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.

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.

Preface	p. xi
Contributors	p. xiii
Acknowledgements	p. xvii
The Reproductive Biology and Spawning of Zebrafish in Laboratory Settings	p. 1
Introduction	p. 1
Overview of Zebrafish Reproductive Biology and Behavior	p. 2
Spawning Techniques and Technology	p. 5
Determining Factors for Reproduction in Laboratory Stocks of Zebrafish	p. 8
Conclusions	p. 11
References	p. 11
Developmental Toxicity Assessment in Zebrafish	p. 15
Introduction	p. 15
Methods	p. 16
Results	p. 20
Discussion	p. 23
References	p. 25
Use of Emerging Models for Developmental Toxicity Testing	p. 27
Importance of Assessing Developmental Toxicity	p. 27
Current Methods for Assessing Developmental Toxicity	p. 27
Use of Emerging Models for Developmental Toxicity Testing	p. 28
New Guidelines for Chemical Testing Using Zebrafish	p. 29
References	p. 43
Assessment of Drug-Induced Cardiotoxicity in Zebrafish	p. 45
Introduction	p. 45
Zebrafish Heart	p. 45
Summary of Cardiotoxicity Study Design and Results	p. 47
Materials and Methods	p. 47
Results	p. 50
Conclusions	p. 54
References	p. 54
Cardiotoxicity Studies in Zebrafish	p. 55
Introduction	p. 55
Repolarization Toxicity	p. 56
Initial Screening: Bradycardia	p. 56
High-Resolution Assays of Repolarization	p. 59
Furture Directions	p. 61
References	p. 62
In Vivo Recording of the Adult Zebrafish Electrocardiogram	p. 65
Introduction	p. 65
Optimization of Zebrafish Electrocardiogram Recording	p. 66
Basic Intervas	p. 68
Drug Effects	p. 69
Conclusions	p. 71
References	p. 72
Hematopoietic and Vascular System Toxicity	p. 73
Introduction	p. 73
Hematopoiesis and Vascular Development in the Zebrafish	p. 73
Morphological and Functional Assays to Assess Toxicity	p. 77
Summary	p. 85
Acknowledgement	p. 85
References	p. 85
Hepatotoxicity Testing in Larval Zebrafish	p. 89
Introduction: The Larval Zebrafish Model	p. 89
Liver Development	p. 89
Hepatic Gene Knockdown and Mutation	p. 91
Hepatotoxicity Testing in Drug Discovery	p. 92
Phenotypic-Based Larval Zebrafish Hepatotoxicity Screens	p. 93
Secondary and Mechanistic Liver Assays	p. 96
Conclusions	p. 99
References	p. 99
Whole Zebrafish Cytochrome P450 Assay for Assessing Drug Metabolism and Safety	p. 103
Introduction	p. 103
Background and Significance	p. 104
Materials and Methods	p. 105
Results	p. 107
Conclusions	p. 113
Acknowledgement	p. 113
References	p. 113
Methods for Assessing Neurotoxicity in Zebrafish	p. 117
Introduction	p. 117
Limitations of Current Neurotoxicity Testing	p. 118
Assessing Neurotoxicity in Zebrafish	p. 118
Summary	p. 130
Acknowledgement	p. 131
References	p. 131
Zebrafish: A Predictive Model for Assessing Cancer Drug-Induced Organ Toxicity	p. 155
Introduction	p. 135
Materials and Methods	p. 136
Results	p. 139
Conclusions	p. 149
References	p. 149
Locomotion and Behavioral Toxicity in Laraval Zebrafish: Background, Methods, and Data	p. 151
Introduction	p. 151
Background	p. 152
Locomotion	p. 153
Zebrafish Models	p. 154
Analyzing Larval Locomotion	p. 155
Chemical Effects on Larval Locomotion	p. 158
Conclusions	p. 161
Acknowledgement	p. 162
References	p. 162
Zebrafish: A Predictive Model for Assessing Seizure Liability	p. 165
Introduction	p. 165
Materials and Methods	p. 167
Results	p. 171
Conclusions	p. 174
References	p. 175
Zebrafish: A New In Vivo Model for Identifying P-Glycoprotein Efflux Modulators	p. 177
Introduction	p. 177
Materials and Methods	p. 179
Results	p. 182
Conclusions	p. 188
Acknowledgments	p. 188
References	p. 189
Assessment of Effects on Visual Function in Larval Zebrafish	p. 191
Introduction	p. 191
Development of Visual System in Zebrafish	p. 192
Methods for Assessing Visual Function in Larval Zebrafish	p. 194
Conclusions	p. 202
References	p. 202
Development of a Hypoxia-Induced Zebrafish Choroidal Neovascularization Model	p. 205
Introduction	p. 205
Materials and Methods	p. 207
Results	p. 210
Discussion	p. 215
Acknowledgments	p. 217
References	p. 217
Zebrafish Xenotransplant Cancer Model for Drug Screening	p. 219
Introduction	p. 219
Background and Significance	p. 219
Materials and Methods	p. 221
Results
Conclusions	p. 230
References	p. 231
Zebrafish Assays for Identifying Potential Muscular Dystrophy Drug Candidates	p. 233
Introduction	p. 233
Materials and Methods	p. 238
Results	p. 242
Discussion	p. 251
Acknowledgment	p. 252
References	p. 252
Cytoprotective Activities of Water-Soluble Fullerenes in Zebrafish Models	p. 257
Introduction	p. 257
Materials and Methods	p. 261
Results	p. 265
Discussion	p. 277
Conclusions	p. 278
Acknowledgments	p. 278
References	p. 279
Fishing to Design Inherently Safer Nanoparticles	p. 283
Introduction	p. 283
Application of Embryonic Zebrafish	p. 284
Tier 1: Rapid Toxicity Screening	p. 286
Tier 2: Cellular Toxicity and Distribution	p. 288
Tier 3: Molecular Expression	p. 289
Embryonic Zebrafish Data to Design "Safer" Nanoparticles	p. 291
Conclusions	p. 292
References	p. 292
Radiation-Induced Toxicity and Radiation Response Modifiers in Zebrafish	p. 295
Introduction	p. 295
Materials and Methods	p. 296
Validation of Zebrafish Embryos as a Model System for Radiation Protectors/Sensitizers	p. 298
Gross Morphological Alterations Associated with Radiation Exposure	p. 299
Radiation-Associated Apoptosis Incidence	p. 299
Radiation-Associated Gastrointestinal Toxicity	p. 300
Radiation-Associated Nephrotoxicity	p. 301
Ototoxicity in Irradiated Zebrafish	p. 301
Radiation Protectors in Zebrafish	p. 302
Summary	p. 303
References	p. 304
Caudal Fin Regeneration in Zebrafish	p. 307
Introduction	p. 307
Signaling and Epimorphic Regeneration	p. 308
Caudal Fin Architecture	p. 308
Stages of Epimorphic Regeneration	p. 309
Methodology	p. 311
Strategies Used to Manipulate Gene Function During Fin Regeneration	p. 312
The Largal Fin Regeneration Model	p. 316
Summary	p. 317
Acknowledgement	p. 317
References	p. 317
Index	p. 321
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