title: Cell cycle progression, but not genotoxic activity, mainly contributes to citrinin-induced renal carcinogenesis.
abstract: Citrinin (CTN) is a food-contaminating mycotoxin that efficiently induces renal tumors in rats. However, the modes of carcinogenic action are still unknown, preventing assessment of the risks of CTN in humans. In the present study, the proliferative effects of CTN and its causal factors were investigated in the kidneys of gpt delta rats. In addition, three in vivo genotoxicity assays (reporter gene mutation using gpt delta rats and comet and micronucleus assays using F344 rats) were performed to clarify whether CTN was genotoxic in vivo. CTN was administrated at 20 and 40mg/kg/day, the higher dose being the maximal tolerated dose and a nearly carcinogenic dose. In the kidney cortex of gpt delta rats, significant increases in the labeling indices of proliferating cell nuclear antigen (PCNA)-positive cells were observed at all doses of CTN. Increases in the mRNA expression levels of Ccna2, Ccnb1, Ccne1, and its transcription factor E2f1 were also detected, suggesting induction of cell cycle progression at all tested doses of CTN. However, histopathological changes were found only in rats treated with the higher dose of CTN, which was consistent with increases in the mRNA expression levels of mitogenic factors associated with tissue damage/regeneration, such as Hgf and Lcn2, at the same dose. Thus, the proliferative effects of CTN may result not only from compensatory reactions, but also from direct mitogenic action. Western blot analysis showed that ERK phosphorylation was increased at all doses, implying that cell cycle progression may be mediated by activation of the ERK pathway. On the other hand, in vivo genotoxicity analyses were negative, implying that CTN did not have the potential for inducing DNA damage, gene mutations, or chromosomal aberrations. The overall data clearly demonstrated the molecular events underlying CTN-induced cell cycle progression, which could be helpful to understand CTN-induced renal carcinogenesis.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kuroda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Shinji
authors.initials: S
authors.lastname: Takasu
authors.forename: Aki
authors.initials: A
authors.lastname: Kijima
authors.forename: Kohei
authors.initials: K
authors.lastname: Matsushita
authors.forename: Maiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Haruo
authors.initials: H
authors.lastname: Takahashi
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Sugita-Konishi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sakai
authors.forename: Tokuma
authors.initials: T
authors.lastname: Yanai
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ogawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Umemura
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000235:genetics; D002953:Citrinin / Q000633:toxicity*; D020552:Comet Assay; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics; D008297:Male; D015162:Micronucleus Tests; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D002953:Citrinin; D017228:Hepatocyte Growth Factor; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine
keywords: Cell proliferation; Citrinin; In vivo genotoxicity; Renal carcinogenesis