Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT209
V. Desai
In recent years, mitochondria have gained significant attention in toxicology because of their involvement in several drug-induced toxicities and in the pathogenesis of a number of degenerative diseases. Thus far, numerous molecular and biochemical assays have been developed and utilized to understand the association between mitochondria and drug toxicities or disease processes. However, the knowledge gained by these assays is inadequate to obtain a comprehensive outlook of the mitochondrial activity during toxic exposures and the underlying pathologies. High-throughput technologies, such as DNA microarray, have great potential in advancing genomic research in toxicology. This technology allows expression profiling of thousands of genes in a single experiment. Building on this technology, a mitochondria-specific mouse oligonucleotide microarray (MitoChip) was developed, which is described in this review. This review also discusses results generated using the MitoChip in studies that were designed to elucidate the molecular mechanisms of altered mitochondrial function induced by anti-HIV drugs (zidovudine and lamivudine) and a weight-loss dietary supplement (usnic acid) in mice. The results from these studies clearly demonstrate that the MitoChip is a valuable genomic tool and can help unravel the underlying molecular basis of impaired mitochondrial function in drug-induced toxicities. Keywords: anti-HIV drugs; gene expression profiles; mitochondria; MitoChip; mouse; usnic acid
{"title":"Mitochondria‐Specific Mouse Gene Array and its Application in Toxicogenomics","authors":"V. Desai","doi":"10.1002/9780470744307.GAT209","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT209","url":null,"abstract":"In recent years, mitochondria have gained significant attention in toxicology because of their involvement in several drug-induced toxicities and in the pathogenesis of a number of degenerative diseases. Thus far, numerous molecular and biochemical assays have been developed and utilized to understand the association between mitochondria and drug toxicities or disease processes. However, the knowledge gained by these assays is inadequate to obtain a comprehensive outlook of the mitochondrial activity during toxic exposures and the underlying pathologies. High-throughput technologies, such as DNA microarray, have great potential in advancing genomic research in toxicology. This technology allows expression profiling of thousands of genes in a single experiment. Building on this technology, a mitochondria-specific mouse oligonucleotide microarray (MitoChip) was developed, which is described in this review. This review also discusses results generated using the MitoChip in studies that were designed to elucidate the molecular mechanisms of altered mitochondrial function induced by anti-HIV drugs (zidovudine and lamivudine) and a weight-loss dietary supplement (usnic acid) in mice. The results from these studies clearly demonstrate that the MitoChip is a valuable genomic tool and can help unravel the underlying molecular basis of impaired mitochondrial function in drug-induced toxicities. \u0000 \u0000 \u0000Keywords: \u0000 \u0000anti-HIV drugs; \u0000gene expression profiles; \u0000mitochondria; \u0000MitoChip; \u0000mouse; \u0000usnic acid","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"117135431","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.GAT232
Z. Su, B. Ning, H. Fang, H. Hong, R. Perkins, W. Tong, Leming Shi
Over the past five years, DNA sequencing has been undergoing fundamental changes due to the rapid development of next-generation sequencing (NGS) technologies. NGS technologies have been offering unprecedented opportunities for high-throughput functional genomic research, and opening up new fields and novel applications in biology, life sciences, and biomedicine. The major advantages of NGS technologies over conventional Sanger sequencing include sequencing cost reduction from about 0.50 per kilobase to as little as 0.001 per kilobase, and massive parallelism that dramatically increases sequencing throughput. However, Sanger-based approaches provide advantages in terms of read-length and base call accuracy. In this chapter, we first describe the fundamental principles of four currently commercialized NGS platforms from Roche/454, Illumina, Life Technologies, and Helicos BioSciences. Next we discuss the challenges in analyzing short reads from NGS, and outline major applications of these new technologies. Finally, we compare data between NGS and microarrays with a toxicogenomics study aiming at gene expression profiling. Keywords: next-generation sequencing (NGS); ultra high-throughput sequencing; RNA-Seq; ChIP-Seq; transcriptome; toxicogenomics; sequence alignment
{"title":"Next-Generation Sequencing: A Revolutionary Tool for Toxicogenomics","authors":"Z. Su, B. Ning, H. Fang, H. Hong, R. Perkins, W. Tong, Leming Shi","doi":"10.1002/9780470744307.GAT232","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT232","url":null,"abstract":"Over the past five years, DNA sequencing has been undergoing fundamental changes due to the rapid development of next-generation sequencing (NGS) technologies. NGS technologies have been offering unprecedented opportunities for high-throughput functional genomic research, and opening up new fields and novel applications in biology, life sciences, and biomedicine. The major advantages of NGS technologies over conventional Sanger sequencing include sequencing cost reduction from about 0.50 per kilobase to as little as 0.001 per kilobase, and massive parallelism that dramatically increases sequencing throughput. However, Sanger-based approaches provide advantages in terms of read-length and base call accuracy. \u0000 \u0000 \u0000 \u0000In this chapter, we first describe the fundamental principles of four currently commercialized NGS platforms from Roche/454, Illumina, Life Technologies, and Helicos BioSciences. Next we discuss the challenges in analyzing short reads from NGS, and outline major applications of these new technologies. Finally, we compare data between NGS and microarrays with a toxicogenomics study aiming at gene expression profiling. \u0000 \u0000 \u0000Keywords: \u0000 \u0000next-generation sequencing (NGS); \u0000ultra high-throughput sequencing; \u0000RNA-Seq; \u0000ChIP-Seq; \u0000transcriptome; \u0000toxicogenomics; \u0000sequence alignment","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"117181588","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.GAT238
Ludmila V. Danilova, M. Ochs
{"title":"Biomarkers of System Response to Therapeutic Intervention","authors":"Ludmila V. Danilova, M. Ochs","doi":"10.1002/9780470744307.GAT238","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT238","url":null,"abstract":"","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128931897","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.GAT215
M. Sepúlveda, K. Ralston-Hooper, Brian C. Sanchez, Amber Hopf-jannasch, S. D. Baker, N. Diaz, J. Adamec
Over the last decade, the environmental sciences have witnessed an incredible movement towards the utilization of high through-put molecular tools that are capable of detecting simultaneous changes of hundreds and even thousands of molecules and molecular components after exposure of organisms to different environmental stressors. These techniques have received lots of attention because they not only offer the potential to unravel novel mechanisms of physiological and toxic action, but they also are amenable for the discovery of biomarkers of exposure and effects. In this chapter we will review the state of knowledge of two of these holistic tools in ecotoxicological research: Proteomics and metabolomics. We will follow this review with a presentation of three of our own case studies utilizing proteomic and metabolomic tools: (i) Analysis of proteomic responses in fish exposed to different types of contaminants using GeneGo™; (ii) Comparison of proteomic and metabolomic responses in aquatic invertebrates exposed to herbicides; and (ii) Use of metabolomics to characterize egg quality in fish eating birds exposed to persistent organic pollutants. We will end with some ideas for future studies and research needs. Keywords: proteomics; metabolomics; ecotoxicology; fish; invertebrates; birds; aquatic; wildlife; biomarkers; contaminants; toxicity; pollution
{"title":"Use of Proteomic and Metabolomic Techniques in Ecotoxicological Research","authors":"M. Sepúlveda, K. Ralston-Hooper, Brian C. Sanchez, Amber Hopf-jannasch, S. D. Baker, N. Diaz, J. Adamec","doi":"10.1002/9780470744307.GAT215","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT215","url":null,"abstract":"Over the last decade, the environmental sciences have witnessed an incredible movement towards the utilization of high through-put molecular tools that are capable of detecting simultaneous changes of hundreds and even thousands of molecules and molecular components after exposure of organisms to different environmental stressors. These techniques have received lots of attention because they not only offer the potential to unravel novel mechanisms of physiological and toxic action, but they also are amenable for the discovery of biomarkers of exposure and effects. In this chapter we will review the state of knowledge of two of these holistic tools in ecotoxicological research: Proteomics and metabolomics. We will follow this review with a presentation of three of our own case studies utilizing proteomic and metabolomic tools: (i) Analysis of proteomic responses in fish exposed to different types of contaminants using GeneGo™; (ii) Comparison of proteomic and metabolomic responses in aquatic invertebrates exposed to herbicides; and (ii) Use of metabolomics to characterize egg quality in fish eating birds exposed to persistent organic pollutants. We will end with some ideas for future studies and research needs. \u0000 \u0000 \u0000Keywords: \u0000 \u0000proteomics; \u0000metabolomics; \u0000ecotoxicology; \u0000fish; \u0000invertebrates; \u0000birds; \u0000aquatic; \u0000wildlife; \u0000biomarkers; \u0000contaminants; \u0000toxicity; \u0000pollution","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132020826","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.GAT220
Athina Zira, S. Theocharis
The report and understanding of interactions among genes, proteins and metabolites is of crucial importance in the classification of mechanisms involved in chemical/drug-induced toxicity. Consequently, the application of the “omics” technologies (genomics, proteomics and metabonomics), and mainly metabonomics, is imperative in toxicological studies. Metabonomics has been widely used in established models of target organ toxicity in order to monitor the effect of the toxic agents and possibly identify novel biomarkers of toxicity. In the present review, the applications of metabonomics in toxicological studies have been reported. Although limitations from the use of this technology in toxicology still exist, its combination with genomics and proteomics could provide valuable information for the underlying mechanisms of target organ toxicity. Keywords: brain; heart; kidney; liver; metabolomics; toxicity
{"title":"Application of Metabonomic Approach in Target Organ Toxicity","authors":"Athina Zira, S. Theocharis","doi":"10.1002/9780470744307.GAT220","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT220","url":null,"abstract":"The report and understanding of interactions among genes, proteins and metabolites is of crucial importance in the classification of mechanisms involved in chemical/drug-induced toxicity. Consequently, the application of the “omics” technologies (genomics, proteomics and metabonomics), and mainly metabonomics, is imperative in toxicological studies. Metabonomics has been widely used in established models of target organ toxicity in order to monitor the effect of the toxic agents and possibly identify novel biomarkers of toxicity. In the present review, the applications of metabonomics in toxicological studies have been reported. Although limitations from the use of this technology in toxicology still exist, its combination with genomics and proteomics could provide valuable information for the underlying mechanisms of target organ toxicity. \u0000 \u0000 \u0000Keywords: \u0000 \u0000brain; \u0000heart; \u0000kidney; \u0000liver; \u0000metabolomics; \u0000toxicity","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122786994","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.GAT248
J. Sina, F. Sistare
The concept of integrating molecular and biochemical data from new technologies with more traditional endpoints to develop a more complete understanding of risks and benefits in drug development has gained wide acceptance as a reasonable way to advance human health. However, actual implementation of this systems approach is not straightforward. While technology keeps advancing, our ability to accurately interpret the complexity of human biology has not kept pace. Indeed, sometimes the case seems to be one of the deeper we investigate, the more we realize what we do not understand. Additionally, in developing ethical pharmaceuticals, a major issue is establishing the necessary level of confidence to extrapolate from a series of endpoint measurements to accurately predict beneficial and/or potentially adverse responses in the diverse population of patients. The evidentiary standard for acceptance of new models and biomarkers in clinical practice is necessarily high, although the concept of “fit-for-purpose” may help expedite the application of new knowledge in specific clinical situations. This chapter will present a view of both the progress and hurdles to applying systems toxicology to drug development in a regulated environment. Keywords: systems toxicology; drug development; biomarkers; clinical translation; pre-clinical; pathways; review; genomics; metabolomics; proteomics
{"title":"Implementing Systems Toxicology in Drug Development for Regulatory Decision Making","authors":"J. Sina, F. Sistare","doi":"10.1002/9780470744307.GAT248","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT248","url":null,"abstract":"The concept of integrating molecular and biochemical data from new technologies with more traditional endpoints to develop a more complete understanding of risks and benefits in drug development has gained wide acceptance as a reasonable way to advance human health. However, actual implementation of this systems approach is not straightforward. While technology keeps advancing, our ability to accurately interpret the complexity of human biology has not kept pace. Indeed, sometimes the case seems to be one of the deeper we investigate, the more we realize what we do not understand. Additionally, in developing ethical pharmaceuticals, a major issue is establishing the necessary level of confidence to extrapolate from a series of endpoint measurements to accurately predict beneficial and/or potentially adverse responses in the diverse population of patients. The evidentiary standard for acceptance of new models and biomarkers in clinical practice is necessarily high, although the concept of “fit-for-purpose” may help expedite the application of new knowledge in specific clinical situations. This chapter will present a view of both the progress and hurdles to applying systems toxicology to drug development in a regulated environment. \u0000 \u0000 \u0000Keywords: \u0000 \u0000systems toxicology; \u0000drug development; \u0000biomarkers; \u0000clinical translation; \u0000pre-clinical; \u0000pathways; \u0000review; \u0000genomics; \u0000metabolomics; \u0000proteomics","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129905689","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.GAT236
T. Knudsen, R. Dewoskin
High-throughput or high-content studies are now providing a rich source of data that can be applied to in vitro profiling of chemical compounds for biological activity and potential in vivo toxicity. EPA's ToxCast™ project, and the broader Tox21 consortium, as well as other projects worldwide, are providing high-throughput and high-content screening data (HTS-HCS) focusing on the in vitro targets and cellular bioactivity profiles for thousands of chemical compounds in commerce or entering the environment. A goal of chemical profiling is to rapidly identify and efficiently classify signatures of biological activity that are potentially diagnostic of in vivo toxicities using automated technologies. Predictive modeling of developmental toxicity faces several challenges: correlating in vitro concentration–response with internal dose–response kinetics; understanding how in vitro bioactivity profiles extrapolate from one cell-type or technology platform to another; and linking individual targets of in vitro bioactivity to complex signatures associated with pathways of in vivo toxicity. Toxicity in the intact organism is an expression of complex and interwoven events that follow from cellular perturbations. As such, multicellular computer models known as ‘virtual tissues’ that recapitulate developmental events can provide a technology platform to simulate non-linear behaviors of dynamical systems and to model perturbations. A virtual embryo, for example, might be envisaged as a toolbox of computational (in silico) models that execute morphogenetic programs to simulate developmental toxicity. Keywords: computational toxicology; high-throughput; screening; developmental toxicity; chemical profiling; toxicity pathways; predictive models; risk assessment; mechanistic models; systems biology; virtual tissues
{"title":"Systems Modeling in Developmental Toxicity","authors":"T. Knudsen, R. Dewoskin","doi":"10.1002/9780470744307.GAT236","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT236","url":null,"abstract":"High-throughput or high-content studies are now providing a rich source of data that can be applied to in vitro profiling of chemical compounds for biological activity and potential in vivo toxicity. EPA's ToxCast™ project, and the broader Tox21 consortium, as well as other projects worldwide, are providing high-throughput and high-content screening data (HTS-HCS) focusing on the in vitro targets and cellular bioactivity profiles for thousands of chemical compounds in commerce or entering the environment. A goal of chemical profiling is to rapidly identify and efficiently classify signatures of biological activity that are potentially diagnostic of in vivo toxicities using automated technologies. Predictive modeling of developmental toxicity faces several challenges: correlating in vitro concentration–response with internal dose–response kinetics; understanding how in vitro bioactivity profiles extrapolate from one cell-type or technology platform to another; and linking individual targets of in vitro bioactivity to complex signatures associated with pathways of in vivo toxicity. Toxicity in the intact organism is an expression of complex and interwoven events that follow from cellular perturbations. As such, multicellular computer models known as ‘virtual tissues’ that recapitulate developmental events can provide a technology platform to simulate non-linear behaviors of dynamical systems and to model perturbations. A virtual embryo, for example, might be envisaged as a toolbox of computational (in silico) models that execute morphogenetic programs to simulate developmental toxicity. \u0000 \u0000 \u0000Keywords: \u0000 \u0000computational toxicology; \u0000high-throughput; \u0000screening; \u0000developmental toxicity; \u0000chemical profiling; \u0000toxicity pathways; \u0000predictive models; \u0000risk assessment; \u0000mechanistic models; \u0000systems biology; \u0000virtual tissues","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126986048","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.GAT243
Jinsong Zhang, J. Spallholz
Selenium is a necessary dietary constituent of at least 25 human selenoproteins and enzymes all containing selenocysteine. In excessive amounts, all selenium compounds become toxic in a dose-dependent fashion to cells in vitro and to the primary target tissue of chronic selenium toxicity, the liver. Elemental selenium of zero valence state has long been considered to be biologically inert. With bovine serum albumin or other dispersant agents such as polysaccharide, biologically active nano-selenium particles (Nano-Se) are formed from sodium selenite and glutathione. Different from the biologically inert black elemental selenium with coarse size, red Nano-Se manifests toxicity which conforms to the concern of nanotoxicity. However, compared with selenium compounds such as sodium selenite, selenomethionine and Se-methylselenocysteine, Nano-Se is not compromised in increasing the activities of selenoenzymes including glutathione peroxidase and thioredoxin reductase at nutritional levels and phase 2 detoxification enzymes such as glutathione S-transferase at supranutritional levels, but exhibits much lower toxicities. Nano-Se is thus a potential selenium source with a prominent characteristic of lower toxicity for supplementation. Keywords: toxicity; selenite; selenomethionine; Se-methylselenocysteine; nano-selenium particles
{"title":"Toxicity of Selenium Compounds and Nano‐Selenium Particles","authors":"Jinsong Zhang, J. Spallholz","doi":"10.1002/9780470744307.GAT243","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT243","url":null,"abstract":"Selenium is a necessary dietary constituent of at least 25 human selenoproteins and enzymes all containing selenocysteine. In excessive amounts, all selenium compounds become toxic in a dose-dependent fashion to cells in vitro and to the primary target tissue of chronic selenium toxicity, the liver. Elemental selenium of zero valence state has long been considered to be biologically inert. With bovine serum albumin or other dispersant agents such as polysaccharide, biologically active nano-selenium particles (Nano-Se) are formed from sodium selenite and glutathione. Different from the biologically inert black elemental selenium with coarse size, red Nano-Se manifests toxicity which conforms to the concern of nanotoxicity. However, compared with selenium compounds such as sodium selenite, selenomethionine and Se-methylselenocysteine, Nano-Se is not compromised in increasing the activities of selenoenzymes including glutathione peroxidase and thioredoxin reductase at nutritional levels and phase 2 detoxification enzymes such as glutathione S-transferase at supranutritional levels, but exhibits much lower toxicities. Nano-Se is thus a potential selenium source with a prominent characteristic of lower toxicity for supplementation. \u0000 \u0000 \u0000Keywords: \u0000 \u0000toxicity; \u0000selenite; \u0000selenomethionine; \u0000Se-methylselenocysteine; \u0000nano-selenium particles","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133649698","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 : 2009-12-15DOI: 10.1002/9780470744307.GAT177
R. Olson, B. Cusack
Cardiotoxicity of anthracyclines limits their therapeutic potential. In the in vitro acute model, anthracyclines produce cardiotoxicity in minutes or hours at concentrations near 100 μM, through a mechanism involving impairment of sarcoplasmic reticulum (SR) function and requiring the quinone moiety, most likely through a non-free-radical process. The chronic cardiotoxicity is more complex, but may also involve SR. Additional mechanisms in the chronic model of anthracycline cardiotoxicity may include impairment of triiodothyronine function, cardiac protein degradation, free-radical generation, apoptosis, cardiac metabolite formation, impairment of iron metabolism and oestrogen-dependent up-regulation of nitric oxide synthase (NOS). Thus, prevention or attenuation of anthracycline cardiotoxicity may be achieved by favourably manipulating these mechanisms.Keywords:anthracyclines;cardiotoxicity;heart failure;calcium;free radicals;ageing
{"title":"Cardiac Toxicity of Anthracyclines","authors":"R. Olson, B. Cusack","doi":"10.1002/9780470744307.GAT177","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT177","url":null,"abstract":"Cardiotoxicity of anthracyclines limits their therapeutic potential. In the in vitro acute model, anthracyclines produce cardiotoxicity in minutes or hours at concentrations near 100 μM, through a mechanism involving impairment of sarcoplasmic reticulum (SR) function and requiring the quinone moiety, most likely through a non-free-radical process. The chronic cardiotoxicity is more complex, but may also involve SR. Additional mechanisms in the chronic model of anthracycline cardiotoxicity may include impairment of triiodothyronine function, cardiac protein degradation, free-radical generation, apoptosis, cardiac metabolite formation, impairment of iron metabolism and oestrogen-dependent up-regulation of nitric oxide synthase (NOS). Thus, prevention or attenuation of anthracycline cardiotoxicity may be achieved by favourably manipulating these mechanisms.Keywords:anthracyclines;cardiotoxicity;heart failure;calcium;free radicals;ageing","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"117222758","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 : 2009-12-15DOI: 10.1002/9780470744307.GAT018
S. Kitamura, K. Sugihara, Kazuo Nakamura, Y. Kotake, A. Kashiwagi, N. Fujimoto
Many endocrine-disrupting agents, including industrial materials, pesticides, pharmaceuticals and phytochemicals, have been identified with their use by in vitro assay systems and in vivo studies in laboratory animals. These chemicals are widely distributed in the environment, and are able to mimic or antagonize the biological functions of natural hormones. Indeed, abnormalities thought to be due to such agents have been found in animals throughout the world. There is also thought to be a risk to humans, for example, DES syndrome. Xenoestrogens can accumulate in our environment, and may play a role in the increasing incidences of breast cancer, testicular cancer and other problems of the reproductive system in humans. Risks due to endocrine disruptors in the environment are discussed in this chapter. Keywords: endocrine disrupting activity; oestrogen; antiandrogen; reproductive system; central nervous system; immune system
{"title":"Endocrine Disruption in Toxic Responses","authors":"S. Kitamura, K. Sugihara, Kazuo Nakamura, Y. Kotake, A. Kashiwagi, N. Fujimoto","doi":"10.1002/9780470744307.GAT018","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT018","url":null,"abstract":"Many endocrine-disrupting agents, including industrial materials, pesticides, pharmaceuticals and phytochemicals, have been identified with their use by in vitro assay systems and in vivo studies in laboratory animals. These chemicals are widely distributed in the environment, and are able to mimic or antagonize the biological functions of natural hormones. Indeed, abnormalities thought to be due to such agents have been found in animals throughout the world. There is also thought to be a risk to humans, for example, DES syndrome. Xenoestrogens can accumulate in our environment, and may play a role in the increasing incidences of breast cancer, testicular cancer and other problems of the reproductive system in humans. Risks due to endocrine disruptors in the environment are discussed in this chapter. \u0000 \u0000 \u0000Keywords: \u0000 \u0000endocrine disrupting activity; \u0000oestrogen; \u0000antiandrogen; \u0000reproductive system; \u0000central nervous system; \u0000immune system","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125916660","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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