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

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CHAPTER 16In Vitro Methods for the Study of Mechanismsof Developmental ToxicologyCraig Harris and Jason M. HansenCONTENTSI. Introduction ........................................................................................................................648II. Use of In Vitro Developmental Systems in Studies of Mechanisms ................................649A. Mammalian Embryo Culture.....................................................................................6491. Preimplantation Embryo Culture.........................................................................6492. Peri-implantation Embryo Culture ......................................................................6553. Postimplantation Embryo Culture .......................................................................655B. Other Systems and <strong>Approach</strong>es Employing Whole Embryo Culture ......................6661. Transgenic Animals .............................................................................................6662. Proteomics and Genomics ...................................................................................668C. Nonmammalian Whole Embryo Cultures.................................................................6701. Caenorhabditis elegans Cultures .........................................................................6702. Drosophila Cultures.............................................................................................6703. Amphibian Embryo Culture ................................................................................6704. Fish Embryo Culture ...........................................................................................6715. Avian Embryo Culture.........................................................................................671D. Organ and Tissue Culture..........................................................................................6721. Limb Bud and Related Perinatal Bone Cultures ................................................6732. Palatal Cultures....................................................................................................6763. Visceral Yolk Sac Cultures ..................................................................................6774. Sex Organs...........................................................................................................6785. Heart.....................................................................................................................6786. Eye and Lens .......................................................................................................6787. Embryonic Tooth Germ.......................................................................................6788. Spinal Cord ..........................................................................................................6789. Lung Buds............................................................................................................678E. Cell Culture and Clonal Analysis..............................................................................678III. Summary ............................................................................................................................683References ......................................................................................................................................684647© 2006 by Taylor & Francis Group, LLC
648 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONI. INTRODUCTIONCurrent applications of in vitro developmental systems can be broadly divided into two areas: (1)prescreening for developmental toxicants and (2) testing for elucidation of mechanisms of normaland abnormal embryogenesis. Manifestations of abnormal development are, herein, described asdysmorphogenesis or developmental toxicity to identify the functional or morphological abnormalitiesproduced by chemical or environmental insults in vitro. The relative merits of these modelsfor their respective purposes have been discussed previously at great length. 1–9 It is generally agreedthat in vitro models, such as the rodent whole embryo culture system, may require additionalvalidation before they can be used universally as predictive teratogen prescreens. Nevertheless,clear advantages support the continued development of the various methods as in vitro tools tostudy mechanisms of developmental toxicity. This is especially true for developmental investigationsin viviparous species. Major obstacles encountered in understanding mechanisms of abnormaldevelopment and embryotoxicity include experimental inaccessibility, a paucity of material, andthe numerous confounding maternal, nutritional and physiological influences present in utero. Mostof these limitations can now be overcome through systematic study of the whole conceptus or itsdissociated component parts in vitro at various stages of gestation. A complete understanding of anymechanism, however, is unlikely to emerge from analyses using only a single approach. Ultimately,several in vivo and in vitro methods, utilizing different levels of biological organization and complexity,must be combined in a systematic manner to elucidate mechanisms of developmental toxicity. Inaddition, the likelihood that a single universal mechanism will be found to explain embryotoxicmanifestations caused by environmental extremes and chemical exposure is highly improbable.Various manifestations of embryotoxicity are not expressed uniformly throughout the complex,dynamic and interactive continuum of development and are exhibited during the species’ periodof sensitivity for that specific tissue. Identical maternal exposures to a given chemical agent atdifferent times in gestation may, for example, produce a spectrum of deleterious effects characteristiconly of disturbances in specific developmental processes particularly vulnerable at the timeof exposure. Lesions produced by chemical agents and environmental extremes will, therefore, bemanifest both temporally and spatially at all levels of biological organization. These range fromeffects on the entire conceptus to highly selective alterations at the cellular and molecular levels.In the discussion to follow, emphasis is placed on the use of mammalian cells, tissues, organs, andembryos, although nonmammalian species are highlighted as deemed appropriate.The study of mechanisms of developmental toxicity bears the close and expected resemblanceto similar in vitro methods used for investigating a broad spectrum of toxicological effects in matureorganisms. Systems employing decreasing levels of biological complexity are commonly used toisolate specific processes and probe for specific biochemical and molecular mechanisms that maybe involved in developmental toxicology. Endpoints for analysis can be developed and customized,based on the needs of a particular study. The range of possibilities for analytical endpoints mayinclude (1) an evaluation of gross malformations using visual examination, light microscopy,scanning and transmission electron microscopy, scanning laser confocal microscopy, and computerassisted morphometric analysis; (2) functional and physiological alterations in organs or tissues,including studies of transport, metabolism, biosynthesis, turnover, electrical and metabolic coupling,and maintenance of cellular redox status, and (3) molecular events, including studies of time andtissue-specific gene expression, differentiation, pattern formation, induction, receptor binding andsignal transduction, programmed cell death, and imprinting. Experimental models with higher levelsof biological organization and complexity are useful in the evaluation of mechanisms involvingorgan-organ interactions, pharmacokinetics, and systemic metabolic regulation. Recent advancesin molecular and developmental biology have created new possibilities for evaluation of the dynamicmolecular and biochemical processes of selected cell populations within an intact embryo. Thetechniques involved include the use of specific fluorescent antibody probes and ribonucleotidehybridization markers.© 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 13Use of Toxicokinetics in
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USE OF TOXICOKINETICS IN DEVELOPMEN
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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 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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