E-GEOD-14920 - Role of PPARalpha in the effects of DEHP on the hepatic expression of a selection of mouse genes
Submitted on 20 February 2009, released on 22 May 2010, last updated on 27 March 2012
Role of PPARalpha in the effects of DEHP on the hepatic expression of a selection of mouse genes related to nuclear receptor signaling. Di-(2-ethylhexyl)-phthalate (DEHP), a widely used plasticizer, is detected in consumer’s body fluids. Contamination occurs through environmental and food chain sources. In mouse liver, DEHP activates the peroxisome proliferator-activated receptor alpha (PPARalpha) and regulates the expression of its target genes. Several in vitro investigations support the simultaneous recruitment of additional nuclear receptor pathways. We investigated, in vivo, the hepatic impact of low doses of DEHP on PPARalpha activation, and the putative activation of additional signalling pathways. Wild-type and PPARalpha-deficient mice were exposed to different doses of DEHP. Gene expression profiling delineated the role of PPARalpha and revealed a PPARalpha-independent regulation of several prototypic Constitutive Androstane Receptor (CAR) target genes. This finding demonstrates that CAR also represents a transcriptional regulator sensitive to phthalates. CAR-mediated effects of DEHP provide a new rationale for most endpoints of phthalates toxicity described previously, including endocrine disruption, hepatocarcinogenesis and the metabolic syndrome. Keywords: Treatment effect One-color macroarrays, 6 experimental conditions: Wild type (WT) and PPARalpha-deficient mice (PPAR) were treated with vehicle (Ctrl) or with di-(2-ethylhexyl)-phthalate (DEHP) at 20 mg/kg/day (D20) or 200 mg/kg/day (D200) for 21 days, Biological replicates: 10 for each group, One replicate per array
transcription profiling by array
Pascal GP Martin, Alexandre Eveillard, Frederic Lasserre, Pascal G Martin
Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): a novel signalling pathway sensitive to phthalates. Eveillard A, Mselli-Lakhal L, Mogha A, Lasserre F, Polizzi A, Pascussi JM, Guillou H, Martin PG, Pineau T.