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01-12-2021 | Glucocorticoid | Research article

Dexamethasone induces an imbalanced fetal-placental-maternal bile acid circulation: involvement of placental transporters

Authors: Wen Huang, Jin Zhou, Juanjuan Guo, Wen Hu, Guanghui Chen, Bin Li, Yajie Wen, Yimin Jiang, Kaili Fu, Huichang Bi, Yuanzhen Zhang, Hui Wang

Published in: BMC Medicine | Issue 1/2021

Abstract

Background

The use of prenatal dexamethasone remains controversial. Our recent studies found that prenatal dexamethasone exposure can induce maternal intrahepatic cholestasis and have a lasting adverse influence on bile acid (BA) metabolism in the offspring. The purpose of this study was to investigate the effects of dexamethasone on fetal-placental-maternal BA circulation during the intrauterine period, as well as its placental mechanism.

Methods

Clinical data and human placentas were collected and analyzed. Pregnant Wistar rats were injected subcutaneously with dexamethasone (0.2 mg/kg per day) from gestational day 9 to 20. The metabolomic spectra of BAs in maternal and fetal rat serum were determined by LC-MS. Human and rat placentas were collected for histological and gene expression analysis. BeWo human placental cell line was treated with dexamethasone (20–500 nM).

Results

Human male neonates born after prenatal dexamethasone treatment showed an increased serum BA level while no significant change was observed in females. Moreover, the expression of organic anion transporter polypeptide-related protein 2B1 (OATP2B1) and breast cancer resistance protein (BCRP) in the male neonates’ placenta was decreased, while multidrug resistance-associated protein 4 (MRP4) was upregulated. In experimental rats, dexamethasone increased male but decreased female fetal serum total bile acid (TBA) level. LC-MS revealed that primary BAs were the major component that increased in both male and female fetal serum, and all kinds of BAs were significantly increased in maternal serum. The expression of Oatp2b1 and Bcrp were reduced, while Mrp4 expression was increased in the dexamethasone-treated rat placentas. Moreover, dexamethasone increased glucocorticoid receptor (GR) expression and decreased farnesoid X receptor (FXR) expression in the rat placenta. In BeWo cells, dexamethasone induced GR translocation into the nucleus; decreased FXR, OATP2B1, and BCRP expression; and increased MRP4 expression. Furthermore, GR was verified to mediate the downregulation of OATP2B1, while FXR mediated dexamethasone-altered expression of BCRP and MRP4.

Conclusions

By affecting placental BA transporters, dexamethasone induces an imbalanced fetal-placental-maternal BA circulation, as showed by the increase of primary BA levels in the fetal serum. This study provides an important experimental and theoretical basis for elucidating the mechanism of dexamethasone-induced alteration of maternal and fetal BA metabolism and for exploring early prevention and treatment strategies.

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Title: Dexamethasone induces an imbalanced fetal-placental-maternal bile acid circulation: involvement of placental transporters
Authors: Wen Huang
Jin Zhou
Juanjuan Guo
Wen Hu
Guanghui Chen
Bin Li
Yajie Wen
Yimin Jiang
Kaili Fu
Huichang Bi
Yuanzhen Zhang
Hui Wang
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Glucocorticoid
Dexamethasone
Published in: BMC Medicine / Issue 1/2021
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-021-01957-y

At a glance: The STEP trials

Springer Medicine

Dexamethasone induces an imbalanced fetal-placental-maternal bile acid circulation: involvement of placental transporters

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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