Comparative Toxicogenomic Examination of the Hepatic Effects of PCB126 and TCDD in Immature, Ovariectomized C57BL/6 Mice

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Abstract

Polychlorinated biphenyls are persistent environmental pollutants that elicit a wide range of effects in humans and wildlife, mediated by the aryl hydrocarbon receptor. 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) is the most potent congener with relative effect potencies ranging from 0.0026 to 0.857, and a toxic equivalency factor (TEF) of 0.1 set by an expert panel of the World Health Organization. In this study, the hepatic effects elicited by 300 μg/kg PCB126 were compared with 30 μg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in immature, ovariectomized female C57BL/6 mice. Comprehensive hepatic gene expression analyses with complementary histopathology, high-resolution gas chromatograph/high-resolution mass spectrometer tissue analysis, and clinical chemistry were examined. For temporal analysis, mice were orally gavaged with PCB126 or sesame oil vehicle and sacrificed after 2, 4, 8, 12, 18, 24, 72, 120, or 168 h. In the dose–response study, mice were gavaged with 0.3, 1, 3, 10, 30, 100, 300, 1000 μg/kg PCB126, 30 or 100 μg/kg TCDD and sacrificed after 72 h. 251 and 367 genes were differentially expressed by PCB126 at one or more time points or doses, respectively, significantly less than elicited by TCDD. In addition, there was less vacuolization and necrosis, and no immune cell infiltration, despite comparable or higher TEF-adjusted hepatic PCB126 levels. The functional annotation of differentially expressed genes was consistent with the observed histopathology. Collectively, the data indicate that 300 μg/kg PCB126 elicited a subset of weaker effects compared with 30 μg/kg TCDD in immature, ovariectomized C57BL/6 mice.

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