Effects of DEHP on the hepatic expression of a selection of mouse genes related to nuclear receptor signaling.. Mus musculus

Phthalates are industrial additives widely used as plasticizers. In addition to deleterious effects on male genital development, population studies have documented correlations between phthalates exposure and impacts on reproductive tract development and on the metabolic syndrome in male adults. In this study we investigated potential mechanisms underlying the impact of di-(2-ethylhexyl)-phthalate (DEHP) on adult mouse liver in vivo. A parallel analysis of hepatic transcript and metabolic profiles from adult mice exposed to varying DEHP doses was performed. Hepatic genes modulated by DEHP are predominantly PPARα targets. However, the induction of prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways, including Constitutive Androstane Receptor (CAR). Integration of transcriptomic and metabonomic profiles revealed a correlation between the impacts of DEHP on genes and metabolites related to heme synthesis and on the Rev-erbα pathway that senses endogenous heme level. Keywords: Treatment effect Overall design: One-color macroarrays, 4 experimental conditions: Control mice (vehicle treated), mice treated with di-(2-ethylhexyl)-phthalate (DEHP) at 30 mg/kg/day (D30), 180 mg/kg/day (D180) or 1100 mg/kg/day (D1100) for 14 days, Biological replicates: 6 controls, 4 D30, 4 D180, 5 D1100, One replicate per array

邻苯二甲酸酯（Phthalates）是一类广泛用作增塑剂的工业添加剂。除了对男性生殖器官发育造成有害影响外，人群研究已证实邻苯二甲酸酯暴露与男性成人生殖道发育异常以及代谢综合征之间存在关联。本研究旨在探究邻苯二甲酸二(2-乙基己基)酯（di-(2-ethylhexyl)-phthalate, DEHP）对成年小鼠肝脏体内影响的潜在分子机制。本研究对暴露于不同剂量DEHP的成年小鼠的肝脏转录组与代谢组谱进行了平行分析。DEHP调控的肝脏基因主要为过氧化物酶体增殖物激活受体α（PPARα）的靶基因。然而，典型细胞色素P450基因的诱导表达，有力佐证了额外核受体（NR）通路的激活，其中包括组成型雄甾烷受体（Constitutive Androstane Receptor, CAR）。转录组与代谢组谱的整合分析显示，DEHP对血红素合成相关基因及代谢物的影响，与感知内源性血红素水平的Rev-erbα通路之间存在关联。
关键词：处理效应
实验设计概况：采用单色宏阵列，共设置4组实验条件：对照组（溶剂处理）小鼠、以30 mg/kg/天（D30）、180 mg/kg/天（D180）或1100 mg/kg/天（D1100）剂量的DEHP连续处理14天的小鼠；
生物学重复：对照组6例，D30组4例，D180组4例，D1100组5例，每张芯片对应1个生物学重复。