Behavioral Teratogenesis and Behavioral Mutagenesis: A Primer in Abnormal Development

249 Pages·1989·5.33 MB·English

by  Ernest L. Abel (auth.)

Behavioral
Teratogenesis and
Behavioral
Mutagenesis
A Primer in Abnormal Development
Behavioral
Teratogenesis and
Behavioral
Mutagenesis
A Primer in Abnormal Development
Ernest L. Abel
Wayne State University
Detroit, Michigan
Plenum Press • New York and London
Library of Congress Cataloging in Publication Data
Abel, Ernest L., 1943-
Behavioral teratogenesis and behavioral mutagenesis: a primer in abnormal
development I Ernest L. Abel.
p. cm.
Includes bibliographies and index.
ISBN-13:978-1-4612-8056-9 e-ISBN-13: 978-1-4613-0735-8
DOl: 10.1007/978-1-4613-0735-8
1. Behavioral toxicology. 2. Developmental toxicology. I. Title.
[DNLM: 1. Chromosome Abnormalities. 2. Genetics, Behavioral. 3. Mutagens. 4.
Mutation. 5. Teratogens. QH 457 A139b]
RA1224.A24 1989
616.89'071-dcl9
DNLM/DLC 88-38421
for Library of Congress CIP
© 1989 Plenum Press, New York
Softcover repint of the hardcover 1st edition 1989
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfIlming,
recording, or otherwise, without written permission from the Publisher
Preface
Most textbooks are cumbersome to carry, expensive to buy, difficult to read, and boring.
They have no plot, no characterization, no suspense, no climax. What they have are facts.
If Dragnet's Sgt. Friday were Scientist Friday, the script wouldn't be much different
"just the facts, ma'am."
Students can't escape textbooks. But like death and taxes, they are necessary evils.
Death makes room for new people and the death of old ideas makes room for new ones.
Taxes are the dues we pay to live in a country. Everybody gets stuck with paying some
kind of dues and students are no exception. Students pay dues in the form of tuition to
listen to professors lecture, and they also pay dues in what a former governor of California
called' 'psychic bucks" -time, concentration, independent study, reading textbooks like this
one-to come up with the correct answers to exam questions.
Textbooks on economics will tell you about where our tuition bucks come from. This
book is about where our psychic bucks come from and the forces that can bankrupt our
psychic nest eggs.
Animals and people do not pop up from nowhere. Instead, they are created by sexual
unions that put into motion a series of progressive changes called development. These
changes are controlled by the genetic code inside a single fertilized cell. Despite enormous
progress in genetics, we know almost nothing about how this fertilized egg cell becomes a
complex multimillion-celled organism. We know that genes carry codes for making pro
teins and we know how proteins are made in the cell, but we don't know how coding or
protein building eventually results in different structures. This development continues until
a fully formed creature appears and even then development never ceases.
Despite ignorance of the way development is orchestrated, we know there is a critical
period during development when an organism is particularly vulnerable to chemicals or
physical stimuli. If these agents cause damage to chromosomes they are called mutagens.
If they interfere with the work of chromosomes during development but don't alter the
chromosomes themselves, they are called teratogens. It is sometimes not possible to know
if abnormal development is due to a mutagen or a teratogen. X-irradiation, certain chemi
cals, and a number of viruses are both teratogenic and mutagenic. If a mutation occurs in
a sperm or egg cell, it has the potential for being passed on to another generation. If the
mutation occurs in a nongerm cell it will only affect a single generation.
Until recently, teratologists (scientists interested in the causes of abnormal prenatal
development) mainly concerned themselves with structural defects and the teratogens that
v
vi Preface
caused them. Beginning in the 1960s, teratology expanded to include functional defects,
especially behavioral anomalies. Just as genetics became divided into subspecialties such
as cytogenetics and behavioral genetics, teratology developed its own subspecialty called
behavioral teratology.
One of behavioral teratology's aims is to understand how prenatal exposure to dam
aging chemicals, drugs, or physical agents results in abnormal behavior. Since behavior is
the endpoint, one could as easily speak of behavioral mutagenesis as behavioral teratology.
The main difference between the two involves mechanism, not outcome, and in many cases
the mechanism is simply not known. There is no point in creating artificially divisive
barriers like the nature-nurture arguments with which developmental psychology was once
and, to some extent, is still contending.
Behavioral teratology is now one of the fastest growing, most exciting, and most
challenging fields in neuroscience. One reason for its phenomenal growth is our realization
that the brain is the most sensitive organ in the body and that brain damage is forever. A
missing arm or leg is a terrible misfortune, but artificial arms and legs are now available
to allow people with these misfortunes to live full and satisfying lives. Disfigured bodies
can be surgically corrected. A brain that is damaged is damaged for life.
Another reason for the excitement in behavioral teratology is the fact that it gives
scientists in different fields the opportunity to work together. Although behavioral teratol
ogy has been characterized as a hybrid of teratology and experimental psychology, it is
actually a hybrid drawn from many diverse fields. Identifying mutagens and teratogens and
those areas of the brain and its workings that these agents damage, finding out how that
damage occurs, and determining why it occurs in some people or animals and not in others
are' not one-or two-discipline jobs. Behavioral teratology is an area where psychobiologists,
epidemiologists, neurophysiologists, neuroanatomists, neurochemists, pharmacologists, and
other scientists can integrate their special disciplines and come to an understanding of how
and why some people never reach their full potential.
Scope of the Book
In this book I have tried to create a perspective within which to examine prenatal
determinants of behavior, rather than presenting an overwhelming panorama of details about
specific factors that affect behavioral development. There is still no shortage of facts to
master, but such facts are less important than principles. These principles are drawn from
such diverse fields as molecular biology, genetics, embryology, pharmacology, biochem
istry, toxicology, neuroanatomy, neurophysiology, psychology, and epidemiology. Focus
ing on principles rather than exploring specific agents allows us to at least understand why
and how these forces do what they do.
Besides principles, another basic ingredient for appreciation of any science is a thor
ough understanding of the methodologies used and the problems and pitfalls associated with
these methods. After all, the strength or weakness of any study depends on the procedures
used. Treatments must be administered and outcomes measured in such a way that irrele
vant factors are eliminated and relevant factors--other than those of immediate concem
are at the very least minimized, or at best controlled. These issues are discussed throughout
the book.
In many cases, examples have been provided to illustrate various principles or proce
dures. That some studies are quoted and others are not does not imply that omitted studies
Preface vii
were omitted because they were in any way inferior. There is a bias in my choice of
examples that I readily acknowledge: most of my examples have been taken from the fetal
alcohol literature. This is because I am most familiar with this literature and because alco
hol's effects on development have been more thoroughly studied than the effects of any
other chemical agent.
This book was originally conceived as a "how-to" text for students taking an intro
ductory course in behavioral teratology. After reading it, many may feel that it should have
stayed true to its purpose. But instead, my hidden muse took over and the book took off
in a completely different direction, becoming broader in its scope and going farther away
from its original purpose.
To my knowledge, no one else has ever taught a course in behavioral teratology be
fore. Therefore, what I have emphasized may be completely different from what another
of my colleagues would emphasize should he or she be writing a similar book. This is as
it should be. If everyone thought the same, science would be dull and moribund.
Like all writers, I learned a lot in reading and rereading much of what I finally in
cluded in this book. I hope that I have been able to incorporate some of the interest and
excitement I felt in reviewing these writings.
I have tried to make this text as readable as possible but some ideas just do not lend
themselves to a breezy presentation. New concepts seem foreign and their mastery can
make the going rough. More than a thousand years ago, Ptolemy, the king of Egypt, faced
the same difficulty trying to master geometry. He complained to his teacher, Euclid, the
genius who invented geometry, asking if there were any shortcuts that would make the
subject easier. Euclid's reply was as true then as it is now: "There is no royal road to
geometry." Or, he could have added, any other study.
During its long gestation, this book went through many drafts. Many colleagues were
given various chapters and were kind enough to offer valuable suggestions. Those to whom
special appreciation is due are F. Koppitch, E. Riley, M. Church, C. Zajac, Z. Djuric, and
J. Jacobson.
Contents
Chapter 1. In the Beginning Was the Word and the Word Was ... DNA ..... .
The Living Cell. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Mendel's Model. .. . .. . .. . .. .. . .. . . . . . . . . . .. .. . .. . . . .. . .. .. . 3
Chromosome Theory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
The Cell Cycle ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Mitosis ................................................... 6
Meiosis................................................... 8
Gametogenesis ............................................. 10
Sperm Imprinting ........................................... 12
Genetic Variability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Gene Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
The Double Helix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
How DNA Sends Messages. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
You Are a Degenerate ....................................... 24
Junk Genes? ............................................... 24
What Turns You On? . . .. . .. . . . .. . .. ... .. . .. .. . .. .. . .. .. . .. .. 25
Pleiotropy ................................................. 26
Epistasis .................................................. 26
The Molecular Clock ........................................ 27
Finding Eve. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
The Origin of Species. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Genetic Engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
References ................................................ 31
Chapter 2. Behavior Genetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
The Heritability of Behavior .................................. 34
Paradigms Used in Human Behavioral Genetics Research. . . . . . . . . . . 35
Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Alzheimer Disease .......................................... 42
Alcoholism ................................................ 43
ix
x Contents
Phenylketonuria ........................................... 46
Fragile X . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Intelligence ............................................... 48
A Flutist Needs a Flute to Be a Flutist . . . . . . . . . . . . . . . . . . . . . . . . . 51
Prenatal Learning in the Classwomb . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
References ............................................... 53
Chapter 3. Some DNA Is Born Great, Some Never Achieves Its
Greatness, and Some Has Its Greatness Poisoned before It Can
Be Recognized ............................................ 57
Sources of Mutations: Spontaneous versus Induced. . . . . . . . . . . . . . . 58
Types of Mutations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Somatic versus Gametic Mutations ... . . . . . . . . . . . . . . . . . . . . . . . . . 59
Categories of Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Conditional Mutations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Point Mutation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Death by Beans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Sister Chromatid Exchange .................................. 63
Chromosomal Mutations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Down Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Sex Chromosome Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Genome Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Agents Causing Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Ultraviolet Radiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Chemical Causes of Mutation ................................ 77
Some Laboratory Tests for Mutagens . . . . . . . . . . . . . . . . . . . . . . . . . . 80
DNA Repair Mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Appendix A. Prenatal Testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
References ............................................... 86
Chapter 4. From Gene to Brain 89
Preimplantation ........................................... 90
Implantation .............................................. 94
Gastrulation .............................................. 95
Induction ................................................ 96
Critical Period. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
The Beginning of a Brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Proliferation .............................................. 99
Cell Migration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Pattern Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Differentiation ............................................ 109
Relationship of Animal Brain
Development to Human
Brain Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
The Neuron. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Contents xi
The Nerve Impulse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Synaptogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Neurotransmitters as Inducers ................................ 114
Long-Range Induction ...................................... 1I5
Glia and Myelination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Modification of Synaptic Connections. . . . . . . . . . . . . . . . . . . . . . . . . . 1I9
Appendix A. Malformations of CNS Development Due to
Failure of Neuropore Closure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Appendix B. Basic Functional Neuroanatomy. . . . . . . . . . . . . . . . . . . 122
Appendix C. Research Techniques in Neuroanatomy and
Neurophysiology ........................................ 125
References ............................................... 130
Chapter 5. Behavioral Teratogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
Behavioral Teratology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
Principles of Teratology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Appendix A. Routes of Administration. . . . . . . . . . . . . . . . . . . . . . . . . 160
References ............................................... 167
Chapter 6. Identifying Human Behavioral Teratogens: Designs and Methods ... 173
Definition of Birth Defects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Ascertainment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
Population Being Evaluated . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
Procedures for Identifying Teratogens . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Descriptive Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Analytical Evaluations ...................................... 178
Apgar Test. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Prechtl Exam. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
The Brazelton Test. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Scanlon .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
Bayley Scales. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
Visual Recognition Memory. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . 186
Reaction Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
Intelligence Tests .......................................... 189
Summary and Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
Appendix A. Diagnostic Criteria for Attention Deficit Disorder
with Hyperactivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
References ............................................... 191
Chapter 7. Testing Animal Behavioral Teratogens: Designs and Methods . . . . . . 195
Rationale for Studies in Animals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Methodological Issues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
Test Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
xii Contents
Developmental Landmarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
Learning/Memory Tasks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Active Avoidance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Passive Avoidance ......................................... 209
Maze Learning ............................................ 210
Spontaneous Alteration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
Reversal Learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Observational Techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Rotorod . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Preference Tests ........................................... 217
Sexual Behavior in the Rat. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Acoustic Startle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Seizure Susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Operant Behavior. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Sensitivity to Drugs ........................................ 223
References ............................................... 223
Chapter 8. Regulatory Protocols for Identifying Teratogens. . . . . . . . . . . . . . . . . . 227
FDA Guidelines ........................................... 227
Behavioral Teratology Testing in Japan ........................ 229
Behavioral Teratology Testing in the United Kingdom . . . . . . . . . . . . 230
Behavioral Teratology Testing in France and Italy. . . . . . . . . . . . . . . . 230
Efforts to Create a Behavioral Teratology Test Battery
in the United States. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Summary and Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
References ............................................... 232
Index ......................................................... ". . . . . . 235