Table Of ContentCONTRIBUTORS
Numbers in parentheses indicate the pages on which the authors' Chao, Moses V. (141) Molecular Neurobiology
contributions begins. Program, Skirball Institute, New York University
Medical Center, New York, New York
Adams, Jane (631) Department of Psychology,
University of Massachusetts, Boston, Massachusetts Chen, Hao (321) Department of Pharmacology,
School of Medicine, University of Washington,
Ali, Syed F. (353) Neurochemistry Laboratory,
Seattle, Washington
Division of Neurotoxicology, National Center for
Toxicological Research/FDA, Jefferson, Arkansas Coles, Claire D. (455) Department of Psychiatry and
Behavioral Sciences, Marcus Institute at Emory
Andersen, Melvin (709) ICF Kaiser, Inc., Research
University, and Department of Pediatrics, Emory
Triangle Park, North Carolina
University School of Medicine, Atlanta, Georgia
Aschner, Michael (339) Department of Physiology
Costa, Ludo G. (275) Department of Environmental
and Pharmacology, Wake Forest University School
Health, University of Washington, Seattle,
of Medicine, Winston-Salem, North Carolina
Washington, and Toxicology Units, Fondazione
Audesirk, Gerald (61) Department of Biology, .S Maugeri, Pavia, Italy
University of Colorado, Denver, Colorado
Day, Nancy L. (487) Western Psychiatric Institute
Audesirk, Teresa (61) Department of Biology, and Clinic, University of Pittsburgh School of
University of Colorado, Denver, Colorado Medicine, Pittsburgh, Pennsylvania
Bennett, Gregory D. (189) Departments of Desaiah, Durisala (559) University of Mississippi
Veterinary Anatomy and Public Health, Texas Medical Center, Jackson, Mississippi
A&M University, College Station, Texas
Finnell, Richard H. (189) Departments of Veterinary
Bogle, Margaret L. (371) Delta Nutrition Intervention Anatomy and Public Health, Texas A&M
Research Initiative, U.S. Department of University, College Station, Texas
Agriculture/ARS, Little Rock, Arkansas
Fried, Peter A. (469) Department of Psychology,
Broening, Harry W. (257) Exxon Biomedical Carleton University, Ottawa, Ontario, Canada
Sciences, Inc., East Millstone, New Jersey Friedman, J. M. (497) Department of Medical
Casaccia-Bonnefil, Patrizia (141) Molecular Genetics, University of British Columbia,
Neurobiology Program, Skirball Institute, New Vancouver, British Columbia, Canada
York University Medical Center, New York, Gaylor, David W. (727) Division of Neurotoxicology,
New York National Center for Toxicological Research, Food
Catalano, Susan M. (3) Howard Hughes Medical and Drug Administration, Jefferson, Arkansas
Institute, Department of Molecular and Cell Gladstone, Jonathan (567) The Motherisk Program,
Biology, University of California, Berkeley, Division of Clinical Pharmacology and Toxicology,
California Hospital for Sick Children, Faculty of Medicine,
Chang, Louis W. (507) Departments of Pathology, University of Toronto, Toronto, Ontario, Canada
Pharmacology, and Toxicology, College of Greene, Robert M. (119) Department of Biological
Medicine, University of Arkansas for Medical and Biophysical Sciences, University of Louisville
Sciences, Little Rock, Arkansas School of Dentistry, Louisville, Kentucky
xi
xii Contributors
Grunwald, Gerald B. (43) Department of Pathology, Kong, Haeyoung (141) Molecular Neurobiology
Anatomy, and Cell Biology, Thomas Jefferson Program, Skirball Institute, New York University
University, Philadelphia, Pennsylvania Medical Center, New York, New York
Guilarte, Tom,is R. (285) Department of Koren, Gideon (567) The Motherisk Program,
Environmental Health Sciences, Johns Hopkins Division of Clinical Pharmacology and Toxicology,
University, School of Hygiene and Public Health, Department of Pediatrics, and The Research
Baltimore, Maryland Institute, Hospital for Sick Children, University of
Guo, Grace Liejun (507) Department of Toronto, Toronto, Ontario, Canada
Pharmacology and Toxicology, University of Krishnan, Kannan (709) Group of Research on
Kansas Medical Center, Kansas City, Kansas Human Toxicology, Faculty of Medicine, University
Hansen, Deborah K. (643) Division of Reproductive of Montreal, Montreal, Quebec, Canada
and Developmental Toxicology, Department of Lauder, Jean M. (153) Department of Cell Biology
Health and Human Services, Food and Drug and Anatomy, University of North Carolina School
Administration, National Center for Toxicological of Medicine, Chapel Hill, North Carolina
Research, Jefferson, Arkansas
Levin, Edward D. (587) Departments of Psychiatry
Harry, G. Jean (87) National Toxicology Program,
and Pharmacology, Duke University Medical
National Institute of Environmental Health
Center, Durham, North Carolina
Sciences, Research Triangle Park, North Carolina
Liu, Jiangping (153) Department of Cell Biology and
Hastings, Lloyd (517) Department of Environmental
Anatomy, University of North Carolina School of
Health, College of Medicine, University of
Medicine, Chapel Hill, North Carolina
Cincinnati, Cincinnati, Ohio
Meyer, Jerrold .S (403) Department of Psychology,
Hendrickx, Andrew G. (225) California Regional
Neuroscience and Behavior Program, University of
Primate Research Center, University of California,
Massachusetts, Amherst, Massachusetts
Davis, California
Miller, Marian L. (517) Department of
Holson, R. Robert (631, 643) Division of
Environmental Health, College of Medicine,
Reproductive and Developmental Toxicology,
University of Cincinnati, Cincinnati, Ohio
Department of Health and Human Services, Food
and Drug Administration, National Center for Mirkes, Philip E. (159) Department of Pediatrics,
Toxicological Research, Jefferson, Arkansas University of Washington, Seattle, Washington
Hussain, Saber (353) Neurochemistry Laboratory, Nugent, Paul (119) Department of Biological and
Division of Neurotoxicology, National Center for Biophysical Sciences, University of Louisville
Toxicological Research/FDA, Jefferson, Arkansas School of Dentistry, Louisville, Kentucky
Jensen, Karl F. )3( Neurotoxicology Division, Nulman, Irena (567) The Motherisk Program,
National Health and Environmental Research Division of Clinical Pharmacology and Toxicology,
Laboratory, U.S. Environmental Protection Department of Pediatrics, Hospital for Sick
Agency, Research Triangle Park, North Carolina Children and University of Toronto, Toronto,
Ontario, Canada
,left, David A. (257) Department of Environmental
Health Science, Johns Hopkins University, O'Flaherty, Ellen J. (307) Retired, University of
Baltimore, Maryland Cincinnati Department of Environmental Health,
Juchau, Mont R. (321) Department of Pharmacology, Cincinnati, Ohio
School of Medicine, University of Washington, O'ttayon, Bonnie (567) The Motherisk Program,
Seattle, Washington Division of Clinical Pharmacology and Toxicology,
Kable, Julie A. (455) Marcus Institute at Emory Hospital for Sick Children, Faculty of Medicine,
University, Department of Pediatrics, Emory University of Toronto, Toronto, Ontario, Canada
University School of Medicine, Atlanta, Georgia Paule, Merle G. (427, 617) Behavioral Toxicology
Kimmel, Carole A. (675) National Center for Laboratory, Division of Neurotoxicology, National
Environmental Assessment, U.S. Environmental Center for Toxicological Research, Jefferson,
Protection Agency, Washington, DC Arkansas
Knudsen, Thomas B. (209) Department of Pathology, Peterson, Pamela E. (225) California Regional
Anatomy, and Cell Biology, Jefferson Medical Primate Research Center, University of California,
College, Philadelphia, Pennsylvania Davis, California
Contributors xiii
Pisano, M. Michele (119) Department of Biological Slikker, William Jr. (245, 727) Division of
and Biophysical Sciences, University of Louisville Neurotoxicology, National Center for Toxicological
School of Dentistry, Louisville, Kentucky Research, Food and Drug Administration,
Polifka, Janine E. (383) Department of Pediatrics, Jefferson, Arkansas
University of Washington, Seattle, Washington Slotkin, Theodore A. (587) Departments of
Potchinsky, Merle (119) Department of Pathology, Psychiatry and Pharmacology, Duke University
Anatomy, and Cell Biology, Daniel Baugh Medical Center, Durham, North Carolina
Institute, Jefferson Medical College, Thomas Toews, Arrel D. (87) Department of Biochemistry
Jefferson University, Philadelphia, Pennsylvania and Biophysics and Neuroscience Center and
Rice, Deborah C. (539) Toxicology Research Department of Biology, University of North
Division, Bureau of Chemical Safety, Food Carolina, Chapel Hill, North Carolina
Directorate, Health Protection Branch, Health van Baar, Anneloes (439) Academic Medical Center,
Canada, Ottawa, Ontario, Canada Department of Neonatology, Amsterdam, The
Richardson, Gale A. (487) Western Psychiatric Netherlands, and Saint Joseph Hospital,
Institute and Clinic, University of Pittsburgh School Department of Psychosocial Care, Veldhoven, The
of Medicine, Pittsburgh, Pennsylvania Netherlands
Rodier, Patricia M. (661) Department of Obstetrics Weston, Wayde (119) Department of Pathology,
and Gynecology, University of Rochester, Anatomy, and Cell Biology, Daniel Baugh
Rochester, New York Institute, Jefferson Medical College, Thomas
Schardein, James L. (687) WIL Research Jefferson University, Philadelphia, Pennsylvania
Laboratories, Inc., Ashland, Ohio Wuball, Judith A. (209) Department of Pathology,
Shield, Margaret A. (159) Department of Pediatrics, Anatomy, and Cell Biology, Jefferson Medical
University of Washington, Seattle, Washington College, Philadelphia, Pennsylvania
FOREWORD
The Handbook of Developmental Neurotoxicology her- postmortem studies and the application of sophisticated
alds a remarkable advance in the field of toxicology that brain imaging technology have resulted in compelling
will likely have a substantial impact on policy as it unites evidence that schizophrenia is a neural developmental
developmental neuroscience with the principles of neu- disorder that often results from an interaction between
rotoxicology. Although the demonstration of gross mor- heritable vulnerabilities and perinatal insults.
phologic defects provides clear evidence of neurotoxico- As laid out in the Handbook and verified by experi-
logic effects, the critical issue that has bedeviled the ence, a thorough understanding of the principles that
field of developmental neurotoxicology is the identifi- direct brain development at the molecular, cellular, and
cation of threshold effects. Thus, we must assume that systems levels provides the greatest promise for identify-
doses of neurotoxins below those causing evident struc- ing mechanisms of action for toxins that adversely affect
tural damage still disrupt important but subtle aspects the developing brain. The Handbook provides compel-
of synaptic circuitry and function. ling case studies drawing on the rapidly advancing field
A creative attempt to address this problem was the of developmental neuroscience that have transformed
conceptualization of "behavioral teratology" to identify our understanding of the developmental neurotoxic ef-
behavioral surrogates of neural toxicity in the develop- fects of an expanding family of agents. The important
ing brain. This strategy was based on the inference that message to be derived from this evolving knowledge
toxins might disrupt brain maturation without causing base is that developmental neurotoxicology cannot suc-
gross lesions and that these subtle disruptions could ceed by working in isolation but only through continu-
become apparent from the behavioral deviance of the ous dialogue with developmental neuroscientists. De-
treated subjects compared to controls. It was hoped velopmental neuroscientists, in fact, are opportunistic
that a better understanding of the brain mechanisms and exploit selective agents to alter signal transduction,
responsible for the specific aberrant behaviors might cell-cell interaction, and structural components of cells
disclose neuronal systems at risk. Nevertheless, in the to understand how these processes determine brain mat-
absence of a verifiable "lesion," how could one infer that uration. Thus, toxins become "tools," and "tools" are
a behavioral difference was pathologic and not simply elucidated as toxins.
statistical? Indeed, some have argued that the "redun- An important advance in developmental neurosci-
dancy" and plasticity of the developing brain could ences that has undercut one pathologic criterion for
prove to be self-correcting. identifying lesions has been elucidation of programmed
In fact, the problem of behavioral teratology shares cell death, or apoptosis. Although apoptosis has long
important similarities with the challenge of understand- been known to be an important mechanism for sculpting
ing the causes of severe mental disorders. In the absence the developing nervous system by eliminating excess or
of objective evidence of structural changes in the brain, redundant neurons, its role in neuropathologic pro-
severely disabling disorders such as schizophrenia were cesses such as stroke, Alzheimer's disease, and Hunting-
ascribed in the past to pathologic mother-infant interac- ton's disease is only now coming to the foreground.
tions, the consequences of an oppressive society, cre- A notable characteristic of apoptosis is the negligible
ative adaptations to life circumstances, or abnormal inflammatory response to neuronal loss that it evokes;
brain function. The advances in our understanding of in contrast, necrosis produces microglial proliferation
corticolimbic synaptic circuitry coupled with informed that results in a "scar," a footprint of prior neuronal
XV
xvi Foreword
death. If the neuropathologic criterion for neurotoxin- active signaling agent are transiently expressed in dis-
induced neuronal degeneration requires, as traditionally crete brain structures to cue differentiation. Under-
has been the case, gliosis, then apoptosis represents a standing these spatial-temporal events is essential for
"silent" assassin that leaves no clues. Indeed, the devel- clarifying how a toxin might produce quite focused ad-
oping nervous system is most vulnerable to apoptotic verse effects and is relevant to the expanding number
neuronal elimination. of transiently expressed developmental cues.
The salience of apoptosis has been demonstrated Developmental neurotoxicology must also walk
through the role of glutamate, the brain's major ex- hand-in-hand with the Human Genome Project. Al-
citatory neurotransmitter, in regulating neuronal though population variance in sensitivity to carcinogens
differentiation. The evidence is accumulating that use- is now well appreciated, the same heritable variations
dependent activation of the NMDA subtype of gluta- in enzyme and receptor characteristics likely impact sen-
mate receptors not only has direct trophic effects on sitivity to the neurodevelopmental consequences of tox-
neurons but also enhances their response to endogenous ins. With the ascendance of gene knock-out and trans-
growth factors. These insights have been particularly genic strategies, it si now possible to explore the
helpful in elucidating the developmental neurotoxic ef- consequences of human gene variants on susceptibility
fects of agents that directly or indirectly inhibit NMDA to toxins in animal models. Such heritable variability
receptors, especially the commonly abused substance likely contributes substantially to the developmental
ethanol. In vitro studies indicate that ethanol's inhibition disorders for which no known etiology is obvious. The
of NMDA receptors promotes apoptotic neuronal de- old paradigm of "nature versus nurture" or "gene versus
generation, consistent with the hypoplasia observed in environment" has been replaced by a more sophisti-
certain brain regions as a consequence of fetal ethanol cated appreciation of complex genetic endowment inter-
exposure. The importance of these mechanistic studies acting with environment, including an expanding array
si that they argue against a nonspecific effect of poor of potential developmental neurotoxins.
diet in causing the effects of fetal alcohol syndrome In closing, the Handbook charts a new course. The
on the brain and support a direct neurotoxic effect of future that it projects is not represented by toxicologists
ethanol. The obvious policy implication is that dietary working in isolation, attempting to define the surrogates
supplements alone will not protect against the neuro- of developmental neurotoxicity in experimental ani-
toxic effects of ethanol on the fetal brain. mals. Rather, the future requires the embrace of devel-
Another unfolding story that merits mention si the opmental neuroscience and molecular genetics to define
role of retinoic acid in regulating spatially and tempo- the mechanisms of risk and their temporal relationships
rally specific developmental events in the brain. One of in brain development to achieve findings that compel-
the conundrums of developmental neurotoxicology is lingly will shape policy and thereby reduce risk for fu-
relating toxin exposure to region-specific sequelae in ture generations.
the brain. Recent studies now demonstrate that retinoic
acid dehydrogenases that convert the precursor to the HPESOJ ELYOC
PREFACE
The Congressional designation of the 1990s as the De- cases where human data exist, comparisons may be
cade of the Brain underscores the tremendous opportu- made to data generated in animal models. There is ex-
nities offered by the current and anticipated advances tensive concordance between animal and human data-
in brain research and the enormous cost of mental disor- bases for effects or biomarkers for a variety of human
ders to the national economy. In the United States, developmental toxicants of several different chemical
brain-related disorders account for more hospitaliza- classes. There is ample evidence that effects seen in
tions than any other major disease group, including can- some animal models can be predictive of human out-
cer or cardiovascular diseases. One out of four Ameri- come for every agent. There is also evidence that the
cans will suffer from a brain-related disorder at some selection of an animal model is important because the
point in life, and the cost to the national economy for use of certain animals under certain study conditions
treatment, rehabilitation, and related consequences is results in a lack of concordance.
an estimated $400 billion each year. The discipline of As for developmental toxicity in general, the nature
neurotoxicology is devoted to developing a better un- and extent of neurotoxic effects are often dependent
derstanding of the extent, causes, and underlying mech- on the timing of exposure, and because stages of nervous
anisms of brain-related disorders. system development can vary significantly between spe-
Nowhere is the pain and suffering from brain-related cies in relation to the time of birth, variations in neuro-
disorders felt more than by the very young members of toxic outcome across species are expected. Organogene-
our society who must live with their disabilities for a sis, one of the critical periods of susceptibility when
lifetime. Of the 250,000 malformed or impaired children many organ systems are formed, varies from species to
born each year in the United States, approximately half species in time from conception and in overall length.
suffer from a nervous system or behavioral deficit. With Differences also exist concerning the various stages of
4 to 8% of children born in the United States exhibiting nervous system growth and development in different
anatomical and/or functional deficits, and the occur- species. It is imperative, therefore, that the time and
rence of several tragic clinical syndromes resulting from duration of exposure in the animal model be selected
developmental exposure to such agents as ethanol, lead, to match the window of exposure in the human situation.
and methylmercury, there is good reason to focus atten- The overall strategy to understand developmental
tion on the principles of developmental neurotoxicol- neurotoxicity is based on two assumptions: (1) the devel-
ogy. Various animal models have been used to confirm oping nervous system may be more or less susceptible
the developmental neurotoxicity that results from expo- to neurotoxic insult than the adult depending on the
sure to these agents and, along with clinical evidence, stage of development; and (2) neuropathological, neuro-
have implicated several other chemical classes such as chemical, neurophysiological, and behavioral evalua-
antimitotics, insecticides, polyhalogenated hydrocar- tions are necessary and complimentary approaches to
bons, psychoactive drugs, solvents, and vitamins as spe- determining the type and degree of nervous system tox-
cific agents with developmental neurotoxic potential. icity. The research approach consists of the following
Clinical case reports and other human studies primar- four steps: (1) gather information from all available
ily have been responsible for identifying approximately endpoints and use it to generate a developmental neuro-
two dozen human teratogens. Of these, over half are toxicity profile; (2) correlate structural and chemical
known to affect the developing nervous system. In those lesions with overt behavioral manifestations of neuro-
XVI! oo
xviii ecaferP
toxicity; (3) compare with the adult neurotoxicity profile by various biological, chemical, and physical agents. A
and determine relative susceptibility of the developing presentation of some of the most prominent neurotoxic
organism; and (4) develop a pharmacokinetic/metabolic syndromes, such as fetal Minamata disease, develop-
basis for interspecies extrapolation. mental lead poisoning, and fetal alcohol syndrome are
When provided the opportunity to edit a special vol- provided to underscore the human health impact of
ume of the Handbook of Developmental Neurotoxicol- developmental neurotoxicants. Other sections of the
ogy we accepted because of the tremendous importance volume are presentations and discussions of various as-
of this subject to neurotoxicology. Indeed, develop- sessment approaches including behavioral and clinical
mental neurotoxicology is no longer "an appendix" of processes and the risk assessment process itself. Al-
neurotoxicology; in fact, it has become an independent though there are other books related to this subject, we
discipline of neurotoxicology. It si our belief that to believe that this volume represents the most compre-
understand developmental neurotoxicology, one must hensive and in-depth coverage of the subject of develop-
first be familiar with developmental neuroscience. Por- mental neurotoxicology.
tions of this volume, therefore, are devoted to develop-
mental neurobiology and neurochemistry as well as how MAILLIW ,REKKILS .RJ
the normal developmental processes can be influenced LouIs W. GNAHC
PART
1
Cellular and Molecular
Morphogenesis of the
Nervous System
Developmental neurotoxicology involves the study barrier that influence the development of the brain are
of adverse effects on the developing nervous system also presented. The normal development and function
induced by biological, chemical, or physical agents. It of the nervous system can only be achieved if all these
is therefore important to understand the various stages critical processes and stages of development remain in-
and factors that are critical in the morphogenic develop- tact. Obviously, any disturbance or disruption of these
ment of the nervous system, such as neuronal differenti- processes by exogenous chemicals will result in patho-
ation, neuronal migration, cell-cell interactions, neuritic logic and functional (neurobehavioral) changes of the
developments, synaptogenesis, and myelinogenesis. The brain.
cellular events in the maturation and cytoarchitectural The CNS is uniquely different from other organ sys-
development of the central nervous system (CNS) are tems by having a complex circuitry of communication
underlied by a series of molecular elements and pro- network between various nervous cells, neuronal groups,
cesses such as cytoskeletal elements, adhesion mole- and the glial elements. The abilities of developing nerve
cules, signal transductions, and so on. The role of these cells and glial elements to migrate to their proper and
elements and processes in both normal and chemically "predestined" positions, recognition of the target cells,
intoxicated brains is presented and discussed in Part I. and signaling are largely influenced and directed by cad-
The developing CNS is a constantly remodeling or- herins, a family of calcium-dependent cell adhesion mol-
gan with active neuronal differentation, migration, syn- ecules. In Chapter 2, Gerald B. Grunwald provides a de-
aptogenesis, and circuitry establishments. Chapter 1 by tailed presentation and discussion on the cadherin
Karl F. Jensen introduces and discusses all these basic adhesion molecules and their critical roles in the develop-
processes of morphogenesis of the brain. Factors such ment of both the CNS and the PNS. An informative ac-
as hormonal and nutritional homeostasis, xenobiotic count on the structural and functional diversity of the
metabolism, and the development of the blood-brain cadherin molecules, the regulations and expressions of
Copyright (cid:14)9 1998 by Academic Press.
All rights of reproduction in any form reserved.
2 I Cellular and Molecular Morphogenesis of eht Nervous System
these molecules in relation to neural development, nu- the neurons. The myelin sheath surrounding the axons
clear and ganglionic organization, axonal growth, and -if serves as an insulator and facilitates such impulse trans-
ber tract development is provided and discussed. mission. Development of the myelin is most active at
Another characteristic feature of nerve ceils, differ- an early neonatal age. In Chapter 4 by G. Jean Harry
ent from other cell types, is the existence of neuronal and Arrel D. Toews, the basic structures, morphogene-
processes or neurites for the establishment of the com- sis, and chemistry of myelin are presented. Molecular
municative network (circuitry) among the nerve cells. aspects of myelin assembly, axon-glial interactions, my-
The neuritic development is critically controlled by the elin disorders, and dysmyelination-demyelination in-
cytoskeletal components. The fundamental structures
duced by toxic chemicals are also discussed.
and roles of cytoskeleton in developing neurites (den-
It is obvious that a single neurotoxicant (e.g., lead,
drites and axons) is presented and discussed in Chapter
mercury) can exert its toxic influence and action on
3 by Gerald Audesirk and Teresa Audesirk. The regula-
one or combinations of developmental parimeters (e.g.,
tion fO cytoskeleton by intracellular calcium and by pro-
cadherin adhesion molecules, cytoskeleton, cell migra-
tein phosphorylation, the relationship between cytoskel-
tion, neuritic development, synaptogenesis, myelina-
eton and growth cone formation, and the roles of
tion). Investigators must avoid the "tunnel vision" men-
adhesion, attraction, and repulsion in pathfinding of the
tality, but approach the problem or issue with a broad
growth cones are also discussed in conjunction with
view and the understanding that neural development
neuritic initiation and elongation. Various neurotoxi-
involves multiple factors, processes and stages. Any
cants such as lead, mercury, and ethanol are known to
affect neuritic development. These toxicants and their given developmental neurotoxicant can affect multiple
toxic actions on the developing neurites are provided factors and events at the same time. Neurotoxicology
to illustrate chemical impact on the developing ner- is a complex issue, this complexity is even more so in
vous system. the situation of developmental neurotoxicology.
One of the most fundamental functions of the ner-
vous system is impulse transmission along the axons of Louis .W Chang
CHAPTER
1
Brain Morphogenesis and
Developmental Neurotoxicology
KARL F. JENSEN
Neurotoxicology Division
National Health and Environmental Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
SUSAN M. CATALANO
Howard Hughes Medical Institute
Department of Molecular and Cell Biology
University of California
Berkeley, California 94720
I. Introduction D. Cell Death and Collateral Loss Refine Connectivity
II. Instructive and Selective Processes Shape Brain E. Dendritic Form Is Shaped by Afferent Innervation
F. Activity Patterns Synaptic Connections
Morphogenesis
G. Neurotransmitters and Hormones Regulate
A. Intercellular Signals Organize the Brain
Morphogenetic Events
Primordium
H. Astrocytes Induce Expression of the Blood-Brain
B. Time and Place of Origin of a Neuron in the
Barrier in Endothelial Cells
Neuroepithelium Is Predictive of Its Adult
III. Developmental Neurobehavioral Disorders
Location
Result from Disruption of Morphogenesis
C. Axonal Pathfinding Involves Attractive and
A. Mental Retardation Results from the Disruption of
Repulsive Cues
Diverse Morphogenetic Signals
B. Schizophrenia Is Associated with Structural
*Abbreviations: APP, amyloid precursor protein; BMP, bone Alterations Indicative of Alterations in Development
morphogenetic proteins; ,iC Cubitus Interuptus; Dix, ;ssellatsid C. Predominance of Structural and Functional
,SD Down syndrome; Emx, empty spiracles; ,NE engrailed; Alterations May Be a Reflection of the Relative
FGF, fibroblast growth factor; HASAS, hydrocephalus sa a result of Disruption of Instructive and Selective
stenosis of the Aqueduct of ;suivlyS Mad, Mothers against decap- Morphogenetic Processes
;cigelpat MAP2, microtubule-associated protein ;2 MAPK, mitogen- IV. Convergence of Genetic and Environmental
activated protein kinase; MASA, mental retardation, aphasia, shuf-
Influences May Increase the Severity and Incidence
gnilf gaits and adducted thumbs; NMDA, N-methyl-d-aspartate; NRC,
of Developmental Neurobehavioral Disorders
National Research ;licnuoC Otx, orthodenticle; PCB, polychlorinated
;slynehpib PKC, protein kinase ;C ptc, patched; Shh, Sonic ;gohegdeh A. Developmental Neurotoxicants Disrupt
smo, smothered; ,3T triiodothyrione; ,4T thyroxine; ,~/-FGT trans- Morphogenetic Signals
forming growth factor/~; VEGF, vascular endothelial growth factor; B. Homeostatic Processes Protect the Developing
Wnt, .sselgniw Brain from Xenobiotic Insult
Copyright (cid:14)9 1998 by Academic Press.
HANDBOOK OF DEVELOPMENTAL NEUROTOXICOLOGY All rights of reproduction in any form reserved.
