A Mechanism for the induction of renal tumours in male Fischer 344 rats by short-chain chlorinated paraffins

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 (alpha 2u), and form degradation-resistant complexes in the kidney. The resulting accumulation of alpha 2u 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 alpha 2u 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 alpha 2u 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 alpha 2u synthesis in male rat liver. This down-regulation occurred at the transcriptional level. Since less alpha 2u was produced in C500C-treated rats, there was less available for accumulation in the kidney hence a typical alpha 2u nephropathy did not appear. However, the administration of a radiolabelled SCCP, [C-14]polychlorotridecane (PCTD), to male rats demonstrated its binding to renal alpha 2u. Thus, it is possible that SCCPs bind to alpha 2u and cause a slow accumulation of the protein in the kidney followed by delayed onset of alpha 2u nephropathy. As a consequence of these findings in the current experiments, while evidence exists implicating alpha 2u-globulin in the molecular mechanism of action of the C500C, the classic profile of a alpha 2u-globulin nephropathy seen with other chemicals such as DCB and DL was not reproduced during this experimental protocol.