Comparative toxicogenomic examination of the hepatic effects of PCB126 and TCDD in immature, ovariectomized C57BL/6 mice.
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 microg/kg PCB126 were compared with 30 microg/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 microg/kg PCB126, 30 or 100 microg/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 microg/kg PCB126 elicited a subset of weaker effects compared with 30 microg/kg TCDD in immature, ovariectomized C57BL/6 mice.
Department of Biochemistry & Molecular Biology, Center for Integrative Toxicology, Michigan State University, East Lansing 48824-1319, USA.
Anna K
AK
Kopec
Darrell R
DR
Boverhof
Lyle D
LD
Burgoon
Daher
D
Ibrahim-Aibo
Jack R
JR
Harkema
Colleen
C
Tashiro
Brock
B
Chittim
Timothy R
TR
Zacharewski
D000284:Administration, Oral; D000367:Age Factors; D000375:Aging; D000818:Animals; D001835:Body Weight; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D007441:Intubation, Gastrointestinal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size; D010052:Ovariectomy; D011078:Polychlorinated Biphenyls / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D013997:Time Factors
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D011078:Polychlorinated Biphenyls; C023035:3,4,5,3',4'-pentachlorobiphenyl