Toxicogenomics-Based Cellular Models

Toxicogenomics-Based Cellular Models is a unique and valuable reference for all academic and professional researchers employing toxicogenomic methods with respect to animal testing for chemical safety. This resource offers cutting-edge information on the application of toxicogenomics to developing alternatives to current animal toxicity tests. By illustrating the development of toxicogenomics-based cellular models for critical endpoints of toxicity and providing real-world examples for validation and data analysis, this book provides an assessment of the current state of the field, as well as opportunities and challenges for the future. Written by renowned international toxicological experts, this book explores ‘omics technology for developing new assays for toxicity testing and safety assessment and provides the reader with a focused examination of alternative means to animal testing.

• Describes the state-of-the-art in developing toxicogenomics-based cellular models for chemical-induced carcinogenicity, immunotoxicity, developmental toxicity, neurotoxicity and reproduction toxicity
• Illustrates how to validate toxicogenomics-based alternative test models and provides an outlook to societal and economic implementation of these novel assays
• Includes an overview of current testing methods and risk assessment frameworks
• Provides a real-world assessment by articulating the current development and challenges in toxicogenomics while suggesting ways to move this field forward

Scientists, academics and students within the fields of toxicology and molecular biology, as well as regulatory authorities involved in chemical safety

List of Contributors

Section 1: Introduction to Toxicogenomics-Based Cellular Models

Chapter 1.1. Introduction to Toxicogenomics-Based Cellular Models

1.1.1 The demands for alternatives to current animal test models for chemical safety

1.1.2 The toxicogenomics approach

1.1.3 Upgrading cellular models

1.1.4 Regulatory aspects

1.1.5 This book

References

Section 2: Genotoxicity and Carcinogenesis

Chapter 2.1. Application of In Vivo Genomics to the Prediction of Chemical-Induced (hepato)Carcinogenesis

2.1.1 Introduction

2.1.2 Toxicogenomics-based prediction of hepatocarcinogenic hazard

2.1.3 Conclusion and future perspective

References

Chapter 2.2. Unraveling the DNA Damage Response Signaling Network Through RNA Interference Screening

2.2.1 The DNA-damage-induced signaling response

2.2.2 DNA-damage-induced cellular responses

2.2.3 DNA damage in the context of cancer formation and treatment

2.2.4 RNAi screens to study the DDR signaling network

References

Section 3: Immunotoxicity

Chapter 3.1. Immunotoxicity Testing: Implementation of Mechanistic Understanding, Key Pathways of Toxicological Concern, and Components of These Pathways

3.1.1 Introduction

3.1.2 Animal-free assays to detect immunotoxicological endpoints

3.1.3 Toxicogenomics approaches to predicting chemical safety

3.1.4 Gaps and hurdles on the way to risk assessment and human safety

3.1.5 An applied systems toxicology approach to predicting chemical safety

References

Chapter 3.2. Chemical Sensitization

3.2.1 Introduction

3.2.2 Three-dimensional human skin equivalent as a tool for safety testing purposes

3.2.3 Skin sensitization in keratinocytes

3.2.4 Toxicogenomic analysis of cutaneous responses

3.2.5 Alternatives for animal testing of chemical sensitization: an overview

References

Chapter 3.3. ’Omics-Based Testing for Direct Immunotoxicity

3.3.1 Introduction to immunotoxicity

3.3.2 Current guidelines for immunotoxicity testing

3.3.3 Toxicogenomics

3.3.4 Transcriptome quantification tools

3.3.5 Bioinformatics

3.3.6 Immunotoxicogenomics studies: state of the art

3.3.7 Future directions

References

Section 4: Reproduction Toxicity

Chapter 4.1. Implementation of Transcriptomics in the Zebrafish Embryotoxicity Test

4.1.1 The zebrafish embryo as alternative test model for developmental toxicity testing

4.1.2 The zebrafish embryotoxicity test—a variety of methods

4.1.3 Developmental toxicity prediction using the zebrafish embryo

4.1.4 ZET and toxicogenomics

4.1.5 Concentration-dependent gene expression

4.1.6 Relative embryotoxicity using gene expression data

4.1.7 Identification of adaptive and adverse responses using transcriptomics

4.1.8 Interspecies extrapolation of zebrafish gene expression data

4.1.9 Future perspectives

References

Chapter 4.2. Transcriptomic Approaches in In Vitro Developmental Toxicity Testing

4.2.1 Introduction to developmental toxicity testing

4.2.2 Alternative models for developmental toxicity testing

4.2.3 Application of transcriptomics in in vitro developmental toxicity assessments

4.2.4 Outlook

References

Chapter 4.3. Thyroid Toxicogenomics: A Multi-Organ Paradigm

4.3.1 Introduction

4.3.2 The thyroid system

4.3.3 Mode-of-action-based alternative testing strategies for thyroid activity

4.3.4 Conclusion and future perspectives

References

Section 5: Organ Toxicity

Chapter 5.1. Hepatotoxicity Screening on In Vitro Models and the Role of ’Omics

5.1.1 General introduction to hepatotoxicity and its main pathologies

5.1.2 ’Omics-based in vitro approaches for hepatotoxicity screening: the NTC strategy

5.1.3 In vitro liver models used within NTC

5.1.4 Non-’omics-based in vitro approaches for hepatotoxicity screening

References

Chapter 5.2. An Overview of Toxicogenomics Approaches to Mechanistically Understand and Predict Kidney Toxicity

5.2.1 Brief introduction to toxicant-induced renal injury

5.2.2 Use of toxicogenomics in kidney toxicity studies

5.2.3 Functional genomics: a new tool to study target organ toxicity

5.2.4 Conclusions

References

Chapter 5.3. ’Omics in Organ Toxicity, Integrative Analysis Approaches, and Knowledge Generation

5.3.1 Introduction

5.3.2 Gene-expression analysis in the identification of target organ toxicity

5.3.3 Integration of gene-expression data with other ’omics technologies

5.3.4 Systems toxicology approaches for biomarker discovery and mechanisms of toxicity

5.3.5 miRNAs and organ toxicity: putative biomarkers of toxicological processes

References

Chapter 5.4. Hepatotoxicity and the Circadian Clock: A Timely Matter

5.4.1 Introduction

5.4.2 The mammalian circadian clock

5.4.3 Clock-controlled genes

5.4.4 Metabolism and the circadian clock

5.4.5 DNA damage and the circadian clock

5.4.6 Chronotoxicity

5.4.7 In vitro alternatives for toxicity testing

5.4.8 Concluding remarks

Acknowledgments

References

Section 6: Toxicoinformatics

Chapter 6.1. Introduction to Toxicoinformatics

References

Chapter 6.2. Toxicogenomics and Systems Toxicology Databases and Resources: Chemical Effects in Biological Systems (CEBS) and Data Integration by Applying Models on Design and Safety (DIAMONDS)

6.2.1 Introduction

6.2.2 Chemical effects in biological systems

6.2.3 Data integration by applying models on design and safety (DIAMONDS)

References

Chapter 6.3. Bioinformatics Methods for Interpreting Toxicogenomics Data: The Role of Text-Mining

6.3.1 Bioinformatics approaches to toxicogenomics data analysis

6.3.2 Text-mining and its application in toxicogenomics

References

Section 7: Selection and Validation of Toxicogenomics Assays as Alternatives to Animal Tests

Chapter 7.1. Selection and Validation of Toxicogenomics Assays as Alternatives to Animal Tests

7.1.1 Introduction: modern approaches in the development of animal alternatives

7.1.2 Generic elements in the validation of alternative toxicity assays

7.1.3 Stages in the process of development of validated tests

7.1.4 Method validation in relation to its intended use

7.1.5 Generic bottlenecks in the validation process

7.1.6 Feasibility: a practical approach to application

7.1.7 Evaluation criteria for prioritization of scientific tools to enter a pre-validation process

7.1.8 Validation of toxicogenomics assays

7.1.9 Perspectives

References

Section 8: Toxicogenomics Implementation Strategies

Chapter 8.1. Toxicogenomics Implementation Strategies

8.1.1 Introduction

8.1.2 The TGX market is driven by regulations

8.1.3 The European TGX market is still latent

8.1.4 The TGX market develops towards mechanistic understanding of the toxicology mode of action

8.1.5 The best market segments for TGX product/service providers are pharmaceutical and cosmetics companies

8.1.6 Validated predictive and mechanistic toxicology assays and data-analysis/interpretation services

8.1.7 Competitors

8.1.8 Investments

8.1.9 Revenues

8.1.10 Portfolio management

8.1.11 Conclusion

References

Index