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

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.

Epigenetic programming mediates abnormal gut microbiota and disease susceptibility in offspring with prenatal dexamethasone exposure

“…Unlike the most regular course of dexamethasone during pregnancy (single course), a longer intervention (multiple courses) with dexamethasone was used in the PDE rat experiments to better reveal the potential developmental toxicity of dexamethasone exposure during pregnancy. Nevertheless, the PDE rat results of this study may still provide valuable insights for clinical research and practice, as the animal results of this study and some previous studies 14 , 67 , 68 , 69 are relatively consistent with clinical findings. In addition, how the abnormal gut microbiota mediates the occurrence of cholestatic liver injury through influencing intestinal bile acid conversion and how to intervene effectively are worthy of further study.…”

LOX overexpression programming mediates the osteoclast mechanism of low peak bone mass in female offspring rats caused by pregnant dexamethasone exposure

“…For example, serum bile acid levels were elevated in prenatal dexamethasone-treated male fetuses but not in female fetuses. Elevated total serum bile acid in male fetal rats and decreased in female fetal rats were observed in PDE rat model, which was attributed to the dysfunction of placental bile acid transporters [ 64 ]. Recent studies have identified sex-dependent epigenetic mechanisms involved in sex differences in adrenal developmental toxicity induced by PDE, i.e., intrauterine dexamethasone leads to sex differences in histone acetylation and expression levels of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) by decreasing GR binding to the androgen receptor (AR) in male offspring or increasing GR binding to ERβ in female offspring, the latter mediating sex differences in adrenal developmental toxicity.…”

Drug–Drug Interactions Involving Dexamethasone in Clinical Practice: Myth or Reality?

“…In a breast cancer cell line overexpressing BCRP, dexamethasone significantly decreased BCRP activity, thus increasing the entrance of mitoxantrone into the cell and its cytotoxicity [46]. Two further studies confirmed the impact of dexamethasone on the modulation of the placental barrier in pregnant women and revealed that it not only involved P-gp but also other transporters, such as modulation of BCRP transcription and activity and the increase of MRP4 expression, which may affect drug toxicity and efficacy during pregnancy [47,48].…”