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Female-specific activation of pregnane X receptor mediates sex difference in fetal hepatotoxicity by prenatal monocrotaline exposure.

Abstract：

:Pyrrolizidine alkaloids (PAs) are a group of hepatic toxicant widely present in plants. Cytochrome P450 (CYP) 3A plays a key role in metabolic activation of PAs to generate electrophilic metabolites, which is the main cause of hepatotoxicity. We have previously demonstrated the sex difference in developmental toxicity and hepatotoxicity in fetal rats exposed to monocrotaline (MCT), a representative toxic PA. The aim of this study was to explore the underlying mechanism. 20 mg·kg-1·d-1 MCT was intragastrically given to pregnant Wistar rats from gestation day 9 to 20. CYP3As expression and pregnane X receptor (PXR) activation were specifically enhanced in female fetal liver. After MCT treatment, we also observed a significant increase of CYP3As expression in LO2 cells (high PXR level) or hPXR-transfected HepG2 cells (low PXR level). Employing hPXR and CYP3A4 dual-luciferase reporter gene assay, we confirmed the agonism effect of MCT on PXR-dependent transcriptional activity of CYP3A4. Agonism and antagonism of the androgen receptor (AR) either induced or blocked MCT-induced PXR activation, respectively. This study was the first report identifying that MCT served as PXR agonist to induce CYP3A expression. CYP3A induction may increase self-metabolic activation of MCT and subsequently lead to more severe hepatotoxicity in female fetus. While in male, during the intrauterine period, activated AR by testosterone secretion from developing testes represses MCT-induced PXR activation and CYP3A induction, which may partially protect male fetus from MCT-induced hepatotoxicity.

journal_name

Toxicol Appl Pharmacol

journal_title

Toxicology and applied pharmacology

authors

Xiang E,Guo Q,Dai YG,Sun XX,Liu J,Fan CP,Wang YQ,Qiu SK,Wang H,Guo Y

doi

10.1016/j.taap.2020.115137

subject

Has Abstract

pub_date

2020-11-01 00:00:00

pages

115137

eissn

0041-008X

issn

1096-0333

pii

S0041-008X(20)30263-5

journal_volume

406

pub_type

杂志文章

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