ToxSci Advance Access originally published online on November 5, 2007
Toxicological Sciences 2008 101(2):350-363; doi:10.1093/toxsci/kfm275
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o,p'-DDT Elicits PXR/CAR-, Not ER-, Mediated Responses in the Immature Ovariectomized Rat Liver
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* Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Shizuoka 437-0065, Japan
Center for Integrative Toxicology, and the National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan 48824
Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824
|| Wellington Laboratories Inc., Guelph, Ontario N1G 3M5, Canada
1 To whom correspondence should be addressed at Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824. Fax: (517) 353-9334. E-mail: tzachare{at}msu.edu.
Received September 27, 2007; accepted November 1, 2007
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Abstract |
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Technical-grade dichlorodiphenyltrichloroethane (DDT) is an agricultural pesticide and malarial vector control agent that has been designated a potential human hepatocarcinogen. The o,p'-enantiomer exhibits estrogenic activity that has been associated with the carcinogenicity of DDT. The temporal and dose-dependent hepatic estrogenicity of o,p'-DDT was investigated using complementary DNA microarrays in immature ovariectomized Sprague-Dawley rats with complementary histopathology and tissue-level analysis. Animals were gavaged with 300 mg/kg o,p'-DDT either once or once daily for 3 consecutive days. Liver samples were examined 2, 4, 8, 12, 18, or 24 h after a single dose or following three daily doses. For dose-response studies, a single dose of 3, 10, 30, 100, or 300 mg/kg body weight o,p'-DTT was administered for 3 consecutive days. Genes associated with drug metabolism (Cyp2b2 and Cyp3a2), the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), cell proliferation (Ccnd1, Ccnb1, Ccnb2, and Stmn1), and oxidative stress (Gclm and Hmox1) were significantly induced. Cyp2b2 exhibited dose-dependent regulation and was significantly induced across all time points, while cell proliferation– and oxidative stress–related genes exhibited transient induction. The induction of Cyp2b2 and Cyp3a2 mRNA levels suggest PXR/CAR activation, consistent with expression of genes associated with oxidative stress. Few genes known to be estrogen receptor (ER) regulated were differentially expressed when compared to the hepatic gene expression profile elicited by ethynyl estradiol in immature ovariectomized C57BL/6 mice using the same study design and analysis methods. These data indicate that o,p'-DDT elicits PXR/CAR-, not ER-, mediated gene expression in the rat liver. Based on the species-specific differences in CAR regulation, the extrapolation of rodent DDT hepatocarcinogenicity to humans warrants further investigation.
Key Words: DDT; liver; microarray; CAR; carcinogenesis; estrogen.