title: Cellular distribution of cell cycle-related molecules in the renal tubules of rats treated with renal carcinogens for 28 days: relationship between cell cycle aberration and carcinogenesis.
abstract: Some renal carcinogens can induce karyomegaly, which reflects aberrant cell division in the renal tubules, from the early stages of exposure. To clarify the cell cycle-related changes during the early stages of renal carcinogenesis, we performed immunohistochemical analysis of tubular cells in male F344 rats treated with carcinogenic doses of representative renal carcinogens for 28 days. For this purpose, the karyomegaly-inducing carcinogens ochratoxin A (OTA), ferric nitrilotriacetic acid, and monuron, and the non-karyomegaly-inducing carcinogens tris(2-chloroethyl) phosphate and potassium bromate were examined. For comparison, a karyomegaly-inducing non-carcinogen, p-nitrobenzoic acid, and a non-carcinogenic non-karyomegaly-inducing renal toxicant, acetaminophen, were also examined. The outer stripe of the outer medulla (OSOM) and the cortex + OSOM were subjected to morphometric analysis of immunoreactive proximal tubular cells. Renal carcinogens, irrespective of their karyomegaly-inducing potential, increased proximal tubular cell proliferation accompanied by an increase in topoisomerase IIα-immunoreactive cells, suggesting a reflection of cell proliferation. Karyomegaly-inducing carcinogens increased nuclear Cdc2-, γH2AX-, and phosphorylated Chk2-immunoreactive cells in both areas, the former two acting in response to DNA damage and the latter one suggestive of sustained G₂. OTA, an OSOM-targeting carcinogen, could easily be distinguished from untreated controls and non-carcinogens by evaluation of molecules responding to DNA damage and G₂/M transition in the OSOM. Thus, all renal carcinogens examined facilitated proximal tubular proliferation by repeated short-term treatment. Among these, karyomegaly-inducing carcinogens may cause DNA damage and G₂ arrest in the target tubular cells.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Taniai
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Atsunori
authors.initials: A
authors.lastname: Yafune
authors.forename: Maiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Akane
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D002273:Carcinogens; D018797:Cell Cycle Proteins; D006657:Histones; D010750:Phosphoproteins; C577575:gamma-H2AX protein, rat