Ochratoxin A induces karyomegaly and cell cycle aberrations in renal tubular cells without relation to induction of oxidative stress responses in rats |
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Authors: | Eriko Taniai Atsunori Yafune Masahiro Nakajima Shim-Mo Hayashi Fumiyuki Nakane Megu Itahashi Makoto Shibutani |
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Affiliation: | 1. Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan;2. Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan;3. Environmental Health Department, Nagoya City Public Health Research Institute, 1-11 Hagiyama-cho, Mizuho-ku, Nagoya 467-8615, Japan;4. San-Ei Gen F.F.I, Inc., 1-4-9 Hirano-machi, Chuo-ku, Osaka 540-8688, Japan |
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Abstract: | Ochratoxin A (OTA) is a renal carcinogen that induces karyomegaly in target renal tubular cells of the outer stripe of the outer medulla (OSOM). This study was performed to clarify the relationship between oxidative stress and the karyomegaly-inducing potential involving cell cycle aberration of OTA in the OSOM. Rats were treated with OTA for 28 days in combination with enzymatically modified isoquercitrin (EMIQ) or α-lipoic acid (ALA) as antioxidants. OTA increased the mRNA levels of the antioxidant enzyme-related genes Gpx1, Gpx2, Gstm1 and Nfe2l2, but did not increase the levels of Gsta5, Keap1, Nqo1, Hmox1, Aldh1a1, Por, Prdx1 and Txn1. OTA also did not change the levels of thiobarbituric acid-reactive substances, glutathione disulfide/reduced glutathione, and the immunoreactive tubular cell distribution of nuclear factor erythroid 2-related factor 2 in the OSOM. Co-treatment with EMIQ or ALA did not cause any changes in these parameters. As previously reported, OTA increased cell proliferation activity, apoptosis and immunohistochemical cellular distributions of molecules suggestive of induction of DNA damage and cell cycle aberrations involving spindle checkpoint disruption and cell cycle arrest. However, co-treatment with EMIQ or ALA did not suppress these changes, and ALA co-treatment increased the cell proliferation activity induced by OTA. These results suggest that OTA facilitates cell cycling involving cell cycle aberrations and apoptosis as a basis of the mechanism behind the development of karyomegaly and subsequent carcinogenicity targeting the OSOM, without relation to induction of oxidative stress. On the other hand, ALA may promote the OTA-induced proliferation of carcinogenic target cells. |
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Keywords: | ALA, α-lipoic acid CMD, choline-methionine deficient diet Cox-2, cyclooxygenase-2 DENA, diethylnitrosamine EMIQ, enzymatically modified isoquercitrin Gpx, glutathione peroxidase ISOM, the inner stripe of the outer medulla Mcm3, minichromosome maintenance 3 Nrf2, nuclear factor erythroid 2-related factor 2 OTA, ochratoxin A GSSG, glutathione disulfide p-Chk2, phosphorylated Chk2 γH2AX, phosphorylated histone H2AX on serine 139 PCNA, proliferating cell nuclear antigen GSH, reduced glutathione TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling TBARS, thiobarbituric acid-reactive substances OSOM, the outer stripe of the outer medulla Topo IIα, topoisomerase IIα tGSH, total glutathione Ubd, ubiquitin D. |
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