Published in

Oxford University Press (OUP), Journal of Clinical Endocrinology and Metabolism, 2020

DOI: 10.1210/clinem/dgaa852

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Establishment of a novel human fetal adrenal culture model that supports de novo and manipulated steroidogenesis

This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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Abstract

Abstract Context Disorders affecting adrenal steroidogenesis promote an imbalance in the normally tightly controlled secretion of mineralocorticoids, glucocorticoids, and androgens. This may lead to differences/disorders of sex development in the fetus, as seen in virilized girls with congenital adrenal hyperplasia (CAH). Despite the important endocrine function of human fetal adrenals, neither normal nor dysregulated adrenal steroidogenesis is understood in detail. Objective Due to significant differences in adrenal steroidogenesis between human and model-species (except higher primates), we aimed to establish a human fetal adrenal model that enables examination of both de novo and manipulated adrenal steroidogenesis Design and Setting Human adrenal tissue from 54 1 st trimester fetuses were cultured ex vivo as intact tissue fragments for 7- or 14-days. Main Outcome Measure(s) Model validation included examination of post-culture tissue morphology, viability, apoptosis and quantification of steroid hormones secreted to the culture media measured by liquid chromatography-tandem mass spectrometry. Results The culture approach maintained cell viability, preserved cell populations of all fetal adrenal zones, and recapitulated de novo adrenal steroidogenesis based on continued secretion of steroidogenic intermediates, glucocorticoids, and androgens. Adrenocorticotropic hormone (ACTH) and ketoconazole treatment of ex vivo cultured human fetal adrenal tissue resulted in the stimulation of steroidogenesis and inhibition of androgen secretion, respectively, demonstrating a treatment-specific response. Conclusions Together these data indicate that ex vivo culture of human fetal adrenal tissue constitutes a novel approach to investigate local effects of pharmaceutical exposures or emerging therapeutic options targeting imbalanced steroidogenesis in adrenal disorders including CAH.