Prenatal Exposure to Retrorsine Induces Developmental Toxicity and Hepatotoxicity of Fetal Rats in a Sex-Dependent Manner: The Role of Pregnane X Receptor Activation

• DOI: 10.1021/acs.jafc.0c06748
• Publication Date: 2021-03-09T06:26:29Z
• Authors: Yongguo Dai; Jinyuan Luo; E Xiang; Qi Guo; Zheng He; Zheng Gong; Xiaoxiang Sun; Hao Kou; Kequan Xu; Chengpeng Fan; Jie Liu; Shuaikai Qiu; Yanqing Wang; Hui Wang; Yu Guo
• Keywords: Pregnane X receptor; CYP3A; Reproductive toxicity; Developmental toxicity

Pyrrolizidine alkaloids (PAs) are a type of natural phytotoxin that contaminate food and feed become an environmental health risk to humans livestock. PAs exert toxicity requires metabolic activation by cytochrome P450 (CYP) 3A, case reports showed fetuses quite susceptible toxicity. The aim this study was explore the characteristics developmental fetal hepatotoxicity induced retrorsine (RTS, typcial toxic PA) underlying mechanism. Pregnant Wistar rats were intragastrically administered with 20 mg/(kg·day) RTS from gestation day (GD) 9 20. Results prenatal exposure lowered bodyweights, reduced hepatocyte numbers, potentiated hepatic apoptosis in fetuses, particularly females. Simutaneously, increased CYP3A expression pregnane X receptor (PXR) female liver. We further confirmed PXR agonist LO2 HepG2 cell lines. Furthermore, agonism or antagonism androgen (AR) either blocked RTS-mediated activation, respectively. As agonist, exacerbated fetus due induction self-metabolism, while inhibitory effect AR on susceptibility male RTS. Our findings indicated may be potential therapeutic target for PA