Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): a novel signalling pathway sensitive to phthalates.
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. Thus, we developed an original hepatic cell line expressing CAR to investigate its activation by DEHP. By means of a pharmacological inhibitor or CAR-targeting shRNAs, we established that CAR is required for the effect of DEHP on Cyp2b10, a recognized CAR target gene. Moreover, DEHP dose-dependently induced CYP2B6 in human primary hepatocyte cultures. 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.
Laboratoire de Pharmacologie et Toxicologie, Institut National de la Recherche Agronomique, INRA UR66, Toulouse, France.
Alexandre
A
Eveillard
Laïla
L
Mselli-Lakhal
Ariane
A
Mogha
Frédéric
F
Lasserre
Arnaud
A
Polizzi
Jean-Marc
JM
Pascussi
Hervé
H
Guillou
Pascal G P
PG
Martin
Thierry
T
Pineau
D000818:Animals; D018929:Cell Culture Techniques; D000090702:Constitutive Androstane Receptor; D004247:DNA / Q000235:genetics; D017931:DNA Primers; D004051:Diethylhexyl Phthalate / Q000494:pharmacology*; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000172:deficiency / Q000187:drug effects / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
D000090702:Constitutive Androstane Receptor; D017931:DNA Primers; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D004247:DNA; D004051:Diethylhexyl Phthalate