ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 18, No.

2
Copyright © 1988, Institute for Clinical Science, Inc.

Teratogens and Teratogenesis:

General Principles of Clinical Teratology
J. L. FRIAS, M .D., and I. T. THOMAS, M.D.
Department of Pediatrics,
University of Nebraska Medical Center,
Omaha, NE 68105

ABSTRACT
Numerous factors hinder our ability to recognize fully human terato­
gens. Among these are the limitations of animal and epidemiologic stud­
ies, the lack of understanding of the mechanisms of action of most terato­
gens, and the variability in expression of the clinical manifestation. Dose
and timing of exposure, interactions with other environmental agents, and
host susceptibility influence this variable expressivity. Recent studies sug­
gest the genetic constitution of the mother and the fetus play a central role
in the teratogenic response. Techniques currently being developed may
help in a near future to identify susceptible individuals and to prevent
specific types of drug-induced birth defects.

Introduction of most of these substances rem ains

In 1941, Gregg reported the associa­
tion of cataracts, deafness, and congeni­
tal heart disease in the offspring of
women exposed to rubella during gesta­
tio n .13 U ntil then, it was generally
believed that the placenta isolated and
protected the conceptus from the detri­
mental effects of environmental factors.
The thalidomide tragedy further demon­
strated the fallacy of this concept.24’26
Today, it is a well-recognized fact that
exposure to certain environm ental
agents may represent a hazard to the
fetus. However, there is a sharp contrast
betw een the widespread exposure to
potentially teratogenic drugs, chemicals,
and environmental pollutants prevalent
in our society and the small number of
disorders known to be caused by these
agents. In fact, the teratogenic potential
174
0091-7370/88/0300-0174 $01.20 © Institute for Clinical Science, Inc.
largely unknown mainly because of the
problems that beleaguer their study in
man.15,16 Interspecies and intraspecies
differences in the susceptibility to the
effects of teratogens hinder the extrapo­
lation of data from animal studies to
humans.31,42 Most epidemiologic studies
are fraught with méthodologie problems
and often lack the sensitivity to identify
low d eg ree te ra to g e n s.7,27 Lack of
understanding of the pathogenesis of
most teratogens limits the recognition of
biologically sound associations and, con­
sequently, our ability to discrim inate
between true causal relationships and
chance occurrences. In addition, the
well-recognized variability in phenotypic
expression in environmentally-induced
patterns of malformation further compli­
cates the recognition of human terato­
gens.
 TERATOGENS AND TERATOGENESIS
Clinical Expression
The effect of teratogens on human
development follows a limited repertoire
of pathogenic mechanisms. This includes
excessive or reduced cell death, interfer­
ence with cell interactions, decreased
biosynthesis, abnormal morphogenetic
movements, and disruption of tissues.42
These general pathways are common to
different agents. Therefore, it is not sur­
prising that a wide range of teratogens
produce similar types of developmental
defects, including infertility or embry­
onic/fetal loss, intrauterine growth defi­
ciency, abnormal central nervous system
(CNS) performance, and abnormal mor­
phogenesis.14 The potential carcinogenic
and mutagenic effect of some teratogenic
agents should be added to this list,
although their mechanisms of action are
different. Cancer and mutation induc­
tion, as mentioned later on, are stochas­
tic phenom ena induced by changes in
DNA and, as such, can result from dam­
age to a single cell.4
Fifteen to 20 percent of recognized
pregnancies term inate spontaneously
before the 20th week of gestation, and
many of them exhibit developmental
abnormalities.29 Chromosomal aberra­
tions are responsible for most of these
abortions, but environm ental factors
may account for some of them since the
human conceptus is most vulnerable to
the deleterious effect of teratogenic
agents during the first eight weeks of
prenatal development. Animal studies at
comparable stages have amply demon­
strated that death and malformations are
most likely to be induced during this
period.42
While it is well-recognized that terato­
gens produce growth retardation in addi­
tion to resorption and malformations in
experimental animals, the effects that
most drugs used in pregnancy have on
human fetal growth are unknown.5 How­
17 5
ever, if one classifies cigarette smoking
and alcohol as drugs, teratogens are
among the most prevalent causes of
intrauterine growth retardation.30
Growing attention to the non-struc-
tural abnormalities produced by prenatal
exposure to known teratogens has led to
w ider recognition and m ore precise
delineation of the behavioral problems
th a t may be associated w ith th e se
agents.18
Clinical studies have dem onstrated
that: (1) teratogens rarely produce single
anomalies; (2) no single anomaly is spe­
cific for any given teratogen; (3) terato­
gens generally produce specific patterns
of malformation; (4) variability of expres­
sion is the rule rather than the excep­
tion; and (5) not every p reg n an cy
exposed to a teratogenic agent during
the critical period and at doses above the
threshold will result in an abnormal off­
spring.14,34,40 This is true even for tha­
lidom ide, one of the m ost pow erful
teratogens known to man. Paucity of reli­
able epidemiologic data makes any state­
ment about the risk factors for this drug
at best speculative. However, even the
highest estimates place the chances of an
abnormal offspring following exposure
during the critical period below 50 per­
cent.28,41
Factors Contributing to the Variability
in Expression
The cause of the variability in pheno­
typic expression of m ost teratogens
remains largely undefined. However, as
noted by Wilson as well as other investi­
gators, data on both animal and human
studies suggest that the following factors
play major roles in its determination: (1)
dose of the agent; (2) timing of exposure;
(3) interaction with other environm en­
tal factors; and (4) host suscep tib il­
i t y 14,22,39,42
176 FRIAS AND THOMAS
Since teratogenesis is a threshold phe­
nomenon, the dose of a teratogen is one
of the essential determinants in the pre­
natal effect of drugs and chemicals. To
produce a teratogenic effect, a drug must
surpass a specific level.4,22 As an exam­
ple, 50 mg of thalidomide, if given dur­
ing the critical period, can affect the
majority of embryos in a litter, but 0.5
mg will have no effect. Conversely,
almost any drug, if administered at a suf­
ficiently high dose, can adversely affect
embryonic and/or fetal development.
Furthermore, as noted by Brent, terato­
genesis is a multicellular phenomenon
and both the incidence and the severity
of malformations increase with the dose.
This is in marked contrast with carcino­
genesis or mutagenesis, which are sto­
chastic phenomena.4 It should be noted
also that the dose determines maternal
serum concentration and, hence, the
rate of diffusion of most compounds
through the placenta. This is specially
significant because passive diffusion is
the primary mechanism of transfer of
drugs through the placenta.39
Major structural defects occur when
exposure to a given teratogenic agent
takes place during the critical period of
development. This period is relatively
short, only lasting eight weeks. During
the preimplantation period, when the
blastocyst lies free within the uterine
cavity, exogenous agents may kill the
embryo, but there is no evidence that
they produce malformations. At this
stage, because of the pluripotency of
some of its cells, it is possible for the
conceptus to overcome minor damage.
During the embryonic period, each
organ system undergoes a critical stage
of differentiation, which occurs at a pre­
cise moment. It is at these specific times
that the developing embryo is most vul­
nerable to the effect of environmental
agents and that specific malformations
can be produced. The critical period
ends by the 56th day of gestation, when
most differentiation has been completed.
This is followed by the fetal period, dur­
ing which the most important events are
accrual of body mass, reduction of the
umbilical hernia, closure of the palate,
differentiation of the genitalia, and histo­
genesis of the CNS, which is completed
in post-natal life. Therefore, exposure to
teratogens during the fetal period does
not produce a pattern of malformation
w ith m u ltip le organ inv o lv em ent.
Instead, it may result in varying degrees
of intrauterine growth retardation and
defects of the areas undergoing comple­
tion of their m orphogenic processes,
including abnormalities in the histogen­
esis of the central nervous system.40
The concurrent administration of two
or more drugs or chemicals may influ­
ence the effects of a teratogen.21,33,39,43
The interactions between the chemicals
can be eith er hom ergic — w hen the
chem icals produce the sam e overt
effects— or hetergic— when one of the
chemicals produces an effect and the
other causes synergism or antagonism.33
Recent studies suggest that perhaps
the m ost im p o rtan t factors in the
response to teratogens are the genetic
constitutions of the m other and the
fetus. It is a well established fact that the
unequal sensitivity of different species
and strains to the teratogenic effects of a
given environm ental agent depends
largely on th e ir g en etic c o n stitu ­
tion.8,31,32 As noted by Kalter, this inter­
species and intraspecies variability may
be manifested in a number of ways: (1)
an environmental agent may have a tera­
togenic effect in some species and be
innocuous in others; (2) it may cause the
same type of abnormalities in different
species, but with varying incidence and
severity from one species to another; and
(3) it may cause dissimilar defects in dif­
ferent species.17
While the source of this variability is
 TERATOGENS AND TERATOGENESIS
believed to be genetic, its basic mecha­
nisms are not yet fully understood.
Fraser suggested that the different rate
of cleft palate induced by cortisone in
the Ajax (100 percent) and the C57BL
mice (18 percent) can be explained by
the multifactorial/threshold model. He
based this assertion on the correlation
betw een tim ing of palate closure in
untreated embryos and the frequency of
cleft palate in embryos exposed to corti­
sone or 6-aminonicotineamide.8,9 On the
other hand, Goldman et al attribute the
differences in the incidence of cortisone-
induced cleft palate in inbred mouse
strains to the number of steroid recep­
tors present in each strain.11 Others have
suggested that the interspecies and
intraspecies differences in response to a
teratogen may be due to genetically
determ ined differences in m etabolic
rates and pathways. For example, Chlor-
cyclizine, an antihistaminic drug, is tera­
togenic in rats but not in humans. The
drug is metabolized to norchlorcyclizine
in both species, but the steady state
level of the metabolite is approximately
three times higher in the rat than in
man, which may account for the dispar­
ity of response.19 Differences in meta­
bolic pathways and resultant metabolites
may be responsible for the dissimilar
defects caused by imipramine in experi­
mental animals of different species.38
There is ample evidence that the tera­
togenic effects of many drugs are not
mediated by the drugs themselves, but
by highly reactive metabolites. If these
are not detoxified, they interact cova­
lently with macromolecules within the
cell and interfere with normal develop­
m ent by altering cell metabolism and
function.35,36 Blake, M artz, and co­
workers2,25 postulated that phenytoin
teratogenicity results from the formation
of an epoxide metabolite and its subse­
quent covalent binding to fetal rat mac­
romolecules. They inhibited the activity
of the hydratase controlling the rate of
17 7
transhydrodiol formation from phenytoin
and showed that the amount of covalent
binding of this arene oxide correlated
w ith the severity of m alform ations.
These, as well as other studies, suggest
that the rates of formation and detoxifi­
cation of these reactive metabolites are
under genetic control.12,20,35,36 Shum et
al stu died the terato genic effect of
benzo[a]pyrene (BP) to test this hypoth­
esis.32 They used inbred mouse strains
with high and low cytochrome Pl-450
inducibility, which is under the control
of a single gene, the Ah locus, and
showed that differences at this Ah locus
c o rre la te d w ith te ra to g e n e sis. In
mothers with low Pl-450 inducibility,
fetuses heterozygous at the Ah locus had
more resorptions, deaths, growth defi­
ciency, malformations, and reactive BP
metabolites than fetuses from the same
uterus homozygous for high inducibility.
When the mother had high cytochrome
Pl-450 inducibility and activity, there
was no difference between fetuses with
high or low cytochrome Pl-450 inducibil­
ity. This dem onstrates, first, that the
fetuses producing the largest amounts of
BP reactive metabolites, because of their
genetic constitution, w ere the m ost
severely affected and, second, that the
m other’s genotype can determ ine ulti­
mate fetal outcome.
In humans, the capacity of the liver to
metabolize drugs may be less lim ited
than in other species. In vitro studies
have dem onstrated the presence of a
microsomal drug-oxidizing enzyme sys­
tem in human fetal liver early in gesta­
tion, and recent works suggest that
hydratase dehydrogenase may be found
in liver peroxisomes.1,10,23 Buehler and
Delimont observed decreased epoxide
hydratase levels in children with stig­
mata of Dilantin teratogenesis and sug­
gested that the enzyme deficiency fol­
lows an autosomal recessive pattern of
inheritance.6 Using an in vitro assay,
Strickler et al demonstrated an increase
178 FRIAS AND THOMAS
in arene oxide metabolites in children
w ith ph en ytoin-in duced m alform a­
tions.37
These studies have opened a new
chapter in our understanding of the basic
mechanisms of teratogenesis. Refine­
ment of these techniques may allow, in a
near future, the identification of suscep­
tible individuals and thus help to pre­
ven t the occurrence of som e drug-
induced birth defects.
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