A Mechanism for the induction of renal tumours in male Fischer 344 rats by short-chain chlorinated paraffins
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- 作者：Gayathri D. Warnasuriya (1)
Barbara M. Elcombe (2)
John R. Foster (3)
Clifford R. Elcombe (2) - 关键词：Short ; chain chlorinated paraffins ; Chlorowax 500C ; Alpha ; 2 ; urinary globulin nephropathy ; 1 ; 4 ; Dichlorobenzene ; d ; Limonene
- 刊名：Archives of Toxicology
- 出版年：2010
- 出版时间：March 2010
- 年：2010
- 卷：84
- 期：3
- 页码：233-243
- 全文大小：516KB
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49. Wyatt I, Coutts CT, Hasmall SC, Davies DT, Foster JR, Elcombe CR (2006) Chlorinated paraffins: Mechanisms of non-genotoxic carcinogenesis in Fischer 344 rats. Toxicology (Submitted) - 作者单位：Gayathri D. Warnasuriya (1)
Barbara M. Elcombe (2)
John R. Foster (3)
Clifford R. Elcombe (2)
1. Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 5JJ, UK
2. CXR Biosciences Ltd, James Lindsay Place, Dundee Technopole, Dundee, DD1 5JJ, UK
3. AstraZeneca, Global Safety Assessment, Alderley Park, Cheshire, Macclesfield, SK10 4TF, UK - ISSN：1432-0738
文摘
Short-chain chlorinated paraffins (SCCPs) cause kidney tumours in male rats, but not in female rats or mice of either sex. Male rat-specific tumours also occur in rats dosed with a range of compounds including 1,4-dichlorobenzene (DCB) and d-limonene (DL). These compounds bind to a male rat-specific hepatic protein, alpha-2-urinary globulin (α2u), and form degradation-resistant complexes in the kidney. The resulting accumulation of α2u causes cell death and sustained regenerative cell proliferation, which in turn leads to the formation of renal tumours. To investigate whether the SCCP, Chlorowax 500C (C500C), causes tumours via the accumulation of α2u male rats were orally dosed with either C500C (625?mg/kg of body weight), DCB (300?mg/kg of body weight), or DL (150?mg/kg of body weight) for 28 consecutive days. An increase in renal α2u and cell proliferation was observed in DCB- and DL-treated rats but not in C500C-treated rats. C500C caused peroxisome proliferation and a down-regulation of α2u synthesis in male rat liver. This down-regulation occurred at the transcriptional level. Since less α2u was produced in C500C-treated rats, there was less available for accumulation in the kidney hence a typical α2u nephropathy did not appear. However, the administration of a radiolabelled SCCP, [14C]polychlorotridecane (PCTD), to male rats demonstrated its binding to renal α2u. Thus, it is possible that SCCPs bind to α2u and cause a slow accumulation of the protein in the kidney followed by delayed onset of α2u nephropathy. As a consequence of these findings in the current experiments, while evidence exists implicating α2u-globulin in the molecular mechanism of action of the C500C, the classic profile of a α2u-globulin nephropathy seen with other chemicals such as DCB and DL was not reproduced during this experimental protocol.