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 (α2u), and form degradationresistant 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.
Warnasuriya
Gayathri D
GD
Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 5JJ, UK.
Elcombe
Barbara M
BM
Foster
John R
JR
Elcombe
Clifford R
CR
D000510:Alpha-Globulins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D002722:Chlorobenzenes / Q000378:metabolism / Q000633:toxicity; D053138:Cyclohexenes / Q000378:metabolism / Q000633:toxicity; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006843:Hydrocarbons, Chlorinated / Q000378:metabolism* / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000077222:Limonene; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020675:Peroxisomes / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D013729:Terpenes / Q000378:metabolism / Q000633:toxicity; D014158:Transcription, Genetic / Q000187:drug effects
D000510:Alpha-Globulins; D002273:Carcinogens; D002722:Chlorobenzenes; D053138:Cyclohexenes; D006843:Hydrocarbons, Chlorinated; D013729:Terpenes; C013803:alpha 2u globulin; C010555:chlorowax 500C; D000077222:Limonene; C018511:4-dichlorobenzene