foundation; DIA2022-708 Diabetes Foundation; 2023-0005 Karolinska Institutet KID; 2020-00990 Karolinska Institutet KID; Regional Agreement on Medical Training and Clinical Research; Stockholm County Council; 20 190 079 Karolinska Institutet central faculty funding

Keywords: developmental programming; human trophoblast organoids; placental development; polycystic ovary syndrome

0 (Androgens)
0 (Receptors, Androgen)

Date Created: 20240730 Date Completed: 20240925 Latest Revision: 20240927

20240927

PMC11423211

10.1002/advs.202309429

39075722