A Practical Approach, Second Edition=Ronald D. Ho.pdf

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CHAPTER 15Functional Genomics and Proteomics inDevelopmental and Reproductive ToxicologyOfer Spiegelstein, Robert M. Cabrera, and Richard H. FinnellCONTENTSI. Introduction ........................................................................................................................622II. Gene Expression ................................................................................................................622A. Background................................................................................................................622B. Microarrays................................................................................................................6231. Complementary DNA (cDNA) Arrays................................................................6232. Oligonucleotide Microarrays...............................................................................6283. Data Analysis and Bioinformatics.......................................................................6294. Experimental Considerations...............................................................................631C. Serial Analysis of Gene Expression..........................................................................6331. General.................................................................................................................6332. Methodology........................................................................................................6333. Limitations ...........................................................................................................6354. SAGE and Developmental Biology.....................................................................635III.Proteomics..........................................................................................................................636A. Background................................................................................................................636B. Protein Expression Analysis......................................................................................6361. Protein Isolation...................................................................................................6362. Protein Identification ...........................................................................................6383. Protein Arrays ......................................................................................................640IV. Predictive Values ................................................................................................................640V. Relevant Websites and Databases......................................................................................641A. Microarrays................................................................................................................641B. SAGE .........................................................................................................................641C. Proteomics..................................................................................................................641References ......................................................................................................................................642621© 2006 by Taylor & Francis Group, LLC
622 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONI. INTRODUCTIONOngoing worldwide efforts continue to produce sequences for genomic assembly and single nucleotidepolymorphism (SNP) typing of DNA, from model organisms to humans, with the initial draftof the human genome having been published in 2001. 1,2 The significance of genetic information isderived from the transcription of genomic DNA into messenger ribonucleic acids (mRNA) thatencode the amino acid sequences of translated proteins. The process culminates in posttranslationalmodifications that are required to form biologically active and functional proteins that participateas enzymes in metabolic pathways. To understand the factors involved in dynamics of biologicalactivity, the intricate relationships between DNA sequences (genomics), RNA levels (functionalgenomics), and expressed proteins (functional proteomics) must be examined. 3,4 Developmentaland reproductive toxicological phenomena in model organisms can also be discerned by carefulexamination at these three fundamental levels. Environmental and pharmaceutical agents can induceabnormal expression of genes, which, should it occur at specific gestational time points of highsusceptibility, may result in abnormal developmental processes that culminate in the birth of aninfant with congenital defects. Such deleterious effects may be examined by techniques that aredescribed in this chapter. Another level of topical organization to study involves protein-toxicantinteractions. This level of inquiry seeks to elucidate altered protein presence, altered binding, orconformational changes that interfere with or damage developmental biological processes.This chapter provides an overview of information and procedures used by contemporary investigatorsto study functional genomics and proteomics. These new cutting edge tools provide themeans to explore the etiology of developmental and reproductive toxicants. Each topic is presentedin such a way as to provide the reader not only with the background information but also with thetheory and assay limitations that can help make practical decisions about the application of thesenew techniques.A. BackgroundII. GENE EXPRESSIONGene expression studies may be approached using several different RNA-based technologies:• In situ hybridization (ISH)• Northern blotting• Ribonuclease protection assays (RPA)• Gene reporter assay• Branched DNA amplification• Reverse transcription–polymerase chain reaction (RT-PCR)• Real-time quantitative RT-PCR• Differential display• Scintillation proximity assay• Rapid analysis of gene expression (RAGE)• Serial analysis of gene expression (SAGE)• MicroarraysEach of these methods provides the means to gather information on gene expression levels.Specific experiments must be designed around the limitations of each assay and the type of dataneeded to fulfill the aims of a given study. To study complex biological processes at the molecularlevel, these approaches are best used in combination. For instance, microarrays can initially beused to screen thousands of both previously characterized and unknown genes for changes inexpression following exposure to a model compound. Once genes of interest have been identified,© 2006 by Taylor & Francis Group, LLC
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Second EditionDEVELOPMENTALandREPRO
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Published in 2006 byCRC PressTaylor
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Chapter 12Chapter 13Chapter 14Chapt
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The EditorRonald D. Hood, Ph.D., is
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Alan M. HobermanArgus ResearchHorsh
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APPENDIX ATerminology of Anatomical
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TERMINOLOGY OF ANATOMICAL DEFECTS 9
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Organ/StructureCodeNumberObservatio
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Organ/Structure10145 Ocular colobom
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Organ/StructurePulmonaryarteryPulmo
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Terminology of developmental abnorm
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Organ/StructureCervicalcentrumCodeN
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Organ/Structure10689 Misshapen thor
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Organ/StructureSacralcentrumSacralv
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968 DEVELOPMENTAL REPRODUCTIVE TOXI
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1000 DEVELOPMENTAL REPRODUCTIVE TOX
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Table 1Human Non-human Primate Rat
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Table 1 (continued)Sertoli CellsHum
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Table 2 (continued) Landmarks in th
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Table 2 (continued) Landmarks in th
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POSTNATAL DEVELOPMENTAL MILESTONES
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PART IPrinciples and Mechanisms© 2
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4 DEVELOPMENTAL REPRODUCTIVE TOXICO
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10 DEVELOPMENTAL REPRODUCTIVE TOXIC
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Table 2.6Receptor(Official Name a )
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Clearly, more research needs to be
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CHAPTER 6Comparative Features of Ve
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COMPARATIVE FEATURES OF VERTEBRATE
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Table 6.2Comparative reproductive a
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Maturation andRelease ofGametesSper
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Amniotic cavity 9.5 1.5 1-4 1-4,6,9
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Posteriorcardinal veinsestablishedT
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PosteriorcardinaldegenerationRight
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StomachappearsThirdpharyngealpouch;
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Table 6.6DescriptionComparative ges
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ParathyroidParathyroids 12.5 6.2 41
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Table 6.8DescriptionComparative ges
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Formation ofchoroid plexusof latera
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Optic nervefibers presentDifferenti
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Table 6.10DescriptionMuscular Syste
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Distalphalanges offingersseparatedF
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Table 6.11DescriptionIntermediateme
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Table 6.12DescriptionComparative ge
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CHAPTER 7Developmental Toxicity Tes
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DEVELOPMENTAL TOXICITY TESTING —
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Female 0.00-0.69 0.004-0.39 0.00-0.
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Figure 8.11775Pott DescribesScrotal
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The underlying physiology of juveni
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Table 8.5Total body composition by
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Table 8.6Serum chemistry values for
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Table 8.7Parameter bHematology valu
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CHAPTER 9Significance, Reliability,
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DEVELOPMENTAL AND REPRODUCTIVE TOXI
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Prior to the early 1980s, numerous
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Figure 9.51906Food andDrugs Act2000
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Table 9.18Selected comparison point
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Table 9.33Selected comparison point
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Table 9.48What do regulatorswant to
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CHAPTER 10Testing for Reproductive
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TESTING FOR REPRODUCTIVE TOXICITY 4
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We would like to acknowledge the ef
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CHAPTER 12Role of Xenobiotic Metabo
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ROLE OF XENOBIOTIC METABOLISM IN DE
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y ESR spectrometry. 122 Further ESR
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CHAPTER 17Statistical Analysis for
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STATISTICAL ANALYSIS FOR DEVELOPMEN
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CHAPTER 19Perspectives on the Devel
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PERSPECTIVES ON THE DEVELOPMENTAL A
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Guideline OECD 415 (One Generation)
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The Office of Prevention, Pesticide
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CHAPTER 20Human Studies — Epidemi
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HUMAN STUDIES 801I. INTRODUCTIONEpi
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HUMAN STUDIES 803is actively trying
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HUMAN STUDIES 805100908070Induced a
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HUMAN STUDIES 8071009590>37 w33-36
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HUMAN STUDIES 80940003500Mean birth
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HUMAN STUDIES 811from monstrous, us
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HUMAN STUDIES 813A distinction is s
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HUMAN STUDIES 815G. Childhood Cance
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HUMAN STUDIES 829B. The Formation o
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HUMAN STUDIES 837with spina bifida
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HUMAN STUDIES 83926. Haglund, B. an
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CHAPTER 21Developmental and Reprodu
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