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Zebrafish: Methods for Assessing Drug Safety and Toxicity

ISBN: 978-1-118-10214-5
304 pages
January 2012
Zebrafish: Methods for Assessing Drug Safety and Toxicity (1118102142) cover image
Zebrafish: Methods for Assessing Drug Safety and Toxicity offers a practical guide for using zebrafish as a tool for toxicology studies. 

Consolidating key protocols and approaches to help researchers navigate the important and evolving field of zebrafish models for toxicity screening, this new title describes the methods for using the zebrafish as a model organism to assess compound-induced toxicity on all major organs.  Individual chapters that concentrate on assays for each organ system are included and various analytical tools including microscopy, microplate readers, high content imaging systems, ECG, blood pressure monitors, high speed video and motion detectors are described.

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Preface xi

Contributors xiii

Acknowledgments xvii

1. The Reproductive Biology and Spawning of Zebrafish in Laboratory Settings 1

1.1 Introduction 1

1.2 Overview of Zebrafish Reproductive Biology and Behavior 2

1.3 Spawning Techniques and Technology 5

1.4 Determining Factors for Reproduction in Laboratory Stocks of Zebrafish 8

1.5 Conclusions 11

References 11

2. Developmental Toxicity Assessment in Zebrafish 15

2.1 Introduction 15

2.2 Methods 16

2.3 Results 20

2.4 Discussion 23

References 25

3. Use of Emerging Models for Developmental Toxicity Testing 27

3.1 Importance of Assessing Developmental Toxicity 27

3.2 Current Methods for Assessing Developmental Toxicity 27

3.3 Use of Emerging Models for Developmental Toxicity Testing 28

3.4 New Guidelines for Chemical Testing Using Zebrafish 29

3.5 Conclusions 42

References 43

4. Assessment of Drug-Induced Cardiotoxicity in Zebrafish 45

4.1 Introduction 45

4.2 Zebrafish Heart 45

4.3 Summary of Cardiotoxicity Study Design and Results 47

4.4 Materials and Methods 47

4.5 Results 50

4.6 Conclusions 54

References 54

5. Cardiotoxicity Studies in Zebrafish 55

5.1 Introduction 55

5.2 Repolarization Toxicity 56

5.3 Initial Screening: Bradycardia 56

5.4 High-Resolution Assays of Repolarization 59

5.5 Future Directions 61

References 62

6. In Vivo Recording of the Adult Zebrafish Electrocardiogram 65

6.1 Introduction 65

6.2 Optimization of Zebrafish Electrocardiogram Recording 66

6.3 Basic Intervals 68

6.4 Drug Effects 69

6.5 Conclusions 71

References 72

7. Hematopoietic and Vascular System Toxicity 73

7.1 Introduction 73

7.2 Hematopoiesis and Vascular Development in the Zebrafish 73

7.3 Morphological and Functional Assays to Assess Toxicity 77

7.4 Summary 85

Acknowledgment 85

References 85

8. Hepatotoxicity Testing in Larval Zebrafish 89

8.1 Introduction: The Larval Zebrafish Model 89

8.2 Liver Development 89

8.3 Hepatic Gene Knockdown and Mutation 91

8.4 Hepatotoxicity Testing in Drug Discovery 92

8.5 Phenotypic-Based Larval Zebrafish Hepatotoxicity Screens 93

8.6 Secondary and Mechanistic Liver Assays 96

8.7 Conclusions 99

References 99

9. Whole Zebrafish Cytochrome P450 Assay for Assessing Drug Metabolism and Safety 103

9.1 Introduction 103

9.2 Background and Significance 104

9.3 Materials and Methods 105

9.4 Results 107

9.5 Conclusions 113

Acknowledgment 113

References 113

10. Methods for Assessing Neurotoxicity in Zebrafish 117

10.1 Introduction 117

10.2 Limitations of Current Neurotoxicity Testing 118

10.3 Assessing Neurotoxicity in Zebrafish 118

10.4 Summary 130

Acknowledgments 131

References 131

11. Zebrafish: A Predictive Model for Assessing Cancer Drug-Induced Organ Toxicity 135

11.1 Introduction 135

11.2 Materials and Methods 136

11.3 Results 139

11.4 Conclusions 149

Reference 149

12. Locomotion and Behavioral Toxicity in Larval Zebrafish: Background, Methods, and Data 151

12.1 Introduction 151

12.2 Background 152

12.3 Locomotion 153

12.4 Zebrafish Models 154

12.5 Analyzing Larval Locomotion 155

12.6 Chemical Effects on Larval Locomotion 158

12.7 Conclusions 161

Acknowledgments 162

References 162

13. Zebrafish: A Predictive Model for Assessing Seizure Liability 165

13.1 Introduction 165

13.2 Materials and Methods 167

13.3 Results 171

13.4 Conclusions 174

References 175

14. Zebrafish: A New In Vivo Model for Identifying P-Glycoprotein Efflux Modulators 177

14.1 Introduction 177

14.2 Materials and Methods 179

14.3 Results 182

14.4 Conclusions 188

Acknowledgment 188

References 189

15. Assessment of Effects on Visual Function in Larval Zebrafish 191

15.1 Introduction 191

15.2 Development of Visual System in Zebrafish 192

15.3 Methods for Assessing Visual Function in Larval Zebrafish 194

15.4 Conclusions 202

References 202

16. Development of a Hypoxia-Induced Zebrafish Choroidal Neovascularization Model 205

16.1 Introduction 205

16.2 Materials and Methods 207

16.3 Results 210

16.4 Discussion 215

Acknowledgments 217

References 217

17. Zebrafish Xenotransplant Cancer Model for Drug Screening 219

17.1 Introduction 219

17.2 Background and Significance 219

17.3 Materials and Methods 221

17.4 Results 226

17.5 Conclusions 230

References 231

18. Zebrafish Assays for Identifying Potential Muscular Dystrophy Drug Candidates 233

18.1 Introduction 233

18.2 Materials and Methods 238

18.3 Results 242

18.4 Discussion 251

Acknowledgment 252

References 252

19. Cytoprotective Activities of Water-Soluble Fullerenes in Zebrafish Models 257

19.1 Introduction 257

19.2 Materials and Methods 261

19.3 Results 265

19.4 Discussion 277

19.5 Conclusions 278

Acknowledgments 278

References 279

20. Fishing to Design Inherently Safer Nanoparticles 283

20.1 Introduction 283

20.2 Application of Embryonic Zebrafish 284

20.3 Tier 1: Rapid Toxicity Screening 286

20.4 Tier 2: Cellular Toxicity and Distribution 288

20.5 Tier 3: Molecular Expression 289

20.6 Embryonic Zebrafish Data to Design “Safer” Nanoparticles 291

20.7 Conclusions 292

References 292

21. Radiation-Induced Toxicity and Radiation Response Modifiers in Zebrafish 295

21.1 Introduction 295

21.2 Materials and Methods 296

21.3 Validation of Zebrafish Embryos as a Model System for Radiation Protectors/Sensitizers 298

21.4 Gross Morphological Alterations Associated with Radiation Exposure 299

21.5 Radiation-Associated Apoptosis Incidence 299

21.6 Radiation-Associated Gastrointestinal Toxicity 300

21.7 Radiation-Associated Nephrotoxicity 301

21.8 Ototoxicity in Irradiated Zebrafish 301

21.9 Radiation Protectors in Zebrafish 302

21.10 Summary 303

References 304

22. Caudal Fin Regeneration in Zebrafish 307

22.1 Introduction 307

22.2 Signaling and Epimorphic Regeneration 308

22.3 Caudal Fin Architecture 308

22.4 Stages of Epimorphic Regeneration 309

22.5 Methodology 311

22.6 Strategies Used to Manipulate Gene Function During Fin Regeneration 312

22.7 The Larval Fin Regeneration Model 316

22.8 Summary 317

Acknowledgments 317

References 317

Index 321

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Patricia McGrath, MBA, is President and CEO of Phylonix Pharmaceuticals, Inc. She has some twenty-five years of experience in high-tech and biotechnology management. Phylonix Pharmaceuticals develops and markets novel in vivo zebrafish-based assays for therapeutic and industrial screening for cancers, central nervous system and cardiovascular diseases, apoptosis, and toxicity.
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“This book should prove a useful reference for students, researchers and biomedical science professionals working with this species as an evolving model for toxicity assessment.”  (British Toxicology Society New, 1 November 2012)

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