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Title: PCB153-elicited hepatic responses in the immature, ovariectomized C57BL/6 mice: comparative toxicogenomic effects of dioxin and non-dioxin-like ligands.

Authors: Kopec, Anna K; Burgoon, Lyle D; Ibrahim-Aibo, Daher; Mets, Bryan D; Tashiro, Colleen; Potter, Dave; Sharratt, Bonnie; Harkema, Jack R; Zacharewski, Timothy R

Published In Toxicol Appl Pharmacol, (2010 Mar 15)

Abstract: Polychlorinated biphenyls (PCBs) are ubiquitous contaminants found as complex mixtures of coplanar and non-coplanar congeners. The hepatic temporal and dose-dependent effects of the most abundant non-dioxin-like congener, 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153), were examined in immature, ovariectomized C57BL/6 mice, and compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the prototypical aryl hydrocarbon receptor (AhR) ligand. Animals were gavaged once with 300 mg/kg PCB153 or sesame oil vehicle and sacrificed 4, 12, 24, 72 or 168 h post dose. In the dose-response study, mice were gavaged with 1, 3, 10, 30, 100 or 300 mg/kg PCB153 or sesame oil for 24 h. Significant increases in relative liver weights were induced with 300 mg/kg PCB153 between 24 and 168 h, accompanied by slight vacuolization and hepatocellular hypertrophy. The hepatic differential expression of 186 and 177 genes was detected using Agilent 4 x 44 K microarrays in the time course (|fold change|> or =1.5, P1(t)> or =0.999) and dose-response (|fold change|> or =1.5, P1(t)> or =0.985) studies, respectively. Comparative analysis with TCDD suggests that the differential gene expression elicited by PCB153 was not mediated by the AhR. Furthermore, constitutive androstane and pregnane X receptor (CAR/PXR) regulated genes including Cyp2b10, Cyp3a11, Ces2, Insig2 and Abcc3 were dose-dependently induced by PCB153. Collectively, these results suggest that the hepatocellular effects elicited by PCB153 are qualitatively and quantitatively different from TCDD and suggestive of CAR/PXR regulation.

PubMed ID: 20005886 Exiting the NIEHS site

MeSH Terms: Animals; Body Weight/drug effects; DNA/biosynthesis; DNA/isolation & purification; Dioxins/toxicity*; Dose-Response Relationship, Drug; Environmental Pollutants/toxicity*; Female; Gas Chromatography-Mass Spectrometry; Ligands; Liver/drug effects; Liver/metabolism; Liver/pathology*; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Organ Size/drug effects; Ovariectomy; Polychlorinated Biphenyls/toxicity*; Polychlorinated Dibenzodioxins/toxicity; RNA/biosynthesis; RNA/isolation & purification; Reverse Transcriptase Polymerase Chain Reaction; Tissue Fixation; Toxicogenetics; Triglycerides/metabolism

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