High Expression of Adrenal Cortisol Synthases Is Acquired After Intrauterine Inflammation in Periviable Sheep Fetuses

Shinichi Sato; Shimpei Watanabe; Yuya Saito; Aika Takanashi; Hideyuki Ikeda; Yoshie Sakurai; Shouta Koshinami; Yusaku Kumagai; Haruo Usuda; Takushi Hanita; Atsuo Kikuchi; Masatoshi Saito

doi:10.1210/jendso/bvad100

High Expression of Adrenal Cortisol Synthases Is Acquired After Intrauterine Inflammation in Periviable Sheep Fetuses

J Endocr Soc. 2023 Jul 27;7(9):bvad100. doi: 10.1210/jendso/bvad100. eCollection 2023 Aug 1.

Authors

Shinichi Sato^{1

2}, Shimpei Watanabe^{1

2}, Yuya Saito¹, Aika Takanashi^{1

2}, Hideyuki Ikeda^{1

2}, Yoshie Sakurai^{1

2}, Shouta Koshinami^{1

2}, Yusaku Kumagai¹, Haruo Usuda^{1

2

3}, Takushi Hanita^{1

2}, Atsuo Kikuchi², Masatoshi Saito¹

Affiliations

¹ Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi 980-8574, Japan.
² Department of Pediatrics, Tohoku University Hospital, Sendai, Miyagi 980-8574, Japan.
³ School of Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.

Abstract

Context: Intrauterine inflammation, a representative stressor for the fetus, has been shown to alter the hypothalamus-pituitary-adrenal (HPA) axis reactivity in preterm fetuses and increase postnatal cortisol production. However, the mechanism of this alteration has not yet been elucidated.

Objective: We aimed to clarify the effects of endotoxin-induced intrauterine inflammation on the HPA axis of periviable sheep fetuses.

Methods: Fetal sheep (0.63 term) were divided into 2 groups: (1) the endotoxin group, in which the endotoxin was injected into the amniotic fluid; and (2) the control group, in which the saline solution was injected instead. A corticotropin-releasing hormone (CRH) challenge test was performed on the third day after injection to evaluate the cortisol-producing capacity of each group. Gene expression levels in the fetal adrenal glands of each group were analyzed by RNA-seq.

Results: The cortisol levels were significantly higher in the endotoxin group than in the control group after CRH challenge (P = .02). There were no significant differences in the responsiveness of adrenocorticotropin and cortisone between the 2 groups. Gene expression levels of the following enzymes involved in cortisol synthesis were significantly elevated in the endotoxin group: cytochrome P450 family (CYP) 11 subfamily A member 1 (log₂FC 1.75), CYP 17 subfamily A member 1 (log₂FC 3.41), 3β-hydroxysteroid dehydrogenase type I (log₂FC 1.13), steroidogenic acute regulatory protein (log₂FC 1.09), and CYP 21 (log₂FC 0.89).

Conclusion: Periviable fetuses exposed to inflammation in utero have altered the responsiveness of the HPA axis with increased expression of enzymes involved in cortisol synthesis in the adrenal gland.

Keywords: RNA sequence; adrenal gland; corticotropin-releasing hormone; cortisol; intrauterine inflammation; preterm fetus.