Kyosuke Yamashita, H. Matsumoto, Fumiyo Saito, M. Takeyoshi
Anesthesia is used for pain control and is necessary in toxicological studies. In this study, we examined the effects of anesthesia on gene expression profiles caused by different types of anesthesia. To elucidate the effects of anesthesia on gene expression profiles, DNA microarray analysis was performed with CO2-O2 anesthesia and isoflurane anesthesia, and gene expression profiles in the liver were analyzed. Consequently, a total of 209 probes out of 61,573 showed higher or lower expression levels in the isoflurane anesthesia group compared with CO2-O2 anesthesia. This is less than 0.34% of all probes, indicating that the effects of different types of anesthesia on gene expression profiles are limited. However, careful consideration should be taken in the cases of handling the disturbed genes using DNA microarray, especially in case of research on glutathione-related pathway under isoflurane anesthesia.
{"title":"Differences in gene expression profiles in liver caused by different types of anesthesia: cases of CO2-O2 and isoflurane.","authors":"Kyosuke Yamashita, H. Matsumoto, Fumiyo Saito, M. Takeyoshi","doi":"10.2131/jts.40.829","DOIUrl":"https://doi.org/10.2131/jts.40.829","url":null,"abstract":"Anesthesia is used for pain control and is necessary in toxicological studies. In this study, we examined the effects of anesthesia on gene expression profiles caused by different types of anesthesia. To elucidate the effects of anesthesia on gene expression profiles, DNA microarray analysis was performed with CO2-O2 anesthesia and isoflurane anesthesia, and gene expression profiles in the liver were analyzed. Consequently, a total of 209 probes out of 61,573 showed higher or lower expression levels in the isoflurane anesthesia group compared with CO2-O2 anesthesia. This is less than 0.34% of all probes, indicating that the effects of different types of anesthesia on gene expression profiles are limited. However, careful consideration should be taken in the cases of handling the disturbed genes using DNA microarray, especially in case of research on glutathione-related pathway under isoflurane anesthesia.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"38 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121876416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jin Li, Dao Li, Chao-rong Tie, Ji Wu, Qiong Wu, Qixiong Li
Cisplatin (CP) is a major antineoplastic drug for the treatment of solid tumors, but it has dose-dependent renal tubular toxicity. Previous studies have shown that induction of cytochrome P450 (CYP) by CP may play a role in the renal injury of CP. The aim of this study was to investigate the relationship between CP-induced toxicity and CYP4A11 expression in human renal tubular epithelial cells (HK-2). 20-Hydroxyeicosatetraenoic acid (20-HETE) is a CYP4A11 metabolite of arachidonic acid that plays an important role in renal injury. The activity of lactate dehydrogenase (LDH) was determined by spectrophotometer. CYP4A11 expression was analyzed by immunocytochemistry. CYP4A11 mRNA and protein expression were evaluated by RT-PCR and Western blot analyses. Results showed that 20-HETE (1, 10, 50 μM), a CYP4A11 metabolite of arachidonic acid, significantly increased lactate dehydrogenase (LDH) release in these cells. When CP (10(-4) M) and 20-HETE (1, 10, 50 μM) were co-applied to these cells, CP-induced LDH release was significantly exaggerated by 20-HETE. Furthermore, clofibrate, a CYP4A inducer, also increased LDH release in CP-treated cells. In contrast, the CYP4A inhibitor N-Hydrocy-N'-(-4-butyl-2-methylphenyl) formamidine (HET-0016) decreased LDH release in CP-treated cells. Immunocytochemical analysis showed that CYP4A11expression was much stronger in CP-(10(-4) M) treated cells than that in clofibrate-treated cells. Further RT-PCR and Western blot analyses demonstrated that CYP4A11 mRNA and protein expression were significantly up-regulated in CP- (10(-4) M) treated cells compared to the clofibrate group. The findings of this study indicate that CP is a potent inducer of CYP4A11, and it exerts its toxic functions via the induction of CYP4A11 and 20-HETE generation.
{"title":"Cisplatin-mediated cytotoxicity through inducing CYP4A 11 expression in human renal tubular epithelial cells.","authors":"Jin Li, Dao Li, Chao-rong Tie, Ji Wu, Qiong Wu, Qixiong Li","doi":"10.2131/jts.40.895","DOIUrl":"https://doi.org/10.2131/jts.40.895","url":null,"abstract":"Cisplatin (CP) is a major antineoplastic drug for the treatment of solid tumors, but it has dose-dependent renal tubular toxicity. Previous studies have shown that induction of cytochrome P450 (CYP) by CP may play a role in the renal injury of CP. The aim of this study was to investigate the relationship between CP-induced toxicity and CYP4A11 expression in human renal tubular epithelial cells (HK-2). 20-Hydroxyeicosatetraenoic acid (20-HETE) is a CYP4A11 metabolite of arachidonic acid that plays an important role in renal injury. The activity of lactate dehydrogenase (LDH) was determined by spectrophotometer. CYP4A11 expression was analyzed by immunocytochemistry. CYP4A11 mRNA and protein expression were evaluated by RT-PCR and Western blot analyses. Results showed that 20-HETE (1, 10, 50 μM), a CYP4A11 metabolite of arachidonic acid, significantly increased lactate dehydrogenase (LDH) release in these cells. When CP (10(-4) M) and 20-HETE (1, 10, 50 μM) were co-applied to these cells, CP-induced LDH release was significantly exaggerated by 20-HETE. Furthermore, clofibrate, a CYP4A inducer, also increased LDH release in CP-treated cells. In contrast, the CYP4A inhibitor N-Hydrocy-N'-(-4-butyl-2-methylphenyl) formamidine (HET-0016) decreased LDH release in CP-treated cells. Immunocytochemical analysis showed that CYP4A11expression was much stronger in CP-(10(-4) M) treated cells than that in clofibrate-treated cells. Further RT-PCR and Western blot analyses demonstrated that CYP4A11 mRNA and protein expression were significantly up-regulated in CP- (10(-4) M) treated cells compared to the clofibrate group. The findings of this study indicate that CP is a potent inducer of CYP4A11, and it exerts its toxic functions via the induction of CYP4A11 and 20-HETE generation.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"70 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131999477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Satoshi Tsuji, Yusuke Kuwahara, H. Takagi, Masayuki Sugiura, Y. Nakanishi, Masaki Wakamatsu, K. Tsuritani, Yasushi Sato
The rasH2 transgenic (Tg) mice are susceptible to genotoxic and some non-genotoxic carcinogens. In carcinogenicity studies carried out using rasH2 Tg mice, the carcinogenic potential of chemicals are evaluated over a 26-week experimental period. In the present study, we examined the comprehensive gene expressions in the lungs of Tg and non-Tg mice prior to the induction of malignant tumors. Urethane (UR), a mutagenic carcinogen, was administered for 4 weeks, and thereafter withdrawn for 22 weeks. N-methylolacrylamide (NMA), a non-mutagenic carcinogen, was administered for 26 weeks. At week 4, gene expression analysis of non-neoplastic part of the lungs demonstrated changes in the expressions of the cell-cycle and inflammation related genes following UR and NMA treatment, respectively, in both the Tg and non-Tg mice. The gene expressions of epireguline, aurora kinase B, and cyclin B1 increased in the UR-treated Tg mice. We also found an increase in the plasma carcinoembryonic antigen level in the UR-treated Tg mice. Although UR treatment induced the formation of adenomas or adenocarcinomas in the lungs in all mice, earlier induction was apparent in the Tg mice. NMA treatment was found to induce the formation of adenomas and adenocarcinomas at week 26 in the Tg mice, but not in the non-Tg mice, and no expressions of specific genes were apparent in either genotype of mice. Our results indicate that analysis of cancer-related gene expressions in the lungs and plasma biomarkers at week 4 in rasH2 Tg mice could be a screening tool for carcinogenicity, especially of mutagenic carcinogens.
{"title":"Gene expression analysis in the lung of the rasH2 transgenic mouse at week 4 prior to induction of malignant tumor formation by urethane and N-methylolacrylamide.","authors":"Satoshi Tsuji, Yusuke Kuwahara, H. Takagi, Masayuki Sugiura, Y. Nakanishi, Masaki Wakamatsu, K. Tsuritani, Yasushi Sato","doi":"10.2131/jts.40.685","DOIUrl":"https://doi.org/10.2131/jts.40.685","url":null,"abstract":"The rasH2 transgenic (Tg) mice are susceptible to genotoxic and some non-genotoxic carcinogens. In carcinogenicity studies carried out using rasH2 Tg mice, the carcinogenic potential of chemicals are evaluated over a 26-week experimental period. In the present study, we examined the comprehensive gene expressions in the lungs of Tg and non-Tg mice prior to the induction of malignant tumors. Urethane (UR), a mutagenic carcinogen, was administered for 4 weeks, and thereafter withdrawn for 22 weeks. N-methylolacrylamide (NMA), a non-mutagenic carcinogen, was administered for 26 weeks. At week 4, gene expression analysis of non-neoplastic part of the lungs demonstrated changes in the expressions of the cell-cycle and inflammation related genes following UR and NMA treatment, respectively, in both the Tg and non-Tg mice. The gene expressions of epireguline, aurora kinase B, and cyclin B1 increased in the UR-treated Tg mice. We also found an increase in the plasma carcinoembryonic antigen level in the UR-treated Tg mice. Although UR treatment induced the formation of adenomas or adenocarcinomas in the lungs in all mice, earlier induction was apparent in the Tg mice. NMA treatment was found to induce the formation of adenomas and adenocarcinomas at week 26 in the Tg mice, but not in the non-Tg mice, and no expressions of specific genes were apparent in either genotype of mice. Our results indicate that analysis of cancer-related gene expressions in the lungs and plasma biomarkers at week 4 in rasH2 Tg mice could be a screening tool for carcinogenicity, especially of mutagenic carcinogens.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"64 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121518369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhaoju Dong, Zhengping Hu, Haibo Zhu, Ning Li, Huijuan Zhao, Wei Mi, Wanglin Jiang, Xihou Hu, L. Ye
Tris-(2,3-dibromopropyl) isocyanurate (TDBP-TAZTO), an emerging brominated flame retardant, possesses the characteristics of candidate persistent organic pollutants and has displayed toxicity to fish and rodents. TDBP-TAZTO can pass through the blood-brain barrier and accumulate in the brain. TDBP-TAZTO might also induce neuronal cell toxicity. However, the neurotoxicity and mechanisms of TDBP-TAZTO have not yet been studied. We hypothesize that TDBP-TAZTO could induce neurotoxicity in mouse hippocampal neurons and SH-SY5Y cells. The mice were exposed to TDBP-TAZTO of 5 and 50 mg/kg by gavage, daily for 30 days. TDBP-TAZTO resulted in depression-like behaviors, which may be related with TDBP-TAZTO-induced upregulation of oxidative stress markers and overexpression of pro-apoptotic proteins in hippocampus. Furthermore, TDBP-TAZTO treatment for 48 hr (12.5, 25 and 50 µM) damaged SH-SY5Y cells, and led to cell apoptosis and oxidative stress in concentration-dependent manner. Our findings suggested that cell apoptosis and oxidative stress are important mechanisms in neurotoxicity induced by TDBP-TAZTO.
{"title":"Tris-(2,3-dibromopropyl) isocyanurate induces depression-like behaviors and neurotoxicity by oxidative damage and cell apoptosis in vitro and in vivo.","authors":"Zhaoju Dong, Zhengping Hu, Haibo Zhu, Ning Li, Huijuan Zhao, Wei Mi, Wanglin Jiang, Xihou Hu, L. Ye","doi":"10.2131/jts.40.701","DOIUrl":"https://doi.org/10.2131/jts.40.701","url":null,"abstract":"Tris-(2,3-dibromopropyl) isocyanurate (TDBP-TAZTO), an emerging brominated flame retardant, possesses the characteristics of candidate persistent organic pollutants and has displayed toxicity to fish and rodents. TDBP-TAZTO can pass through the blood-brain barrier and accumulate in the brain. TDBP-TAZTO might also induce neuronal cell toxicity. However, the neurotoxicity and mechanisms of TDBP-TAZTO have not yet been studied. We hypothesize that TDBP-TAZTO could induce neurotoxicity in mouse hippocampal neurons and SH-SY5Y cells. The mice were exposed to TDBP-TAZTO of 5 and 50 mg/kg by gavage, daily for 30 days. TDBP-TAZTO resulted in depression-like behaviors, which may be related with TDBP-TAZTO-induced upregulation of oxidative stress markers and overexpression of pro-apoptotic proteins in hippocampus. Furthermore, TDBP-TAZTO treatment for 48 hr (12.5, 25 and 50 µM) damaged SH-SY5Y cells, and led to cell apoptosis and oxidative stress in concentration-dependent manner. Our findings suggested that cell apoptosis and oxidative stress are important mechanisms in neurotoxicity induced by TDBP-TAZTO.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"54 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133787397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Satoshi Takahashi, Koji Morita, M. Kinoshita, S. Fujimori, Toshio Ishikawa
Aryl hydrocarbon receptor (AhR) is a transcription factor activated by xenobiotics, including dioxins and polycyclic aromatic hydrocarbons (PAHs). Although AhR is also activated by some dietary constituents, it has not been completely clarified in what circumstances AhR ligands are ingested in our daily life. Because PAHs are formed by the incomplete combustion of organic materials, we hypothesized that scorched foods might contain and leach out AhR ligands sufficient to stimulate AhR in vitro. To test this hypothesis, scorched foods (bread, cheese, etc.) were mixed vigorously with water, and the supernatants were retrieved as samples. The samples were added to HepG2 cells stably expressing an AhR-responsive reporter gene. Also, expression of CYP1A1, an endogenous AhR-responsive gene, was analyzed by RT-PCR in different cell lines treated with the samples. We further tested whether pretreatment of the samples with activated charcoal would alter their AhR-stimulating activity. All the supernatant samples tested induced AhR-dependent reporter gene activity and CYP1A1 mRNA expression. In some samples, these inductions were inhibited by pretreatment with activated charcoal. Our findings indicate that scorched food leachates stimulate AhR in cultured cells and that activated charcoal adsorbs the AhR-stimulating substances in some leachates. Thus, people who habitually eat scorched foods are exposed to AhR ligands on a regular basis. Further studies are needed to elucidate whether burnt foods actually exert biological effects on our health.
{"title":"Effects of scorched food leachates with or without activated charcoal pretreatment on AhR activation in cultured cells.","authors":"Satoshi Takahashi, Koji Morita, M. Kinoshita, S. Fujimori, Toshio Ishikawa","doi":"10.2131/jts.40.777","DOIUrl":"https://doi.org/10.2131/jts.40.777","url":null,"abstract":"Aryl hydrocarbon receptor (AhR) is a transcription factor activated by xenobiotics, including dioxins and polycyclic aromatic hydrocarbons (PAHs). Although AhR is also activated by some dietary constituents, it has not been completely clarified in what circumstances AhR ligands are ingested in our daily life. Because PAHs are formed by the incomplete combustion of organic materials, we hypothesized that scorched foods might contain and leach out AhR ligands sufficient to stimulate AhR in vitro. To test this hypothesis, scorched foods (bread, cheese, etc.) were mixed vigorously with water, and the supernatants were retrieved as samples. The samples were added to HepG2 cells stably expressing an AhR-responsive reporter gene. Also, expression of CYP1A1, an endogenous AhR-responsive gene, was analyzed by RT-PCR in different cell lines treated with the samples. We further tested whether pretreatment of the samples with activated charcoal would alter their AhR-stimulating activity. All the supernatant samples tested induced AhR-dependent reporter gene activity and CYP1A1 mRNA expression. In some samples, these inductions were inhibited by pretreatment with activated charcoal. Our findings indicate that scorched food leachates stimulate AhR in cultured cells and that activated charcoal adsorbs the AhR-stimulating substances in some leachates. Thus, people who habitually eat scorched foods are exposed to AhR ligands on a regular basis. Further studies are needed to elucidate whether burnt foods actually exert biological effects on our health.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"14 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124818845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cadmium (Cd) is a toxic heavy metal with a long half-life in humans. It causes disorders of various tissue systems, including the kidney, and is associated with protein aggregation. Our previous study demonstrated Cd-induced suppression of the UBE2D gene family, one of the ubiquitin-conjugating enzyme families. However, the precise role of ubiquitin-coding genes in Cd toxicity remains to be understood. In this study, we investigated the effect of Cd on expression of the ubiquitin-coding genes UBB, UBC, UBA80, and UBA52 in HK-2 human proximal tubular cells. Prior to the appearance of Cd toxicity, the UBB, UBC, and UBA80 expression levels increased following Cd treatment. Knockdown of UBB by siRNA transfection significantly decreased Cd cytotoxicity. Notably, Cd induces ubiquitinated protein levels in HK-2 cells, and knockdown of UBB blocked this process. These results suggest that UBB is involved in Cd-induced increase of protein ubiquitination, and that accumulation of ubiquitinated proteins through increased UBB expression may contribute to Cd toxicity in HK-2 cells.
{"title":"Involvement of ubiquitin-coding genes in cadmium-induced protein ubiquitination in human proximal tubular cells.","authors":"Jin-Yong Lee, M. Tokumoto, Y. Fujiwara, M. Satoh","doi":"10.2131/jts.40.901","DOIUrl":"https://doi.org/10.2131/jts.40.901","url":null,"abstract":"Cadmium (Cd) is a toxic heavy metal with a long half-life in humans. It causes disorders of various tissue systems, including the kidney, and is associated with protein aggregation. Our previous study demonstrated Cd-induced suppression of the UBE2D gene family, one of the ubiquitin-conjugating enzyme families. However, the precise role of ubiquitin-coding genes in Cd toxicity remains to be understood. In this study, we investigated the effect of Cd on expression of the ubiquitin-coding genes UBB, UBC, UBA80, and UBA52 in HK-2 human proximal tubular cells. Prior to the appearance of Cd toxicity, the UBB, UBC, and UBA80 expression levels increased following Cd treatment. Knockdown of UBB by siRNA transfection significantly decreased Cd cytotoxicity. Notably, Cd induces ubiquitinated protein levels in HK-2 cells, and knockdown of UBB blocked this process. These results suggest that UBB is involved in Cd-induced increase of protein ubiquitination, and that accumulation of ubiquitinated proteins through increased UBB expression may contribute to Cd toxicity in HK-2 cells.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"10 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132379894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shuso Takeda, Rena Hirota, Sari Teradaira, Masumi Takeda-Imoto, Kazuhito Watanabe, A. Toda, H. Aramaki
The biological activities of cannabidiol (CBD), a major non-psychotropic constituent of the fiber-type cannabis plant, have been examined in detail (e.g., CBD modulation of body weight in mice and rats). However, few studies have investigated the biological activities of cannabidiol-2',6'-dimethyl ether (CBDD), a dimethyl ether derivative of the parent CBD. We herein focused on the effects of CBDD on body weight changes in mice, and demonstrated that it stimulated body weight gain in apolipoprotein E (ApoE)-deficient BALB/c. KOR/Stm Slc-Apoe(shl) mice, especially between 10 and 20 weeks of age.
{"title":"Cannabidiol-2',6'-dimethyl ether stimulates body weight gain in apolipoprotein E-deficient BALB/c. KOR/Stm Slc-Apoe(shl) mice.","authors":"Shuso Takeda, Rena Hirota, Sari Teradaira, Masumi Takeda-Imoto, Kazuhito Watanabe, A. Toda, H. Aramaki","doi":"10.2131/jts.40.739","DOIUrl":"https://doi.org/10.2131/jts.40.739","url":null,"abstract":"The biological activities of cannabidiol (CBD), a major non-psychotropic constituent of the fiber-type cannabis plant, have been examined in detail (e.g., CBD modulation of body weight in mice and rats). However, few studies have investigated the biological activities of cannabidiol-2',6'-dimethyl ether (CBDD), a dimethyl ether derivative of the parent CBD. We herein focused on the effects of CBDD on body weight changes in mice, and demonstrated that it stimulated body weight gain in apolipoprotein E (ApoE)-deficient BALB/c. KOR/Stm Slc-Apoe(shl) mice, especially between 10 and 20 weeks of age.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"139 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134503717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kunihiko Yamashita, Shinsuke Shinoda, Saori Hagiwara, H. Miyazaki, H. Itagaki
The Organisation for Economic Co-operation and Development (OECD) Test Guidelines (TG) adopted the murine local lymph node assay (LLNA) and guinea pig maximization test (GPMT) as stand-alone skin sensitization test methods. However, unsaturated carbon-carbon double-bond and/or lipid acids afforded false-positive results more frequently in the LLNA compared to those in the GPMT and/or in human subjects. In the current study, oleic, linoleic, linolenic, undecylenic, fumaric, maleic, and succinic acid and squalene were tested in a modified LLNA with an elicitation phase (LLNA:DAE), and in a direct peptide reactivity assay (DPRA) to evaluate their skin-sensitizing potential. Oleic, linoleic, linolenic, undecylenic and maleic acid were positive in the LLNA:DAE, of which three, linoleic, linolenic, and maleic acid were positive in the DPRA. Furthermore, the results of the cross-sensitizing tests using four LLNA:DAE-positive chemicals were negative, indicating a chemical-specific elicitation response. In a previous report, the estimated concentration needed to produce a stimulation index of 3 (EC3) of linolenic acid, squalene, and maleic acid in the LLNA was < 10%. Therefore, these chemicals were classified as moderate skin sensitizers in the LLNA. However, the skin-sensitizing potential of all LLNA:DAE-positive chemicals was estimated as weak. These results suggested that oleic, linoleic, linolenic, undecylenic, and maleic acid had skin-sensitizing potential, and that the LLNA overestimated the skin-sensitizing potential compared to that estimated by the LLNA:DAE.
{"title":"Unsaturated fatty acids show clear elicitation responses in a modified local lymph node assay with an elicitation phase, and test positive in the direct peptide reactivity assay.","authors":"Kunihiko Yamashita, Shinsuke Shinoda, Saori Hagiwara, H. Miyazaki, H. Itagaki","doi":"10.2131/jts.40.843","DOIUrl":"https://doi.org/10.2131/jts.40.843","url":null,"abstract":"The Organisation for Economic Co-operation and Development (OECD) Test Guidelines (TG) adopted the murine local lymph node assay (LLNA) and guinea pig maximization test (GPMT) as stand-alone skin sensitization test methods. However, unsaturated carbon-carbon double-bond and/or lipid acids afforded false-positive results more frequently in the LLNA compared to those in the GPMT and/or in human subjects. In the current study, oleic, linoleic, linolenic, undecylenic, fumaric, maleic, and succinic acid and squalene were tested in a modified LLNA with an elicitation phase (LLNA:DAE), and in a direct peptide reactivity assay (DPRA) to evaluate their skin-sensitizing potential. Oleic, linoleic, linolenic, undecylenic and maleic acid were positive in the LLNA:DAE, of which three, linoleic, linolenic, and maleic acid were positive in the DPRA. Furthermore, the results of the cross-sensitizing tests using four LLNA:DAE-positive chemicals were negative, indicating a chemical-specific elicitation response. In a previous report, the estimated concentration needed to produce a stimulation index of 3 (EC3) of linolenic acid, squalene, and maleic acid in the LLNA was < 10%. Therefore, these chemicals were classified as moderate skin sensitizers in the LLNA. However, the skin-sensitizing potential of all LLNA:DAE-positive chemicals was estimated as weak. These results suggested that oleic, linoleic, linolenic, undecylenic, and maleic acid had skin-sensitizing potential, and that the LLNA overestimated the skin-sensitizing potential compared to that estimated by the LLNA:DAE.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121040573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Shirota, J. Kawashima, Tomohiro Nakamura, J. Kamiie, K. Shirota, Midori Yoshida
Xenoestrogen exposure during the critical period of sexual differentiation of the brain causes delayed effects on female reproduction. We investigated the internal dose of orally administered ethynylestradiol (EE) during the critical period and its delayed effects by administering 0 (vehicle control), 0.4, or 2 μg/kg EE to female Sprague-Dawley rats for 5 days from postnatal day (PND) 1. Determination of serum EE level 24 hr after the initial dosing and 6 and 24 hr after the final dosing of 2 μg/kg indicated that the administered EE entered the circulation and cleared after every administration. Although the treatment did not affect physical development, including growth, eyelid opening, and vaginal opening, the estrous cycle was arrested from postnatal week (PNW) 12 even with 0.4 μg/kg EE, with an inverse correlation between doses and arresting ages. Although ovarian morphology at PNW 22-23 indicated that the treatment caused long-term anovulation and cystic follicle formation, the number of primordial follicles at PNW 22-23 was similar among the groups. Because this number was lower than that at PND 10 in all groups, primordial follicles may have been consumed under long-term anovulation. The treatment also caused other abnormalities, including mammary gland hyperplasia, increase in pituitary and liver weights, and decrease in the uterine weight. Because the highest circulating EE level in the 2 μg/kg-treated neonates is considered to be comparable to the physiological range of estradiol-17β, we concluded that a slight increase in the circulating estrogens during the neonatal period exerts irreversible delayed effects.
{"title":"Dose-dependent acceleration in the delayed effects of neonatal oral exposure to low-dose 17α-ethynylestradiol on reproductive functions in female Sprague-Dawley rats.","authors":"M. Shirota, J. Kawashima, Tomohiro Nakamura, J. Kamiie, K. Shirota, Midori Yoshida","doi":"10.2131/jts.40.727","DOIUrl":"https://doi.org/10.2131/jts.40.727","url":null,"abstract":"Xenoestrogen exposure during the critical period of sexual differentiation of the brain causes delayed effects on female reproduction. We investigated the internal dose of orally administered ethynylestradiol (EE) during the critical period and its delayed effects by administering 0 (vehicle control), 0.4, or 2 μg/kg EE to female Sprague-Dawley rats for 5 days from postnatal day (PND) 1. Determination of serum EE level 24 hr after the initial dosing and 6 and 24 hr after the final dosing of 2 μg/kg indicated that the administered EE entered the circulation and cleared after every administration. Although the treatment did not affect physical development, including growth, eyelid opening, and vaginal opening, the estrous cycle was arrested from postnatal week (PNW) 12 even with 0.4 μg/kg EE, with an inverse correlation between doses and arresting ages. Although ovarian morphology at PNW 22-23 indicated that the treatment caused long-term anovulation and cystic follicle formation, the number of primordial follicles at PNW 22-23 was similar among the groups. Because this number was lower than that at PND 10 in all groups, primordial follicles may have been consumed under long-term anovulation. The treatment also caused other abnormalities, including mammary gland hyperplasia, increase in pituitary and liver weights, and decrease in the uterine weight. Because the highest circulating EE level in the 2 μg/kg-treated neonates is considered to be comparable to the physiological range of estradiol-17β, we concluded that a slight increase in the circulating estrogens during the neonatal period exerts irreversible delayed effects.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"108 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128160394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K. Matsunaga, Y. Kuroda, Shinobu Sakai, R. Adachi, R. Teshima, A. Yagami, H. Itagaki
Recent reports suggest that hydrolyzed wheat protein (HWP) variants such as Glupearl® 19S (GP19S) induce immediate-type hypersensitivity via epicutaneous (EC) sensitization. The identification of strong allergens is a key step in product assessment before commercial launch. However, few reports have described the estimation of actual and potential anaphylactic sensitizing capacity. In this study we assessed the strength of both the actual and potential anaphylactic sensitizing capacity by investigating the immediate-type hypersensitivity inducing potential of HWP compared with gluten. We assessed these strengths via the EC route using an EC or intradermal (ID) sensitization method. We quantified the strength of immediate-type hypersensitivity by evaluating the titer of serum antibodies isolated from sensitized subjects using passive cutaneous anaphylaxis (PCA) reactions. We also evaluated the cross-reactivity between GP19S and gluten. GP19S and gluten applied by both the sensitization methods induced obvious IgG1-mediated PCA reactions. GP19S had stronger sensitizing potential than gluten, according to the serum titers and dye spot diameters. The difference in antibody titers between GP19S and gluten was 16-fold for the EC method versus 2-fold for the ID method. GP19S cross-reacted with gluten. Acid hydrolysis of gluten increased anaphylactic sensitizing capacity in the EC method. To our knowledge, our study is the first to quantitatively confirm that HWP and gluten can induce immediate-type hypersensitivity through an intact skin. These findings suggest that acid-HWP imposes a higher risk of EC sensitization than gluten because of the ease with which the former confers a sensitizing effect through the intact skin.
{"title":"Anaphylactic augmentation by epicutaneous sensitization to acid-hydrolyzed wheat protein in a guinea pig model.","authors":"K. Matsunaga, Y. Kuroda, Shinobu Sakai, R. Adachi, R. Teshima, A. Yagami, H. Itagaki","doi":"10.2131/jts.40.745","DOIUrl":"https://doi.org/10.2131/jts.40.745","url":null,"abstract":"Recent reports suggest that hydrolyzed wheat protein (HWP) variants such as Glupearl® 19S (GP19S) induce immediate-type hypersensitivity via epicutaneous (EC) sensitization. The identification of strong allergens is a key step in product assessment before commercial launch. However, few reports have described the estimation of actual and potential anaphylactic sensitizing capacity. In this study we assessed the strength of both the actual and potential anaphylactic sensitizing capacity by investigating the immediate-type hypersensitivity inducing potential of HWP compared with gluten. We assessed these strengths via the EC route using an EC or intradermal (ID) sensitization method. We quantified the strength of immediate-type hypersensitivity by evaluating the titer of serum antibodies isolated from sensitized subjects using passive cutaneous anaphylaxis (PCA) reactions. We also evaluated the cross-reactivity between GP19S and gluten. GP19S and gluten applied by both the sensitization methods induced obvious IgG1-mediated PCA reactions. GP19S had stronger sensitizing potential than gluten, according to the serum titers and dye spot diameters. The difference in antibody titers between GP19S and gluten was 16-fold for the EC method versus 2-fold for the ID method. GP19S cross-reacted with gluten. Acid hydrolysis of gluten increased anaphylactic sensitizing capacity in the EC method. To our knowledge, our study is the first to quantitatively confirm that HWP and gluten can induce immediate-type hypersensitivity through an intact skin. These findings suggest that acid-HWP imposes a higher risk of EC sensitization than gluten because of the ease with which the former confers a sensitizing effect through the intact skin.","PeriodicalId":231048,"journal":{"name":"The Journal of toxicological sciences","volume":"7 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2015-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121052064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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