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P04: Histopathological features of the Bhd gene mutant (Nihon) rat
ARTICLE IN PRESS Abstracts / Experimental and Toxicologic Pathology 61 (2009) 257–295
for rat hepatocellular preneoplastic and neoplastic lesions, undetectable by well established cytochemical markers ‘‘Glutathione S-transferase placental form (GST-P)’’. (Sukata et al. 2004 Am. J. Pathol.) In this study, we examined whether 78-kDa glucoseregulated protein (GRP78), which is a molecular chaperone and a member of the HSP70 family of heat shock proteins and is known as a receptor of alpha2M, also became a candidate for a new marker of these lesions. GST-P-negative hepatocellular altered foci (HAF), hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC) were generated by two initiationpromotion models with N-nitrosodiethylamine (DEN) and peroxisome proliferators, Wy-14,643 and clofibrate. Total RNAs isolated from laser-microdissected GST-Pnegative HAF (amphophilic cell foci) and adjacent normal tissues were applied to microarray analysis. As a result, microarray analysis revealed that GRP78 mRNA expression was not increased in all GST-P negative lesions, regardless of overexpression of alpha2M mRNA. Immunohistochemical staining for GRP78 could be detectable in GST-P-negative HAF in the same way as alpha2M. GRP78-positive reaction was also detectable in HCC. Furthermore, GRP78 was recognized not only in HCC of rats, but also in HCC of mice. These results suggested that GRP78 was also candidate for a novel marker characteristic for GST-P negative rat hepatocellular preneoplastic and neoplastic lesions. More interestingly, since GRP78 was recognized in the mouse HCC, it is suggested that GRP78 has a possibility that it can become a liver carcinogenic marker beyond a species.
283
RCC develops from early preneoplastic lesions, which began to appear as early as 3 weeks of age, to adenocarcinomas by the age of 6 months. The present work was conducted to further characterize aspect of RCC and to investigate extra-renal lesions of the Nihon rat. A total of 492 rats obtained from a colony of the Nihon rats were assigned at an age of 4 weeks to studies to evaluate the histopathological features of RCC and extra renal lesions. All rats were maintained in a barrier facility for up to 12 or 16 months, then the rats were euthanized and necropsied. All organs were fixed in 10% buffered formalin, and routinely processed for embedding in paraffin. Histopathological examination was performed using sections stained with hematoxylin and eosin, special stainings, and immunohistochemical methods, and electron-microscopy. Two out of 4 abdominal nodules were subjected to genomic analysis to detect mutations or loss of heterozygosity. The primary cell types of the RCC were of the clear/ acidophilic cell type where some similarities were evident to RCCs in BHD syndrome. Heterotopic ossification was occasionally found within RCCs. As the extra-renal lesions, the Nihon rats also showed clear cell hyperplasia/adenoma of the endometrium, clear cell change of the epithelium of striated portions of salivary glands, cardiac rhabdomyomatosis and postoperative abdominal desmoid tumor(s). This rat model provides a useful tool for analyzing the series of events leading to renal tumorigenesis and for studying BHD gene functions. doi: 10.1016/j.etp.2009.02.041
doi: 10.1016/j.etp.2009.02.040
P05 Carcinogenicity study of 3-Monochloropropane-1,2-diol in Sprague-Dawley rats P04 Histopathological features of the Bhd gene mutant (Nihon) rat Mami Kouchia, Kazuo Okimotoa, Izumi Matsumotoa, Yoshiko Michimaea, Toru Yamadaa, Tadashi Inouea, Toru Kimuraa, Takaki Sekia, Masashi Yasubaa, Okio Hinob a Dainippon Sumitomo Pharma Co., Ltd., Japan b Department of Pathology and Oncology, Juntendo University, School of Medicine, Japan We have reported that the Nihon rat, a rat model of hereditary renal cell carcinoma (RCC), carries a single germline nucleotide insertion in the rat counterpart of human Birt–Hogg–Dube´ gene (BHD). In heterozygotes,
Beom Seok Han, Wan-Seob Cho, Hakyoung Lee, Ki Taek Nam, Ki Dae Park, Mina Choi, Seung Hee Kim, Jayoung Jeong, Dong Deuk Jang Department of Toxicological Research, Korea Food and Drug Administration, National Institute of Toxicological Research, Seoul 122-704, Republic of Korea 3-Monochloropropane-1,2-diol (a-chlorohydrin, 3-MCPD) is a well-known contaminant which has been detected in a wide range of foods and ingredients and is a suspected cause of cancer. In this study, we investigated the carcinogenicity of 3-MCPD in SD rats. Groups of 50 male and 50 female rats were exposed to drinking water containing 0, 25, 100, 400 ppm 3-MCPD for 2 years. Body weights and water consumption of
for rat hepatocellular preneoplastic and neoplastic lesions, undetectable by well established cytochemical markers ‘‘Glutathione S-transferase placental form (GST-P)’’. (Sukata et al. 2004 Am. J. Pathol.) In this study, we examined whether 78-kDa glucoseregulated protein (GRP78), which is a molecular chaperone and a member of the HSP70 family of heat shock proteins and is known as a receptor of alpha2M, also became a candidate for a new marker of these lesions. GST-P-negative hepatocellular altered foci (HAF), hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC) were generated by two initiationpromotion models with N-nitrosodiethylamine (DEN) and peroxisome proliferators, Wy-14,643 and clofibrate. Total RNAs isolated from laser-microdissected GST-Pnegative HAF (amphophilic cell foci) and adjacent normal tissues were applied to microarray analysis. As a result, microarray analysis revealed that GRP78 mRNA expression was not increased in all GST-P negative lesions, regardless of overexpression of alpha2M mRNA. Immunohistochemical staining for GRP78 could be detectable in GST-P-negative HAF in the same way as alpha2M. GRP78-positive reaction was also detectable in HCC. Furthermore, GRP78 was recognized not only in HCC of rats, but also in HCC of mice. These results suggested that GRP78 was also candidate for a novel marker characteristic for GST-P negative rat hepatocellular preneoplastic and neoplastic lesions. More interestingly, since GRP78 was recognized in the mouse HCC, it is suggested that GRP78 has a possibility that it can become a liver carcinogenic marker beyond a species.
283
RCC develops from early preneoplastic lesions, which began to appear as early as 3 weeks of age, to adenocarcinomas by the age of 6 months. The present work was conducted to further characterize aspect of RCC and to investigate extra-renal lesions of the Nihon rat. A total of 492 rats obtained from a colony of the Nihon rats were assigned at an age of 4 weeks to studies to evaluate the histopathological features of RCC and extra renal lesions. All rats were maintained in a barrier facility for up to 12 or 16 months, then the rats were euthanized and necropsied. All organs were fixed in 10% buffered formalin, and routinely processed for embedding in paraffin. Histopathological examination was performed using sections stained with hematoxylin and eosin, special stainings, and immunohistochemical methods, and electron-microscopy. Two out of 4 abdominal nodules were subjected to genomic analysis to detect mutations or loss of heterozygosity. The primary cell types of the RCC were of the clear/ acidophilic cell type where some similarities were evident to RCCs in BHD syndrome. Heterotopic ossification was occasionally found within RCCs. As the extra-renal lesions, the Nihon rats also showed clear cell hyperplasia/adenoma of the endometrium, clear cell change of the epithelium of striated portions of salivary glands, cardiac rhabdomyomatosis and postoperative abdominal desmoid tumor(s). This rat model provides a useful tool for analyzing the series of events leading to renal tumorigenesis and for studying BHD gene functions. doi: 10.1016/j.etp.2009.02.041
doi: 10.1016/j.etp.2009.02.040
P05 Carcinogenicity study of 3-Monochloropropane-1,2-diol in Sprague-Dawley rats P04 Histopathological features of the Bhd gene mutant (Nihon) rat Mami Kouchia, Kazuo Okimotoa, Izumi Matsumotoa, Yoshiko Michimaea, Toru Yamadaa, Tadashi Inouea, Toru Kimuraa, Takaki Sekia, Masashi Yasubaa, Okio Hinob a Dainippon Sumitomo Pharma Co., Ltd., Japan b Department of Pathology and Oncology, Juntendo University, School of Medicine, Japan We have reported that the Nihon rat, a rat model of hereditary renal cell carcinoma (RCC), carries a single germline nucleotide insertion in the rat counterpart of human Birt–Hogg–Dube´ gene (BHD). In heterozygotes,
Beom Seok Han, Wan-Seob Cho, Hakyoung Lee, Ki Taek Nam, Ki Dae Park, Mina Choi, Seung Hee Kim, Jayoung Jeong, Dong Deuk Jang Department of Toxicological Research, Korea Food and Drug Administration, National Institute of Toxicological Research, Seoul 122-704, Republic of Korea 3-Monochloropropane-1,2-diol (a-chlorohydrin, 3-MCPD) is a well-known contaminant which has been detected in a wide range of foods and ingredients and is a suspected cause of cancer. In this study, we investigated the carcinogenicity of 3-MCPD in SD rats. Groups of 50 male and 50 female rats were exposed to drinking water containing 0, 25, 100, 400 ppm 3-MCPD for 2 years. Body weights and water consumption of