Species-specific regulation of PXR/CAR/ER-target genes in the mouse and rat liver elicited by o, p'-DDT.
Species-specific regulation of PXR/CAR/ER-target genes in the mouse and rat liver elicited by o, p'-DDT.
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DOI：
10.1186/1471-2164-9-487
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发表时间：
2008-10-16
期刊：
影响因子：
4.4
通讯作者：
Zacharewski TR
中科院分区：
文献类型：
--
作者：
Kiyosawa N;Kwekel JC;Burgoon LD;Dere E;Williams KJ;Tashiro C;Chittim B;Zacharewski TR
Dichlorodiphenyltrichloroethane (DDT) is a persistent estrogenic organochlorine pesticide that is a rodent hepatic tumor promoter, with inconclusive carcinogenicity in humans. We have previously reported that o, p'-DDT elicits primarily PXR/CAR-mediated activity, rather than ER-mediated hepatic responses, and suggested that CAR-mediated effects, as opposed to ER-mediated effects, may be more important in tumor promotion in the rat liver. To further characterize species-specific hepatic responses, gene expression analysis, with complementary histopathology and tissue level analyses were investigated in immature, ovariectomized C57BL/6 mice treated with 300 mg/kg o, p'-DDT, and compared to Sprague-Dawley rat data. Rats and mice exhibited negligible histopathology with rapid o, p'-DDT metabolism. Gene expression profiles were also similar, exhibiting PXR/CAR regulation with the characteristic induction of Cyp2b10 and Cyp3a11. However, PXR-specific target genes such as Apoa4 or Insig2 exhibited more pronounced induction compared to CAR-specific genes in the mouse. In addition, mouse Car mRNA levels decreased, possibly contributing to the preferential activation of mouse PXR. ER-regulated genes Cyp17a1 and Cyp7b1 were also induced, suggesting o, p'-DDT also elicits ER-mediated gene expression in the mouse, while ER-mediated effects were negligible in the rat, possibly due to the inhibitory effects of CAR on ER activities. In addition, o, p'-DDT induced Gadd45a, Gadd45b and Cdkn1, suggesting DNA damage may be an additional risk factor. Furthermore, elevated blood DHEA-S levels at 12 h after treatment in the mouse may also contribute to the endocrine-related effects of o, p'-DDT. Although DDT is known to cause rodent hepatic tumors, the marked species differences in PXR/CAR structure, expression patterns and ligand preference as well as significant species-specific differences in steroidogenesis, especially CYP17A1 expression and activity, confound the extrapolation of these results to humans. Nevertheless, the identification of potential modes of action as well as species-specific responses may assist in the selection and further development of more appropriate models for assessing the toxicity of DDT to humans and wildlife.
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影响因子：
10.4
作者：
ITO, N;TSUDA, H;IMAIDA, K
通讯作者：
IMAIDA, K
影响因子：
5.8
作者：
Kiyosawa, N;Ito, K;Matsunuma, N
通讯作者：
Matsunuma, N
影响因子：
1.1
作者：
Eckel, J E;Gennings, C;Zacharewski, T R
通讯作者：
Zacharewski, T R
影响因子：
1.5
作者：
Harada, T;Yamaguchi, S;Maita, K
通讯作者：
Maita, K
DOI：
10.1016/0742-8413(93)90013-b
发表时间：
1993-03-01
期刊：
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-PHARMACOLOGY TOXICOLOGY & ENDOCRINOLOGY
影响因子：
--
作者：
HASSOUN, E;BAGCHI, M;STOHS, SJ
通讯作者：
STOHS, SJ