ToxSci Advance Access published online on November 5, 2007
Toxicological Sciences, 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, MI 48824, USA
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Shizuoka 437-00065, Japan
Center for Integrative Toxicology, and the National Food Safety & Toxicology Center, Michigan State University, East Lansing, MI, 48824, USA
Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, 48824, USA
|| Wellington Laboratories Inc., Guelph, Ontario N1G 3M5, Canada
¶ To whom correspondence should be addressed: Michigan State University, East Lansing, Michigan 48824, USA, E-mail address: tzachare{at}msu.edu, Telephone: 517-355-1607, Facsimile: 517-353-9334
Received September 27, 2007; revision received October 31, 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’-dichlorodiphenyltrichloroethane (o,p'-DDT) was investigated using cDNA 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 three 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 b.w o,p'-DTT was administered for three consecutive days. Genes associated with drug metabolism (Cyp2b2, Cyp3a2), the nuclear receptors CAR and PXR, cell proliferation (Ccnd1, Ccnb1, Ccnb2, Stmn1) and oxidative stress (Gclm, 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.