Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT231
L. Ratnasinghe
Systems toxicology is going through a revolution with advancements in genomics methods. Microarray technology has been a significant driving force in toxicogenomics. Next generation sequencing methods promise to overtake use of microarrays in the toxicology tool kit by overcoming many of the limitations of microarrays. In next generation sequencing, every nucleic acid molecule is sequenced individually and counted. Millions of molecules can be sequenced simultaneously eliminating the need for traditional standards and reference samples. The promise of next generation sequencing is that genome of an entire organism or a cell can be sequenced rapidly and affordably. All the RNA transcripts in a cell can be sequenced, identified, counted, and categorized with almost absolute precision. Systems toxicology, which involves the iterative study of how chemicals influence gene expression and toxicological outcomes will be vastly improved with the adaptation of next generation sequencing. Keywords: sequencing; digital-PCR; microarrays; pharmacogenomics; diagnostics
{"title":"Sequencing Technology Advances and Toxicology","authors":"L. Ratnasinghe","doi":"10.1002/9780470744307.GAT231","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT231","url":null,"abstract":"Systems toxicology is going through a revolution with advancements in genomics methods. Microarray technology has been a significant driving force in toxicogenomics. Next generation sequencing methods promise to overtake use of microarrays in the toxicology tool kit by overcoming many of the limitations of microarrays. In next generation sequencing, every nucleic acid molecule is sequenced individually and counted. Millions of molecules can be sequenced simultaneously eliminating the need for traditional standards and reference samples. The promise of next generation sequencing is that genome of an entire organism or a cell can be sequenced rapidly and affordably. All the RNA transcripts in a cell can be sequenced, identified, counted, and categorized with almost absolute precision. Systems toxicology, which involves the iterative study of how chemicals influence gene expression and toxicological outcomes will be vastly improved with the adaptation of next generation sequencing. \u0000 \u0000 \u0000Keywords: \u0000 \u0000sequencing; \u0000digital-PCR; \u0000microarrays; \u0000pharmacogenomics; \u0000diagnostics","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"4 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121267297","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT211
S. Sahu
The review of literature demonstrates that systems toxicology is a valuable tool for early prediction and mechanistic assessment of liver toxicity. It will provide accurate molecular information for toxicity hazard and risk assessment in relatively short period of time. This technology will find very useful applications in food safety. It is an excellent tool for quick screening of hepatotoxic potential of food-related products that occur naturally or that are added deliberately to the foods and dietary supplements. The published reports show the value of omics technologies in combination with classical histopathology and biochemical assays providing a powerful tool for accurate assessment of “predictive” and “mechanistic” hepatotoxicity. The systems toxicology in vitro offers a powerful cost-effective tool for faster high-throughput toxicity testing. It can be effectively used for high-throughput screening of food-related products for potential hepatotoxicity. Keywords: hepatotoxicity; in vitro toxicity; systems toxicology; risk assessment; omics technology
{"title":"Systems Toxicology: A Valuable Tool for Early Prediction and Mechanistic Assessment of Liver Toxicity of Food‐Related Products","authors":"S. Sahu","doi":"10.1002/9780470744307.GAT211","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT211","url":null,"abstract":"The review of literature demonstrates that systems toxicology is a valuable tool for early prediction and mechanistic assessment of liver toxicity. It will provide accurate molecular information for toxicity hazard and risk assessment in relatively short period of time. This technology will find very useful applications in food safety. It is an excellent tool for quick screening of hepatotoxic potential of food-related products that occur naturally or that are added deliberately to the foods and dietary supplements. The published reports show the value of omics technologies in combination with classical histopathology and biochemical assays providing a powerful tool for accurate assessment of “predictive” and “mechanistic” hepatotoxicity. The systems toxicology in vitro offers a powerful cost-effective tool for faster high-throughput toxicity testing. It can be effectively used for high-throughput screening of food-related products for potential hepatotoxicity. \u0000 \u0000 \u0000Keywords: \u0000 \u0000hepatotoxicity; \u0000in vitro toxicity; \u0000systems toxicology; \u0000risk assessment; \u0000omics technology","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130605640","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT226
W. Tong, Q. Shi, W. Salminen, Minjun Chen, H. Fang, A. Suzuki, D. Mendrick
Liver toxicity accounts for 40% of failed drugs in clinical studies and approximately 21% of drugs that are removed from the market. It is suspected that drug-induced liver injury (DILI) is more common in females, thus impacting women's health to a higher degree. However, it is unclear how common this potential sex-based sensitivity may be and the mechanisms underlying the differences. High-content and high-throughput molecular technologies such as DNA microarrays have contributed significantly to the understanding of health and disease at the molecular level. In 2001, DNA microarray studies began to emerge to investigate sex-associated liver gene expression profiles under physiological and pathological conditions. This review is an analysis of clinical reports published to date to determine the weight of evidence in support of sex-biased sensitivity to DILI. Sex differences related to disease susceptibility/progression and adverse drug events are discussed at the molecular level with emphasis on genomic data in an attempt to place the evidence in a biological context. Keywords: DILI; sex difference; genomics; drug-induced liver injury
{"title":"Unravelling Sex Differences in Drug‐Induced Liver Injury","authors":"W. Tong, Q. Shi, W. Salminen, Minjun Chen, H. Fang, A. Suzuki, D. Mendrick","doi":"10.1002/9780470744307.GAT226","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT226","url":null,"abstract":"Liver toxicity accounts for 40% of failed drugs in clinical studies and approximately 21% of drugs that are removed from the market. It is suspected that drug-induced liver injury (DILI) is more common in females, thus impacting women's health to a higher degree. However, it is unclear how common this potential sex-based sensitivity may be and the mechanisms underlying the differences. High-content and high-throughput molecular technologies such as DNA microarrays have contributed significantly to the understanding of health and disease at the molecular level. In 2001, DNA microarray studies began to emerge to investigate sex-associated liver gene expression profiles under physiological and pathological conditions. This review is an analysis of clinical reports published to date to determine the weight of evidence in support of sex-biased sensitivity to DILI. Sex differences related to disease susceptibility/progression and adverse drug events are discussed at the molecular level with emphasis on genomic data in an attempt to place the evidence in a biological context. \u0000 \u0000 \u0000Keywords: \u0000 \u0000DILI; \u0000sex difference; \u0000genomics; \u0000drug-induced liver injury","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"88 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133542471","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT224
Alexandra Sposny, C. Schmitt, P. Hewitt
We have used modern omics technologies (including Toxicogenomics, proteomics, metabonomics and profiling from FFPE tissues) to ascertain whether a systems biology approach would improve our understanding of the mechanism of toxicity of a compound. Wistar rats were treated for up to 14 days with a non-toxic dose (15 mg kg−1) or a high dose (350 mg kg−1) of a known hepatotoxic compound (EMD 335823), chosen to ensure significant hepatotoxicity (liver necrosis, fibrosis, and bile duct necrosis/hyperplasia). Genomics, proteomics, and metabonomics identified animals with the most severe effects, in good agreement with pathological findings. Protein expression changes correlated well with gene expression changes, indicating that EMD 335823 regulated PPARα signaling. EMD 335823 is an aldose reductase inhibitor resulting in increased glucose metabolism and alterations in fatty acid metabolism. These disturbances result in lower energy resources, contributing to the pathogenesis of liver damage. Proteomics and metabonomics also showed clear separation of the most severely affected animals, although the limited numbers of molecules identified could not reveal the mechanism of toxicity alone. The combination of omics technologies allowed a more detailed analysis and identification of potential mechanisms of action, improving the overall understanding of the compounds toxicity. Additionally, there are indications that a compound-specific signature was visible earlier, when no histopathological changes occurred. Keywords: cross-omics comparison; genomics; hepatotoxicity; metabonomics; proteomics; systems toxicology
我们使用了现代组学技术(包括毒理学基因组学、蛋白质组学、代谢组学和FFPE组织分析)来确定系统生物学方法是否会提高我们对化合物毒性机制的理解。Wistar大鼠用无毒剂量(15 mg kg - 1)或高剂量(350 mg kg - 1)的已知肝毒性化合物(EMD 335823)治疗长达14天，以确保显著的肝毒性(肝坏死、纤维化和胆管坏死/增生)。基因组学、蛋白质组学和代谢组学鉴定出最严重影响的动物，与病理结果很好地一致。蛋白表达变化与基因表达变化具有良好的相关性，表明EMD 335823调控PPARα信号转导。EMD 335823是醛糖还原酶抑制剂，导致葡萄糖代谢增加和脂肪酸代谢改变。这些干扰导致能量资源减少，导致肝损伤的发病机制。蛋白质组学和代谢组学也显示出受影响最严重的动物的明确分离，尽管鉴定的分子数量有限，无法单独揭示毒性机制。组学技术的结合可以更详细地分析和确定潜在的作用机制，提高对化合物毒性的整体理解。此外，有迹象表明，在没有发生组织病理学变化的情况下，化合物特异性标记较早可见。关键词:跨组学比较;基因组学;肝毒性;代谢组学;蛋白质组学;系统毒理学
{"title":"Mechanistic Investigation of EMD335823s Hepatotoxicity Using Multiple Omics Profiling Technologies","authors":"Alexandra Sposny, C. Schmitt, P. Hewitt","doi":"10.1002/9780470744307.GAT224","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT224","url":null,"abstract":"We have used modern omics technologies (including Toxicogenomics, proteomics, metabonomics and profiling from FFPE tissues) to ascertain whether a systems biology approach would improve our understanding of the mechanism of toxicity of a compound. \u0000 \u0000 \u0000 \u0000Wistar rats were treated for up to 14 days with a non-toxic dose (15 mg kg−1) or a high dose (350 mg kg−1) of a known hepatotoxic compound (EMD 335823), chosen to ensure significant hepatotoxicity (liver necrosis, fibrosis, and bile duct necrosis/hyperplasia). \u0000 \u0000 \u0000 \u0000Genomics, proteomics, and metabonomics identified animals with the most severe effects, in good agreement with pathological findings. Protein expression changes correlated well with gene expression changes, indicating that EMD 335823 regulated PPARα signaling. EMD 335823 is an aldose reductase inhibitor resulting in increased glucose metabolism and alterations in fatty acid metabolism. These disturbances result in lower energy resources, contributing to the pathogenesis of liver damage. Proteomics and metabonomics also showed clear separation of the most severely affected animals, although the limited numbers of molecules identified could not reveal the mechanism of toxicity alone. \u0000 \u0000 \u0000 \u0000The combination of omics technologies allowed a more detailed analysis and identification of potential mechanisms of action, improving the overall understanding of the compounds toxicity. Additionally, there are indications that a compound-specific signature was visible earlier, when no histopathological changes occurred. \u0000 \u0000 \u0000Keywords: \u0000 \u0000cross-omics comparison; \u0000genomics; \u0000hepatotoxicity; \u0000metabonomics; \u0000proteomics; \u0000systems toxicology","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"3 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131323089","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT241
Yang Xu, M. Mahmood, A. Biris
Given their unique properties, the nanostructural materials have found a large number of applications in medicine and biology. Some of these applications range from cell visualization, specific targeting and destruction of cancer cells, drug and gene delivery, or scaffolds for tissue regeneration. Novel multifunctional nanomaterials with magnetic properties and graphitic shells were synthesized and were found to act as strong thermal agents for cellular thermal ablation under radio frequency excitation. Also carbon-based nanomaterials were found to synergistically enhance the activity of anti -cancer drugs, opening the possibility of complex approaches for cancer treatment. Keywords: carbon nanotubes (CNTs); magnetic nanoparticles; anti-cancer drugs; radio frequency; cancer cells
{"title":"Multifunctional Nanomaterials for Biomedical Applications: The Onset of Nanomedicine","authors":"Yang Xu, M. Mahmood, A. Biris","doi":"10.1002/9780470744307.GAT241","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT241","url":null,"abstract":"Given their unique properties, the nanostructural materials have found a large number of applications in medicine and biology. Some of these applications range from cell visualization, specific targeting and destruction of cancer cells, drug and gene delivery, or scaffolds for tissue regeneration. Novel multifunctional nanomaterials with magnetic properties and graphitic shells were synthesized and were found to act as strong thermal agents for cellular thermal ablation under radio frequency excitation. Also carbon-based nanomaterials were found to synergistically enhance the activity of anti -cancer drugs, opening the possibility of complex approaches for cancer treatment. \u0000 \u0000 \u0000Keywords: \u0000 \u0000carbon nanotubes (CNTs); \u0000magnetic nanoparticles; \u0000anti-cancer drugs; \u0000radio frequency; \u0000cancer cells","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"15 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133268778","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT240
G. Bernardini, A. Cattaneo, E. Sabbioni, M. Gioacchino, M. Chiriva-Internati, R. Gornati
The wide interest in nanoscience and nanotechnology leads to an ever-increasing presence of nanomaterials in the environment that in turn may be associated with potentially new and largely undefined risks for the human health and for the environment. We reviewed the experimental data on the ecotoxicology of engineered nanometals following their intentional, unavoidable or accidental dispersion in the environment, together with the benefits of their use for bioremediation. Two potential threats for the human health, the carcinogenic and allergenic risks, have been subsequently evaluated in in vitro and in vivo systems. Lung and skin inflammation and possibly mutagenesis are the mainly documented effects, but the available data remain scarce and fragmentary, and toxicity is shared by both metallic and non-metallic nanomaterials. The conclusive paragraph discusses the use of nanometals in traditional medicine and the development of metal based nanodrugs. A careful evaluation of risks and benefits is mandatory even in this case.Keywords:allergy;cancer;ecotoxicology;magnetic nanoparticles;nanomedicine;nanotoxicology
{"title":"Toxicology of Engineered Metal Nanoparticles","authors":"G. Bernardini, A. Cattaneo, E. Sabbioni, M. Gioacchino, M. Chiriva-Internati, R. Gornati","doi":"10.1002/9780470744307.GAT240","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT240","url":null,"abstract":"The wide interest in nanoscience and nanotechnology leads to an ever-increasing presence of nanomaterials in the environment that in turn may be associated with potentially new and largely undefined risks for the human health and for the environment. We reviewed the experimental data on the ecotoxicology of engineered nanometals following their intentional, unavoidable or accidental dispersion in the environment, together with the benefits of their use for bioremediation. Two potential threats for the human health, the carcinogenic and allergenic risks, have been subsequently evaluated in in vitro and in vivo systems. Lung and skin inflammation and possibly mutagenesis are the mainly documented effects, but the available data remain scarce and fragmentary, and toxicity is shared by both metallic and non-metallic nanomaterials. The conclusive paragraph discusses the use of nanometals in traditional medicine and the development of metal based nanodrugs. A careful evaluation of risks and benefits is mandatory even in this case.Keywords:allergy;cancer;ecotoxicology;magnetic nanoparticles;nanomedicine;nanotoxicology","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"98 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123320997","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT201
P. Joseph
Human exposure to toxic chemicals is almost unavoidable. The toxicity owing to human exposure to chemicals may result in adverse health effects such as illnesses and even death. It is therefore important to determine whether human exposure to chemicals may result in toxicity and, if so, to obtain a full understanding of the mechanism(s) underlying the toxicity. Recent developments in genomics and their application in toxicology (toxicogenomics) have facilitated a better understanding of chemical toxicity. Unlike traditional toxicity studies, toxicogenomics studies have the potential to detect toxicity pre-clinically (before the onset of clinical manifestations of toxicity) and this may have implications even in predicting the toxicity of chemicals. Recent studies have demonstrated the potential application of genomics-based toxicity determination in surrogate tissues such as blood, for monitoring human exposure to toxic chemicals. The potential of toxicogenomics in determining the toxicity of chemicals is best illustrated in the case of hepatotoxic chemicals. It is anticipated that toxicogenomics studies, in conjunction with the traditional toxicity determination approaches, may be useful to determine the systems toxicity of chemicals. Keywords: blood; gene expression; hepatotoxicity; microarray; surrogate tissue; toxicogenomics
{"title":"Toxicogenomics — Applications in Systems Toxicology","authors":"P. Joseph","doi":"10.1002/9780470744307.GAT201","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT201","url":null,"abstract":"Human exposure to toxic chemicals is almost unavoidable. The toxicity owing to human exposure to chemicals may result in adverse health effects such as illnesses and even death. It is therefore important to determine whether human exposure to chemicals may result in toxicity and, if so, to obtain a full understanding of the mechanism(s) underlying the toxicity. Recent developments in genomics and their application in toxicology (toxicogenomics) have facilitated a better understanding of chemical toxicity. Unlike traditional toxicity studies, toxicogenomics studies have the potential to detect toxicity pre-clinically (before the onset of clinical manifestations of toxicity) and this may have implications even in predicting the toxicity of chemicals. Recent studies have demonstrated the potential application of genomics-based toxicity determination in surrogate tissues such as blood, for monitoring human exposure to toxic chemicals. The potential of toxicogenomics in determining the toxicity of chemicals is best illustrated in the case of hepatotoxic chemicals. It is anticipated that toxicogenomics studies, in conjunction with the traditional toxicity determination approaches, may be useful to determine the systems toxicity of chemicals. \u0000 \u0000 \u0000Keywords: \u0000 \u0000blood; \u0000gene expression; \u0000hepatotoxicity; \u0000microarray; \u0000surrogate tissue; \u0000toxicogenomics","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"27 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122835515","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT225
Lei Guo, J. Fuscoe, P. Fu, N. Mei
Herbal dietary supplements are used extensively worldwide and the consumption has dramatically increased in the United States in recent years. Although side effects of many herbal dietary supplements have been reported, safety assurance has not been addressed adequately and toxicological data on most herbal dietary supplements are lacking. To address the issue of human health protection, there are currently more than 30 herbal dietary supplements or active ingredients under study by the US National Toxicology Program (NTP). Herbal products often exhibit great variability in quality because of different processing methods, cultivation conditions, and harvest time, as well as the strain and species differences. Authentication of plant species used for preparation of herbal dietary supplements is a critical step of safety assurance. Botanical extracts differ from drugs in that they are mixtures of many active constituents. At present, there are no well-established methodologies for evaluating the toxicity or determining the toxic mechanisms of herbal plant extracts due to the complexity of chemical components. In this chapter, we describe the applications of DNA microarray for plant authentication and mechanistic studies of herbal dietary supplements. Keywords: authentication of plant species; gene expression; herbal dietary supplements; microarray; pathway analysis; toxicity
{"title":"Application of DNA Microarray in Studies of Herbal Dietary Supplements","authors":"Lei Guo, J. Fuscoe, P. Fu, N. Mei","doi":"10.1002/9780470744307.GAT225","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT225","url":null,"abstract":"Herbal dietary supplements are used extensively worldwide and the consumption has dramatically increased in the United States in recent years. Although side effects of many herbal dietary supplements have been reported, safety assurance has not been addressed adequately and toxicological data on most herbal dietary supplements are lacking. To address the issue of human health protection, there are currently more than 30 herbal dietary supplements or active ingredients under study by the US National Toxicology Program (NTP). Herbal products often exhibit great variability in quality because of different processing methods, cultivation conditions, and harvest time, as well as the strain and species differences. Authentication of plant species used for preparation of herbal dietary supplements is a critical step of safety assurance. Botanical extracts differ from drugs in that they are mixtures of many active constituents. At present, there are no well-established methodologies for evaluating the toxicity or determining the toxic mechanisms of herbal plant extracts due to the complexity of chemical components. In this chapter, we describe the applications of DNA microarray for plant authentication and mechanistic studies of herbal dietary supplements. \u0000 \u0000 \u0000Keywords: \u0000 \u0000authentication of plant species; \u0000gene expression; \u0000herbal dietary supplements; \u0000microarray; \u0000pathway analysis; \u0000toxicity","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"118 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115596281","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT203
R. Kulkarni, Dayton M Petibone, Ching-Wei Chang, James J. Chen, W. Tolleson, W. Melchior, M. Churchwell, F. Beland, S. Morris
P53, the tumour suppressor protein, plays a crucial role in the maintenance of genomic stability and is regarded as the ‘guardian of the genome’. To study tissue differences in p53 loss-of-function mutations, we investigated the effect of N-ethyl-N-nitrosourea (ENU), a highly potent mutagen, on gene expression at 4 and 24 h after exposure in the liver of p53+/+, p53+/− and p53−/− mice. Quantitative PCR and a targeted array were used to analyse the expression of 84 genes known to be involved in the p53 pathway at each time point. In addition, the levels of O6-ethyldeoxyguanosine, a major mutagenic DNA adduct, and the expression of Mgmt were determined at the 4- and 24-h time points. Significant differences were found among the three genotypes for the expression of the functional gene groupings of apoptosis, cell cycle, cell growth and proliferation and DNA repair. Furthermore, the loss of O6-ethyldeoxyguanosine from the DNA paralleled the expression of Mgmt in p53+/+ and p53+/− mice. The data from this study will aid in understanding variation in the DNA damage response across tissues and the biological effects of loss of function in p53. Keywords: P53; ENU; gene expression; DNA Adducts
{"title":"Effect of p53 Genotype on Gene Expression and DNA Adducts in ENU-Exposed Mice","authors":"R. Kulkarni, Dayton M Petibone, Ching-Wei Chang, James J. Chen, W. Tolleson, W. Melchior, M. Churchwell, F. Beland, S. Morris","doi":"10.1002/9780470744307.GAT203","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT203","url":null,"abstract":"P53, the tumour suppressor protein, plays a crucial role in the maintenance of genomic stability and is regarded as the ‘guardian of the genome’. To study tissue differences in p53 loss-of-function mutations, we investigated the effect of N-ethyl-N-nitrosourea (ENU), a highly potent mutagen, on gene expression at 4 and 24 h after exposure in the liver of p53+/+, p53+/− and p53−/− mice. Quantitative PCR and a targeted array were used to analyse the expression of 84 genes known to be involved in the p53 pathway at each time point. In addition, the levels of O6-ethyldeoxyguanosine, a major mutagenic DNA adduct, and the expression of Mgmt were determined at the 4- and 24-h time points. Significant differences were found among the three genotypes for the expression of the functional gene groupings of apoptosis, cell cycle, cell growth and proliferation and DNA repair. Furthermore, the loss of O6-ethyldeoxyguanosine from the DNA paralleled the expression of Mgmt in p53+/+ and p53+/− mice. The data from this study will aid in understanding variation in the DNA damage response across tissues and the biological effects of loss of function in p53. \u0000 \u0000 \u0000Keywords: \u0000 \u0000P53; \u0000ENU; \u0000gene expression; \u0000DNA Adducts","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"11 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122205933","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT230
T. Ushijima, E. Okochi‐Takada, Hideyuki Takeshima
Epigenetic modifications are essential for development, differentiation, and reprogramming. They are inherited upon somatic cell replication, and include DNA methylation and histone modifications. Abnormality of epigenetic modifications is deeply involved in human cancers, as known by global hypomethylation and regional hypermethylation. Recent findings on the high fraction of cells affected in normal-appearing tissues indicated that epigenomic alterations are also involved in acquired disorders other than cancers. In spite of the deep involvement of epigenomic alterations in human diseases, only limited information is available for inducers of epigenetic changes, including aging, chronic inflammation, virus infection, disturbances in one carbon metabolism, and some chemicals. One of the reasons why a very limited number of chemicals are known as inducers of epigenetic alterations (epimutagens) is the lack of a sufficiently convenient and sensitive assay system. Toxicological considerations from the viewpoint of epigenomics are critically important, and epigenomic toxicology has just started. Keywords: epigenetics; DNA methylation; histone modification; epigenome; cancer; epimutation; epimutagen
{"title":"Epigenomic Analysis in Toxicology","authors":"T. Ushijima, E. Okochi‐Takada, Hideyuki Takeshima","doi":"10.1002/9780470744307.GAT230","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT230","url":null,"abstract":"Epigenetic modifications are essential for development, differentiation, and reprogramming. They are inherited upon somatic cell replication, and include DNA methylation and histone modifications. Abnormality of epigenetic modifications is deeply involved in human cancers, as known by global hypomethylation and regional hypermethylation. Recent findings on the high fraction of cells affected in normal-appearing tissues indicated that epigenomic alterations are also involved in acquired disorders other than cancers. In spite of the deep involvement of epigenomic alterations in human diseases, only limited information is available for inducers of epigenetic changes, including aging, chronic inflammation, virus infection, disturbances in one carbon metabolism, and some chemicals. One of the reasons why a very limited number of chemicals are known as inducers of epigenetic alterations (epimutagens) is the lack of a sufficiently convenient and sensitive assay system. Toxicological considerations from the viewpoint of epigenomics are critically important, and epigenomic toxicology has just started. \u0000 \u0000 \u0000Keywords: \u0000 \u0000epigenetics; \u0000DNA methylation; \u0000histone modification; \u0000epigenome; \u0000cancer; \u0000epimutation; \u0000epimutagen","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"24 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116689025","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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