| 书目名称 | Drug Toxicity in Embryonic Development I | | 副标题 | Advances in Understa | | 编辑 | Robert J. Kavlock (Director),George P. Daston | | 视频video | | | 丛书名称 | Handbook of Experimental Pharmacology | | 图书封面 |  | | 描述 | Having received the invitation from Springer-Verlag to produce a volume on drug-induced birth defects for the Handbook of Experimental Pharmacology, we asked ourselves what new approach could we offer that would capture the state of the science and bring a new synthesis of the information on this topic to the world‘s literature. We chose a three-pronged approach, centered around those particular drugs for which we have a relatively well established basis for understanding how they exert their unwanted effects on the human embryo. We then supplemented this information with a series of reviews of critical biological processes involved in the established normal developmental patterns, with emphasis on what happens to the embryo when the processes are perturbed by experimental means. Knowing that the search for mechanisms in teratology has often been inhibited by the lack of understanding of how normal development proceeds, we also included chapters describing the amazing new discoveries related to the molecular control of normal morphogenesis for several organ systems in the hope that the experimental toxicologists and molecular biologists will begin to better appreciate each others q | | 出版日期 | Book 1997 | | 关键词 | Geburtsschaden; Morphogenese; abnormal development; birth; birth defects; drug; drugs; embryo; morphogenesis | | 版次 | 1 | | doi | https://doi.org/10.1007/978-3-642-60445-4 | | isbn_softcover | 978-3-642-64408-5 | | isbn_ebook | 978-3-642-60445-4Series ISSN 0171-2004 Series E-ISSN 1865-0325 | | issn_series | 0171-2004 | | copyright | Springer-Verlag Berlin Heidelberg 1997 |
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Front Matter |
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Abstract
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Introduction |
R. J. Kavlock,G. P. Daston |
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Abstract
Between three and six of every 100 babies born are afflicted with a major congenital malformation. Congenital malformations are the leading cause of infant mortality in developed nations. The rate of congenital malformations has not changed appreciably since records began to be kept systematically in the 1930s, although the overall rate of perinatal morbidity and mortality has decreased markedly over the past 50–60 years. The decline in perinatal mortality can be attributed to factors such as the broader availability of prenatal care and the development of effective treatments for infections, neonatal respiratory distress, and other maladies that have their onset around the time of birth and can be cured by treatments administered at that time. However, malformations occur many months before birth, often before the mother is aware of her pregnancy. Once initiated, the processes leading to the development of malformations tend to be irreversible. These factors make it diffcult to decrease the malformation rate. Therefore, it is clear that prevention is the key to solving the dilemma of congenital malformations.
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Abstract
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Cardiac Morphogenesis: Formation and Septation of the Primary Heart Tube |
R. Markwald,T. Trusk,A. Gittenberger-de Groot,R. Poelmann |
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Abstract
Overt morphological and biochemical differentiation of the heart occurs abruptly. The formation of a single, beating, tubular heart is one of the earliest events in vertebrate embryogenesis. Acquisition of function precedes complete morphogenesis. Accordingly, it is not surprising that malformations of the heart occur frequently, approaching 1% of all births, and remain the single largest cause of infant mortality from congenital defects, exceeding cystic fibrosis, hemophilia, or childhood cancer (C. 1987). To be born with a congenital heart defect largely means to have (a) an abnormal communication through which blood shunts inappropriately between the two sides of the heart, (b) defective communication between the chambers on each side of the heart, or (c) faulty “plumbing” exhibited by reductions in size of the two great outlet arteries or misalignment of these arteries with ventricular chambers. In each of these situations, the developmental basis of the defect has been the cause of the failure to solve the morphogenetic riddle of heart development, i.e., how a tubular heart with a single, hollow channel is established that can be subsequently subdivided into four asymmetrical
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Vertebrate Limb Development |
K. Muneoka,R. Anderson |
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Abstract
The developing vertebrate limb is one of the most carefully studied model systems for examining how complex patterns of differentiated tissues form in secondary embryonic fields. The mature vertebrate limb contains a large number of distinct cell types that develop side by side in a highly coordinated and orchestrated manner, and it is the molecular underpinnings of this patterning mechanism that lie at the heart of our understanding of how genetic alterations and toxicological insults result in developmentally defective organs. The limb is an excellent experimental model system because it is a nonessential organ that can be easily manipulated. Because limb-specific defects do not generally result in embryolethality, a large number of mutations in man, mouse, and chicken that alter limb morphogenesis have been characterized, and in some cases studied in some detail. For similar reasons, the limb is also a highly visible target for toxicology studies. In addition, the developing limb bud has been used extensively as a source of cells to study issues concerning cellular differentiation, the control of cell proliferation, and the production of morphogenetic signals; thus the behavior
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Axial Skeleton |
A. Neubüser,R. Balling |
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Abstract
The development of the axial skeleton is a complex process that requires the coordinate regulation of many molecular and cellular events. Although we are still far from understanding it in detail, the availability of molecular markers and the use of in vitro culture techniques has recently opened up a new avenue towards a molecular analysis and has already added much to our understanding of the process.
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Molecular Mechanisms Regulating the Early Development of the Vertebrate Nervous System |
J. D. Burrill,H. Saueressig,M. Goulding |
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Abstract
The vertebrate nervous system arises from a pseudostratified epithelium, the neural plate, that is formed from the dorsal ectoderm of the embryo. Development of the nervous system is marked by a number of morphological events that involve first the induction of “neural tissue”, and then the patterning and refinement of cell fate within this neural tissue. The end result of these morphogenetic events is the generation of topologically defined classes of neurons each with distinct patterns of interconnections and neurotransmitter phenotypes, together with various glial cell types and other accessory cells such as the ependymal cells that line the meninges.
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Genetic Control of Kidney Morphogenesis |
R. Maas,M. Rauchman |
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Abstract
The vertebrate excretory unit, the nephron, is functionally conserved and found in all vertebrates, even dating back to the fossil record (T. 1965). As might well be expected from this degree of functional conservation across species, the genes thus far implicated in nephrogenesis are also conserved at the molecular level, with sequence conservation extending even to genes expressed in the primitive excretory organ of the fruit fly, .. The purpose of this chapter is to review recent advances in the molecular genetics of kidney development and to correlate this information with a rich body of information on nephrogenesis derived from experimental embryology and developmental biology. A definitive monograph on the cell biology of kidney organogenesis has been published (S. 1987), and two recent mini-reviews and a “kidney gene-expression database” are also available (C. and A. 1993; B. et al. 1994, 1996).
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Palate |
E. F. Zimmerman |
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Abstract
Development of the mammalian secondary palate is a complex series of events whose perturbation in humans is characterized by the birth defect cleft palate (CP). Human cleft palate is usually thought to be multifactorially inherited with a frequency of 4 per 10 000 live births and is genetically distinct from cleft lip (CL) with or without cleft palate, which has a frequency of 8 per 10 000 live births (B. et al. 1994). A number of reviews have been written on palate development (Z. 1984; P. and G. 1986; F. 1988).
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Abstract
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Cell Death |
T. B. Knudsen |
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Abstract
One of the major challenges facing teratologists is the elucidation of mechanisms by which birth defects occur. This requires an understanding of the primary targets of physiological and environmental agents that affect the health and well-being of the conceptus, the cellular events of pathogenesis, and the genes which place the embryo at risk. Cell death is gene-directed event in the developing embryo. Its’ broad phylogenetic representation is consistent with a selective advantage in development for the involution of vestigial structures which have importance in phylogenetic but not ontogenetic development, reduction of superfluous cells, disposal of cells that have already completed their functions, elimination of cells which differentiate inappropriately, and suppression of potentially harmful or abnormal cells (S. 1966; E. et al 1991).
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Cellular Responses to Stress |
P. E. Mirkes |
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Abstract
Since the evolution of the cellular phenotype, prokaryotic and eukaryotic cells have had to cope with adverse changes in their environment. Although cells have evolved many distinct stress responses, this chapter will focus on three major, highly conserved, response systems, i.e., the genotoxic response system, which is activated by DNA damage; the oxidative stress response system, which is activated by excess reactive oxygen species (ROS) and imbalances in the oxidant/antioxidant status within cells; and the heat shock response, which is activated by exposure to heat and other agents that adversely affect protein folding (Fig. 1). The sections dealing with each of the stress response systems begin with a description of the prokaryotic stress response because, in most instances, the prokaryotic systems are the best understood. This is followed by a discussion of the eukaryotic stress response systems, focusing on yeast and mammals. Finally, each section concludes with a discussion about what is known concerning the induction of these stress response systems in mammalian embryos, particularly postimplantation mammalian embryos. Normal embryonic development requires a precisely orche
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Cell-Cell Interactions |
P. J. Linser |
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Abstract
My initial contact with teratology occurred in 1974 while I was in graduate school studying developmental biology and teratology at the University of Cincinnati. At that time my teachers included such world-renowned teratologists as James G. Wilson, Josef Warkany, Ernest Zimmerman, William Scott, and Harold Kalter. Also at that time, the University of Cincinnati was one of only a very few institutions that actually granted a Ph.D. degree in “Developmental Biology.” This interdisciplinary degree was based firmly on the study of abnormal development as a window into the regulation of normal embryogenesis.
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Growth Factor Disturbance |
G. T. O’Neill,R. J. Akhurst |
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Abstract
Growth factors are extracellular polypeptides that, by interaction with their corresponding transmembrane receptors, induce a cascade of intracellular signalling responses, which culminate in changes to the phenotype of the target cell (N.-H. 1994). These phenotypic changes include alterations in cellular proliferation or differentiation or alterations in extracellular matrix deposition, which when observed as effects on tissues, can result in altered tissue integrity or morphogenesis.
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Targeted Gene Disruptions as Models of Abnormal Development |
T. W. Sadler,E. T. Liu,K. A. Augustine |
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Abstract
For years teratologists have had access to mice with spontaneously occurring mutations resulting in unique phenotypes. Animals with defects in many organ systems are available and provide valuable information about the origin of specific congenital malformations. However, most of these mutations involve recessive genes, and the genes themselves are unknown (K. 1980). Consequently, there are no markers available to identify mutant embryos before they overtly exhibit an altered phenotype. Thus it is difficult to investigate the earliest cellular events and mechanisms responsible for abnormal phenotypes, since only 25% of all embryos in a litter are affected and there is no way to identify which embryos they are before they exhibit grossly abnormal morphology. As a result, the amount of information provided by these models has been limited, and interpretations of the cellular mechanisms of teratogenesis somewhat speculative.
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Nucleotide Pool Imbalance |
C. Lau |
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Abstract
Ribonucleotides (NTP) and deoxyribonucleotides (dNTP) are the basic building blocks of RNA and DNA. While the major nucleotides are found in all mammalian cells their relative pool sizes are quite different depending on the cell type and species. These unique nucleotide pool patterns are maintained to a large extent, by the tightly regulated biosynthetic and metabolic pathways through a number of feedback controls. Disruption of these balances have been shown to have profound effects on DNA synthesis and replication in cultured cells (A. and D. 1981; T. and B. 1982; D. et al. 1983; N. and M. 1983; M. 1984; N. and R. 1985; Y. et al. 1987; P. and M. 1989; K. et al. 1991; W. et al. 1993). In fact, this biological feature has become a fundamental tenet for the design of chemotherapeutic agents in the past half century.
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Interference with Embryonic Intermediary Metabolism |
E. S. Hunter III |
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Abstract
The purpose of this chapter is to describe normal intermediary metabolism during development and, where possible, to discuss how metabolic perturbation leads to dysmorphogenesis. Embryonic metabolism is dynamic, and what is true about substrate utilization at any specific stage of development may not be true at other stages. For this reason, this review will focus on metabolism during the period of organogenesis.
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Alterations in Folate Metabolism as a Possible Mechanism of Embryotoxicity |
D. K. Hansen |
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Abstract
Interest in folic acid has increased recently as a result of reports of a protective effect of dietary supplementation on the incidence of neural tube defects (NTD) in humans. This chapter will describe folic acid, assays for this vitamin, and characteristics of the deficient state. Biochemical reactions involving folic acid will be reviewed, as will studies which report a protective effect with respect to NTD. A number of compounds which adversely affect folic acid concentrations will be reviewed along with any evidence of a role for folic acid in the developmental toxicity of these compounds.
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Prostaglandin Metabolism |
M. P. Goto,A. S. Goldman |
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Abstract
Prostaglandins are 20-carbon polyunsaturated fatty acids containing a cyclopentane ring and two side chains, and they are distinguished by their very potent biological activities. The basic skeleton, prostanoic acid, and a typical naturally occurring prostaglandin, prostaglandin E. (PGE.), are depicted in Fig. 1. Each prostaglandin is designated by a letter of the alphabet, A–J, according to the composition of its cyclopentane ring, and by a numerical subscript indicating the number of double bonds in the alkyl side chains. In prostaglandins of the F series, subscripts α or β indicate the orientation of the hydroxyl group at C-9 in the ring.
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Reactive Intermediates |
P. G. Wells,P. M. Kim,C. J. Nicol,T. Parman,L. M. Winn |
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Abstract
The teratogenicity of a number of xenobiotics is thought to depend upon their metabolism, termed “bioactivation”, to highly reactive and potentially toxic intermediary metabolites. Thus, while the parent xenobiotic, or “proteratogen”, is relatively inert and non-toxic, reactive intermediates, depending upon their chemical nature, can irreversibly (“covalently”) bind to and/or oxidise embryonic molecular targets such as DNA, protein and lipid. These irreversible molecular lesions are thought to initiate embryopathic responses such as in utero death, growth retardation and teratogenesis. This mechanism is distinct from the reversible binding of other xenobiotics or their stable metabolites to a specific protein receptor evoking an embryopathic response (Fig. 1). Receptor-mediated toxicity generally requires exposure to an excessive concentration of the xenobiotic, the effect increasing with rising concentration and dissipating as the concentration decreases. In contrast, the toxicity of a reactive intermediate can occur in biochemically predisposed individuals at therapeutic drug doses or supposedly safe concentrations of environmental chemicals. Such toxicological predisposition occ
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发表于 2025-3-21 16:34:13
