Data from: Neonatal activation of the xenobiotic-sensors PXR and CAR results in acute and persistent down-regulation of PPARα-signaling in mouse liver

Safety concerns have emerged regarding the potential long-lasting effects due to developmental exposure to xenobiotics. The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are critical xenobiotic-sensing nuclear receptors that are highly expressed in liver. The goal of this study was to test our hypothesis that neonatal exposure to PXR- or CAR-activators not only acutely but also persistently regulates the expression of drug-processing genes (DPGs). A single dose of the PXR-ligand PCN (75 mg/kg), CAR-ligand TCPOBOP (3 mg/kg), or vehicle (corn oil) was administered intraperitoneally to 3-day-old neonatal wild-type mice. Livers were collected 24 h post-dose or from adult mice at 60 days of age, and global gene expression of these mice was determined using Affymetrix Mouse Transcriptome Assay 1.0. In neonatal liver, PCN up-regulated 464 and down-regulated 449 genes, whereas TCPOBOP up-regulated 308 and down-regulated 112 genes. In adult liver, there were 15 persistently up-regulated and 22 persistently down-regulated genes following neonatal exposure to PCN, as well as 130 persistently up-regulated and 18 persistently down-regulated genes following neonatal exposure to TCPOBOP. Neonatal exposure to both PCN and TCPOBOP persistently down-regulated multiple Cyp4a members, which are prototypical-target genes of the lipid-sensor PPARα, and this correlated with decreased PPARα-binding to the Cyp4a gene loci. RT-qPCR, western blotting, and enzyme activity assays in livers of wild-type, PXR-null, and CAR-null mice confirmed that the persistent down-regulation of Cyp4a was PXR and CAR dependent. In conclusion, neonatal exposure to PXR- and CAR-activators both acutely and persistently regulates critical genes involved in xenobiotic and lipid metabolism in liver.发育阶段暴露于外源性化学物（xenobiotics）所产生的潜在长期效应，已引发安全关切。孕烷X受体（Pregnane X receptor, PXR）与组成型雄烷受体（Constitutive Androstane Receptor, CAR）是关键的外源性化学物感应核受体，在肝脏中呈高表达。本研究旨在验证下述假说：新生期暴露于PXR或CAR激活剂，不仅会急性调控药物代谢基因（drug-processing genes, DPGs）的表达，还会对其产生持久调控作用。 研究人员对3日龄的野生型小鼠腹腔注射单剂量PXR配体PCN（75mg/kg）、CAR配体TCPOBOP（3mg/kg）或溶剂（玉米油）。分别在给药后24小时采集幼鼠肝脏，或在小鼠60日龄（成年阶段）采集肝脏，随后通过Affymetrix Mouse Transcriptome Assay 1.0检测各组小鼠的全基因组基因表达水平。 在新生期肝脏中，PCN可上调464个基因、下调449个基因；而TCPOBOP可上调308个基因、下调112个基因。在新生期暴露于PCN的小鼠成年肝脏中，存在15个持续上调、22个持续下调的基因；而新生期暴露于TCPOBOP的小鼠成年肝脏中，则存在130个持续上调、18个持续下调的基因。 新生期暴露于PCN或TCPOBOP，均会持久下调多个Cyp4a家族成员的表达；Cyp4a是脂质感应受体过氧化物酶体增殖物激活受体α（Peroxisome Proliferator-Activated Receptor α, PPARα）的经典靶基因，该调控效应与PPARα结合Cyp4a基因位点的能力降低相关。 对野生型、PXR敲除（PXR-null）及CAR敲除（CAR-null）小鼠的肝脏开展实时定量聚合酶链反应（RT-qPCR）、蛋白质印迹法（western blotting）及酶活性检测，结果证实Cyp4a的持久下调依赖于PXR与CAR的介导。 综上，新生期暴露于PXR与CAR激活剂，可在肝脏中对参与外源性化学物代谢与脂质代谢的关键基因同时产生急性与持久的调控效应。