See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/321913698

Teratogenesis

Article · December 2017

DOI: 10.1002/9780470015902.a0026056

CITATION READS

1 13,801

2 authors:

Neil Vargesson Lucas Rosa Fraga

University of Aberdeen Universidade Federal do Rio Grande do Sul
97 PUBLICATIONS   2,474 CITATIONS    53 PUBLICATIONS   245 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Thalidomide View project

All content following this page was uploaded by Neil Vargesson on 14 May 2019.

The user has requested enhancement of the downloaded file.

Teratogenesis
Neil Vargesson, School of Medicine, Medical Sciences and Nutrition, Institute of
Medical Sciences, University of Aberdeen, Aberdeen, UK
Lucas Fraga, School of Medicine, Medical Sciences and Nutrition, Institute of Med-
ical Sciences, University of Aberdeen, Aberdeen, UK
Teratogenesis is a process that causes birth defects
or malformations in an embryo or foetus. Tera-
tology is the study of the causes and underlying
mechanisms leading to birth defects or malfor-
mations. These may include disorders without any
obvious structural malformations, such as intellec-
tual disabilities. A teratogen is a substance (from
outside the body) that causes birth defects or
malformations. Examples of teratogens include
medicinal drugs, such as thalidomide; environ-
mental toxins, for example cadmium as well as
environmental pollutants, including pesticides and
endocrine-disrupting compounds. Other causes of
teratogenesis include viruses, for example rubella
and Zika virus; physical compression in utero and
poor diet. Animal models are used to study the
mechanisms by which teratogens result in birth
defects or malformations, and these studies can
also give insights into normal development. The
study and understanding of teratogenesis is also
essential for making safer and more targeted ther-
apeutic drugs.
Introduction
Teratology is the study of the mechanisms resulting in birth
defects and malformations caused by environmental factors, that
is nongenetic. The origins of malformation have been studied
since Greek times, and the term ‘teratology’ derives from Greek
and translates broadly to the ‘study of monsters’.
Given the incredible and complex events that underlie the
amazing journey the fertilised egg must go through to produce
an embryo and then a foetus, it is amazing that any baby is born
normally. Around 3% of births suffer from some sort of birth
defects/malformations (Sadler, 2012; Schardein, 2000; also see
http://www.cdc.gov/ncbddd/birthdefects/features/birthdefects-
keyfindings.html) (see also: Birth Defects: Overview;
eLS subject area: Developmental Biology
How to cite:
Vargesson, Neil and Fraga, Lucas (December 2017)
Teratogenesis. In: eLS. John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0026056
eLS © 2017, John Wiley & Sons, Ltd. www.els.net
Introductory article
Article Contents
• Introduction
• How Are Teratogenic Events Studied?
• Experimental Teratology
• Conclusions
Online posting date: 15th December 2017
Molecular Genetics of Human Congenital Limb Malforma-
tions). The causes of birth defects can be genetic, chromosomal
or environmental (e.g. drugs), although sadly in many cases, we
do not know the cause of the defect.
Any agent that can cause a birth defect or malformation is
termed a teratogen. Many developmental biologists study ter-
atogens and how they cause malformations (teratogenesis) using
animal models that display a similar defect to that seen in humans
(Gilbert-Barness, 2010; Cassina et al., 2012; Schardein, 2000;
Tables 1 and 2).
Many factors have been linked to causing teratogenesis, which
include the following:
• Chemical agents, such as medicinal drugs, for example
thalidomide and retinoic acid; recreational drugs, for
example alcohol and cocaine; environmental toxins, for
example heavy metals such as cadmium and environ-
mental pollutants, for example pesticides that are linked
to reproductive and fertility malformations, for example
diethylstilbestrol in pregnancy.
• Infections such as rubella and Zika virus.
• Physical restraint or in utero damage – for example due to
oligohydramnios, where the amniotic fluid is lost causing the
foetus to be restrained – and clubfoot can result from this.
Amniotic band syndrome is an example of in utero physical
damage due to the wrapping of strands of the amnion around
body parts of the foetus and causing damage or, in severe
cases, death.
• Hyperthermia.
• Maternal conditions such as pre-eclampsia and gestational
diabetes.
The study of teratogenesis is also very important with regard
to drug safety – it is vitally important to ensure that drugs are
safe and/or do not cause birth defects that is that they are non-
teratogenic. To this end, the lesson of thalidomide provides an
excellent example (Vargesson, 2015a; see also: Thalidomide
and Birth Defects). Briefly, thalidomide was prescribed as a non-
barbiturate, nonaddictive sedative between 1957 and 1962 and
given to pregnant women to prevent morning sickness. Sadly,
the drug was potently teratogenic, resulting in more than 10 000
children being born with severe birth defects and countless mis-
carriages and stillbirths (Smithells and Newman, 1992; Varges-
son, 2015b). The thalidomide made it clear that the effects drugs
have upon the embryo/foetus are far from understood. Moreover,
the disaster confirmed that drugs can and do cross the placenta
(Vargesson, 2013, 2015b). Widikund Lenz famously determined
1
 Teratogenesis

Table 1 Examples of teratogens known to cause human birth defects

Agents Malformations
Drugs
Alcohol Foetal alcohol syndrome, intrauterine growth retardation and intellectual disability
Cocaine Intrauterine growth retardation, prematurity, urogenital anomalies and brain developmental
disorders
Diethylstilbestrol (DES) Abnormalities of the reproductive tract
Retinoic acid Neural tube defects, craniofacial anomalies, cleft palate and cardiovascular anomalies
Tetracycline Teeth anomalies and damage
Thalidomide Abnormal limb development – typically shortening and loss of proximal bones, facial
anomalies, systemic anomalies including urogenital, cardiac and gastrointestinal tract
Valproic acid Craniofacial anomalies, neural tube defects and heart and skeletal defects
Warfarin Craniofacial anomalies and intellectual disability
Chemicals
Mercury Brain developmental disorders
Cadmium Limb anomalies, cardiovascular anomalies and neural tube defects
Polychlorinated biphenyls (PCBs) Intrauterine growth retardation
Infections
Cytomegalovirus Brain and sensory anomalies
HIV Growth failure, microcephaly and craniofacial defects
Rubella Intrauterine growth retardation, cardiac defects, deafness, eye defects and intellectual
disability
Zika Microcephaly
Ionising radiation Microcephaly, growth delays, skeletal development anomalies and mental retardation

Table 2 Selection of teratogens and their resulting malformations that have been studied in animals
Teratogen Models Malformations
Thalidomide Primates, rabbits, marsupials, rodents, Limb defects, facial defects, spina
chickens, marine fish and zebrafish bifida, microphthalmia and internal
organ abnormalities
Valproate Xenopus, zebrafish, mice and chicken Growth retardation and eyes, heart, tail
and neural tube defects
Cadmium Rodents, zebrafish, lizards and chicken Limbs’ malformation and abnormalities
in heart, vasculature and liver, neural
tube, somites and reproductive
system
Mercury Cats Brain damage
Zika virus Mice and chicken Mortality, growth retardation, ocular
malformations and microcephaly
Alcohol Chicken and fish Mortality, blood vessel formation
inhibition, growth retardation,
pericardial oedema, cyclopia and
CNS defects
Retinoic acid Chicken and fish Mortality, eye defects, facial defects
and heart and limb defects
References
Vargesson (2013)
Gilbert-Barness (2010); Whitsel
et al. (2002)
Yamamoto et al. (2012);
Cullinane et al. (2009)
Gilbert-Barness (2010)
Cugola et al. (2016); Goodfellow
et al. (2016); Miner et al.
(2016)
Ali Laghari et al. (2015); Sylvain
et al. (2010)
Hyatt et al. (1992); Jelínek and
Kistler (1981); Larsen and
Janners (1987)

the time period that thalidomide caused damage in embryogene-
sis, the earlier the exposure occurred, the more severe the damage
(Figure 1; Vargesson, 2015b). Lenz interviewed the parents of the
thalidomide damaged children and studied their medical records
to deduce the time window of sensitivity (Vargesson, 2015b). It
also became clear that species differences in response to drugs
existed, for example rodents are less sensitive to thalidomide than
nonhuman primates and rabbits (Vargesson, 2009, 2013; see also:
Thalidomide and Birth Defects). Furthermore, the thalidomide
disaster completely changed the way drugs were tested, requir-
ing them to be screened in multiple animal models and in vitro
assays, which has given rise to a greater understanding of tera-
tology (Kelsey, 1966; Vargesson, 2015b). Today, we know that
the placenta does allow agents, including drugs, toxins and so on,

2 eLS © 2017, John Wiley & Sons, Ltd. www.els.net

 Teratogenesis

Post conception
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
Days
34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
Post menstruation
External ear missing Inner ear damage
Microphthalmia
Coloboma
Thumb damage
Upper limb/s amelia
Upper limb/s phocomelia and reduction
Hip dislocation
Ear deformation
Lower limb/s amelia
Lower limb/s phocomelia and reduction
Triphalangealism

Figure 1 Outward damage caused by thalidomide exposure of human embryos at different times during pregnancy. Thalidomide caused
outward damage (e.g. to the limbs, ears and eyes) between day 20 and day 36 of embryonic development. Note that there is generally more widespread
damage the earlier the exposure to thalidomide occurs in the time-sensitive window. The action of thalidomide falls within the embryonic ‘critical period’
which is between 2 and 8 weeks of development when all the major tissues and organs are forming and these tissues are most sensitive to disruption.
Reproduced from Vargesson (2015b) © Wiley Periodicals, Inc. under the terms of the Creative Commons Attribution License.

to directly reach the embryo/foetus, which can influence/impact
development. Indeed, the field of teratology now overlaps with
other fields of basic science, including developmental biology,
embryology and genetics.
Teratogens can potentially harm the embryo/foetus throughout
the whole of development; however, the period between the sec-
ond and eighth weeks of development is particularly susceptible
to damage as this is when the majority of the tissues and organs
are forming and taking on the final, adult patterns (Figure 1). This
period is also known as the ‘critical period’ of development, and
interference in these major tissue patterning events can result in
birth defects (Sadler, 2012; Vargesson, 2015b). Before the second
week of development, the embryo is not supplied/connected to
the placenta. It should be noted that exposure to some teratogens
after 8 weeks can have effects on internal organ function and mat-
uration and on the developing brain and nervous system (Varges-
son, 2013, 2015b). Understanding how teratogenesis comes about
through using animal models will shed light on how birth defects
arise and may also give insights into normal developmental pro-
cesses. In addition, such information could help design better and
safer drugs as determining how these events come about could
potentially lead to therapeutic and preventative measures.
How Are Teratogenic Events
Studied?
in 1959 by Wilson (1973 and see Cassina et al., 2012; Schardein,
2000). These include the following:
• Susceptibility to a given teratogenic agent and subsequent ter-
atogenesis depends on the genetic background of the embryo
because embryos, such as adults, exhibit differences in the
way they respond to drugs/agents and so on.
• Timing of exposure to the agent, typically the earlier the expo-
sure occurs in embryonic development, the more severe the
damage, particularly between weeks 2 and 8 of development
when the majority of the major tissues and organs are forming
and being patterned.
• Dosage and duration of exposure. Typically the occurrence
of malformations increases with increased dosage; a scale
for each agent as the dosage increases is produced ranging
from the no observable adverse effect level (NOAEL) to an
LD100 – a dose that results in 100% lethality.
• The route of administration to come into contact with the
embryo which includes if/how the agent can cross the pla-
centa.
• The metabolism and absorption abilities of the agent across
cell membrane (e.g. whether it is lipophilic or requires spe-
cific cross-membrane transporters).
• The range (and consistency) of damage the agent
causes – which can vary depending on the species as
well from individual to individual.

Experimental teratology involves trying to model human condi-
tions/malformations in animal embryos and in vitro cell culture
assays, where appropriate, to gain an understanding of the con-
dition. This methodology can also be used to test potential thera-
peutic strategies.
To understand how an agent causes a teratogenic event, we need
to be aware of several key principles which were first described
Various animals have been used to study teratogenic mech-
anisms including nonhuman primates, domestic animals such
as cats and dogs and farm animals as well as developmental
models such as embryos of zebrafish, chickens, rodents, rabbits,
Xenopus, Caenorhabditis elegans, hydra and sea urchins. The
choice of animal species really depends on the teratogenic event
being addressed. For example, studies looking at the effects of

eLS © 2017, John Wiley & Sons, Ltd. www.els.net 3

 Teratogenesis
environmental toxins on the reproductive development and fertil-
ity utilise farmland animals such as sheep, owing to the similarity
in reproductive development and function to humans. Studies
looking at drug safety and teratogenesis now more commonly
use rodents, rabbits and in vitro cell lines. Nonhuman primates
such as monkeys have also been used (Table 2; Vargesson, 2013).
These studies in mammals involve exposing pregnant animals
to agents and observing the resulting foetuses for gross mor-
phological abnormalities (Gilbert-Barness, 2010; Cassina et al.,
2012). Chicken and zebrafish embryos are being increasingly
used to visualise and monitor the effects and actions of agents
on development and morphogenesis, by direct application to
the embryo (Beedie et al., 2017). Today, this methodology is
enhanced by utilising molecular and genetic technologies to iden-
tify the mechanism(s) through which these agents act, such as
screening drug-exposed embryos for gene expression changes
(Ema et al., 2010).
Agents should be administered to the animal model in a
species-dependent manner that causes the least discomfort. For
example, in pregnant mice, the administration may be by intra-
venous or intraperitoneal injection or by ‘gavaging’ where the
agent is administered directly into the animal’s stomach through
a tube (Gupta, 2017). Agents could be given to the animals’ food,
but this method is not as reliable as the animal may not consume
all the food in one sitting, and thus the dosage received may be
inaccurate. Unexpected or adverse reactions to the agent’s admin-
istration would bring about the termination of the experiment.
For embryonic exposure in chickens, the agents can be applied
in a solution over the embryo. For marine species, the agents can
be administered directly into the water in which the embryos are
bathed, and the resulting embryos can be analysed over a range
of timepoints. Following the administration of agents, animals
would be observed for any developmental, morphological and
behavioural changes. An advantage of chicken and zebrafish
embryos for screening agents for potential teratogenic capabil-
ities is that the embryos develop outside the mother’s body, so
they can be visualised easily, and agents can be directly applied
to the embryo and their effects observed over long time periods.
Understanding how a teratogenic agent causes its effect is
important in understanding how congenital abnormalities arise
and can shed light on the properties that are nonteratogenic,
which has the potential to develop new therapeutic drugs that
are safe for use by pregnant women. Today, this is particularly
relevant in Brazil, as the drug thalidomide is being used again;
this time to treat a complication of leprosy and multiple myeloma
(a cancer affecting white blood cells). Sadly, a new generation
of thalidomide-damaged children have been born in Brazil in
the past decade due to the drug being shared and getting into
the hands of pregnant women (Vianna et al., 2013; Vargesson,
2013). Clearly, if a form or structural variant of thalidomide
can be experimentally identified, which retains clinical benefits
without the teratogenic side effects, this may prevent birth defects
(Vargesson, 2015b).
The 3Rs
Around the world, animal welfare in research has always been
deemed important and is taken seriously. For example, in the
4 eLS © 2017, John Wiley & Sons, Ltd. www.els.net
United Kingdom, animal use is regulated by the Government
and work is licensed. In addition, a National Centre for the
Replacement, Refinement and Reduction of Animals in Research
(NC3Rs; www.nc3rs.org.uk/) has been established to encourage
new techniques/methods that lead to the reduction/replacement
of animals in research. Indeed, early/initial drug testing for
toxicity and teratogenesis is increasingly being considered in
nonmammalian species such as chicken embryos and zebrafish
embryos – these embryos share developmental mechanisms with
embryos of mammals (including humans), and similar morpho-
logical events produce the embryo and its complex array of tis-
sues and organs. Using these embryos of lower vertebrates, it is
possible to identify drugs that have the potential to cause terato-
genic events, which indicates, though does not prove, that the
drugs are likely to be teratogenic in mammalian species. This
reduces the need for screening the drugs initially to determine
their actions in mammalian species, thus reducing the number of
experiments and the number of mammalian embryos used. Once
the actions of the drugs have been worked out in nonmammalian
species, the drugs would then be screened in mammalian species
to ensure that they are indeed safe and are functioning as required.
Relevance to humans and limitations
To prove that an agent is a human teratogen, it is required to
show that the frequency of anomalies in children of mothers who
were exposed to the agent is higher than the spontaneous rate of
anomalies or that children with birth defects have a confirmed
history of greater maternal exposure to the agent than unaffected
children, and damage shows common patterns/characteristics
between affected individuals. This can be difficult, and epidemi-
ological records can be used to help study long-term effects
of the use of an agent on pregnancy outcomes (Cassina et al.,
2012). Epidemiology studies can also identify ethnic differences,
regional differences and seasonal differences in the occurrence
of teratogenic events. These studies provide information about
any possible risks of medications or other exposures in human
pregnancies (Vargesson and Schuler-Faccini, 2016).
Screening agents, whether they are drugs, toxins, pollutants
or simply screening compounds to assess potential action, can
provide information on what the agent can do in vivo and can
give insights into the molecular pathways the agent acts through.
Such studies allow us to determine the dose response of the
agent and the time of activity. Animal embryos develop in a
very similar way to human embryos and use the same or similar
genetic pathways, and so they are relevant models. Obviously, for
the study of birth defects and malformation, animal teratology
experiments allow us to replicate the conditions and study the
causes and potential therapies (see the following section). So,
these experiments provide vital information on potential hazards,
mechanisms of action and contraindications about which we
would not know otherwise and shed light on what the agent might
do in humans. However, care must always be taken when trying
to extrapolate data obtained from animal species to humans.
Animal data can suggest that only similar effects may occur in
humans. If an agent/drug/compound produces teratogenic effects
in two or more species, the probability of the agent being a
human teratogen must be high, but the dosage still needs to be

considered. For example, the thalidomide disaster taught us that
species differences can exist in response to drugs by animals
versus humans – indeed, we know in human adults themselves
that drugs can vary in activity from individual to individual. Why
this occurs remains unclear but may be related to the levels of
metabolic enzymes in the liver and the capacity to breakdown
and excrete drugs. This is why the drug testing procedures are
so tightly regulated to ensure that those compounds that exhibit
the desired effects are then moved into the higher species for
teratogenic testing, and human clinical trials are carried out with
many different conditions including age, weight, gender and so
on tested. The thalidomide disaster brought about changes in the
way we test drugs for safety and function, using multiple animal
systems, in vitro systems and a range of clinical trials in humans
(Kelsey, 1966; Vargesson, 2013). This system has largely been
very successful though it is not infallible, as was demonstrated,
for example in the early 1980s with a drug called Accutane which
contains isotretinoin, which is a modification of vitamin A. This
drug was used to treat severe cases of acne and sadly caused birth
defects in some children whose mothers used the drug during
pregnancy, before being withdrawn in 1983 (Stern et al., 1984;
Gupta, 2017).
Experimental Teratology
Experimental teratology models birth defects in animals to under-
stand the condition and the molecular pathways impacted. Here,
we will briefly discuss some examples of malformations that have
been studied in animal models and which have provided some
understanding of the developmental basis for the defect. We will
use the Zika virus and thalidomide and discuss how experimental
modelling of the defects caused by these agents has allowed a
better understanding of how these teratogens act (see Table 2
for some other examples of human birth defects that have been
modelled in animals and in which the mechanism underlying the
defect has become clearer or is known).
Drugs/medicines
The field of drug identification and drug safety has become cen-
trally associated with developmental teratogenesis. Obviously,
drug safety, in particular, requires that drugs are tested to ensure
that they are not teratogenic. Thalidomide remains the most
infamous drug to cause teratogenesis; however, there are many
other drugs that are teratogenic, which include, for example
sodium valproate, alcohol and retinoic acid (Gilbert-Barness,
2010; Gupta, 2017; Cassina et al., 2012; Table 1), and there
are some drugs suspected of causing teratogenic damage but not
proven to do so, for example Primodos (Vargesson, 2016).
Thalidomide
Today, thalidomide is used to successfully treat inflammatory
disorders, such as leprosy and also cancers such as multi-
ple myeloma (Vargesson, 2015a,b). In humans, thalidomide is
potently teratogenic, resulting in thalidomide embryopathy – the
majority of the tissues of the body can be affected, including eyes,
eLS © 2017, John Wiley & Sons, Ltd. www.els.net
Teratogenesis
ears, limbs, genitalia and internal organs including digestive tract
and heart. However, the brain is largely unaffected.
Thalidomide teratogenicity has been extensively studied in a
wide range of animal species which include nonhuman primates,
rabbits, marsupials, rodents, chickens, marine fish, zebrafish right
the way down to Hydra. Most species are sensitive, but puz-
zlingly, rodents, the preferred animal model for drug screening
and safety, are less sensitive and are now not used to study thalido-
mide teratogenicity (Vargesson, 2009, 2013). The best models of
human thalidomide embryopathy are nonhuman primates, mon-
keys and macaques, and rabbits (Ema et al., 2010). However,
recently, chicken and zebrafish embryos have provided great
insights into the actions of thalidomide (Beedie et al., 2016; Ito
et al., 2010; Knobloch et al., 2007; Therapontos et al., 2009;
Vargesson, 2013).
These studies have led to many proposed hypotheses and theo-
ries of how thalidomide causes defects (Vargesson, 2009, 2013).
Currently favoured mechanisms of the action of the drug are
that it inhibits formation of new blood vessels resulting in cell
death and tissue loss or that it induces reactive oxygen species
or that it acts through binding to the protein cereblon (Ito et al.,
2010; Vargesson, 2009, 2013; Vargesson and Hootnick, 2017).
Cereblon is part of an ubiquitin ligase complex whose role is
to regulate signalling in the cell. Thalidomide binding to cere-
blon (Ito et al., 2010) explains thalidomide’s anti-inflammatory
and antimyeloma actions in adults (Vargesson, 2015b; see also:
Thalidomide and Birth Defects), but as yet it is unknown how
such an interaction leads to and results in thalidomide embryopa-
thy and the broad range of damage the drug induces in the short
time-sensitive window. Other studies using thalidomide-exposed
human embryonic stem cells and thalidomide-exposed monkey
foetuses and carrying out gene profiling screens indicate that over
2000 gene profile changes occur following thalidomide exposure
(reviewed in Vargesson, 2015b). Now, the major challenge is to
identify the temporal order in which the expression of these genes
is affected and the pathways affected by the drug. This should
shed further light on potential therapeutic strategies and safer
drug design.
Virus
Viral infections during pregnancy have been shown to cause birth
defects and even miscarriages. Perhaps, the most notorious and
well known is rubella (German Measles). Vaccinations to prevent
rubella virus infections are commonplace in the developed world
where it is extremely rare to see babies born with rubella-induced
birth defects. Rubella virus was identified as a teratogen in the
1940s and contributed to changing the view that placental mem-
branes protect the embryo from harmful agents.
More recently, the Zika virus has grabbed the attention of the
world (Schuler-Faccini et al., 2016). Originally discovered in
Uganda in the 1940s, the virus was thought to be harmless. Trans-
mitted by Aedes mosquitoes, many babies have been born with
microcephaly (significantly small heads and brains) in Brazil. The
Zika virus is a flavivirus, a group of viruses that include dengue
fever, yellow fever and Nile fever and cause encephalitis (inflam-
mation of the brain) in adults, which can be life-threatening. Zika
virus infections in adults have also been linked in rare cases
5
 Teratogenesis
to a severe adult neurological syndrome, Guillain–Barre Syn-
drome; precisely how Zika virus causes this condition remains
unclear. There were a lot of debates about whether Zika virus
was the cause of microcephaly in newborn babies (Vargesson
and Schuler-Faccini, 2016). Recent work has now confirmed that
this is likely to be the case where calves have been born with
congenital malformations following virus infection of their moth-
ers (Bradley and Nagamine, 2017; Rasmussen et al., 2016). In
addition, chicken and mouse embryos infected with Zika virus
develop microcephaly and nerve cell loss/destruction (Goodfel-
low et al., 2016; Miner et al., 2016; Oh et al., 2017). Recent
research suggests that Zika virus prevents brain stem cells from
proliferating and forming nerves and other nervous system sup-
port tissues (McGrath et al., 2017). Further research is needed
to determine whether the nerve cells are targeted directly by the
virus or if the virus has other actions which secondarily lead to
nerve cell death. This outbreak shocked the world, and with the
introduction of the World Health Organisation Disease Outbreak
News Service (http://www.who.int/csr/don/en/), rapid dissemina-
tion of advice and information has occurred to reduce the spread
of the virus.
These two examples underline how important experimental ter-
atogenesis is, not just determining how the malformation comes
about but also identifying potential molecular targets and/or
mechanisms which can shed further light on normal developmen-
tal processes as well as therapeutic interventions and better/safer
drug design.
Conclusions
Understanding how teratogenesis comes about is essential not
only to try to prevent such events but also to try and identify
sooner those at risk and offer therapeutic strategies. Experimental
teratology offers insights into mechanisms that may be impaired
by agents such as drugs, genes or environmental influences and
therefore sheds light on normal development. What remains clear
is that the developing embryo is fragile, particularly in early
embryogenesis when the body plan is forming and tissues and
organs are maturing. It is essential that agents, drugs and com-
pounds used in the environment and workplace are tested to
ensure that they are nonteratogenic or prevented from being given
to pregnant women. Ideally, by studying teratogenic compounds,
we can gain a better understanding of their mechanisms and pre-
vent birth defects by either making forms of a drug with the
clinical benefit but not the teratogenic side effects (i.e. better drug
design) or ensuring that precautions are in place to prevent expo-
sure to pregnant women.
References
Ali Laghari Z, Ali Samo A, Waryani B, et al. (2015) Effects of a
single dose of ethanol on survival rate and angiogenesis of chick
embryo. Animal and Veterinary Sciences 3: 8–11.
Beedie SL, Rore HM, Barnett S, et al. (2016) In vivo screening and
discovery of novel candidate thalidomide analogs in the zebrafish
embryo and chicken embryo model systems. Oncotarget 7 (22):
33237–33245.
6 eLS © 2017, John Wiley & Sons, Ltd. www.els.net
Beedie SL, Diamond AJ, Fraga LR, Figg WD and Vargesson
N (2017) Vertebrate embryos as tools for anti-angiogenic drug
screening and function. Reproductive Toxicology 70: 49–59. DOI:
10.1016/j.reprotox.2016.11.013.
Bradley MP and Nagamine CM (2017) Animal models of Zika Virus.
Comparative Medicine 67 (3): 242–252.
Cassina M, Salviati L, Di Gianantonio E and Clementi M (2012)
Genetic susceptibility to teratogens: State of the art. Reproductive
Toxicology 34: 186–191.
Cugola FR, Fernandes IR, Russo FB, et al. (2016) The Brazilian Zika
virus strain causes birth defects in experimental models. Nature
534: 267–271.
Cullinane J, Bannigan J and Thompson J (2009) Cadmium terato-
genesis in the chick: period of vulnerability using the early chick
culture method, and prevention by divalent cations. Reproductive
Toxicology 28 (3): 335–341.
Ema M, Ise R, Kato H, et al. (2010) Fetal malformations and
early embryonic gene expression response in cynomolgus mon-
keys maternally exposed to thalidomide. Reproductive Toxicology
29 (1): 49–56.
Gilbert-Barness E (2010) Teratogenic causes of malformations.
Annals of Clinical & Laboratory Science 40: 99–114.
Goodfellow FT, Tesla B, Simchick G, et al. (2016) Zika virus induced
mortality and microcephaly in chicken embryos. Stem Cells and
Development 25 (22): 1691–1697.
Gupta R (ed) (2017) Reproductive and Developmental Toxicity, 2nd
edn. Amsterdam: Elsevier.
Hyatt GA, Schmitt EA, Marsh-Armstrong NR and Dowling JE
(1992) Retinoic acid-induced duplication of the zebrafish retina.
Neurobiology 89: 8293–8297.
Ito T, Ando H, Suzuki T, et al. (2010) Identification of a primary
target of thalidomide teratogenicity. Science 327: 1345–1350.
Jelínek R and Kistler A (1981) Effect of retinoic acid upon the chick
embryonic morphogenetic systems. I. The embryotoxicity dose
range. Teratology 23: 191–195.
Kelsey FO (1966) The evolution of new drug legislation. BMQ 17
(2): 72–81.
Knobloch J, Shaughnessy JD Jr, and Ruther U (2007) Thalidomide
induces limb deformities by perturbing the Bmp/Dkk1/Wnt sig-
nalling pathway. FASEB Journal 21 (7): 1410–1421.
Larsen HL and Janners MY (1987) Teratogenic effects of retinoic
acid and dimethylsulfoxide on embryonic chick wing and somite.
Teratology 36: 313–320.
McGrath EL, Rossi SL, Gao J, et al. (2017) Differential responses of
human fetal brain neural stem cells to Zika virus infection. Stem
Cell Reports 8 (3): 715–727. DOI: 10.1016/j.stemcr.2017.01.008.
Miner JJ, Cao B, Govero J, Smith AM, et al. (2016) Zika virus
infection during pregnancy in mice causes placental damage and
fetal demise. Cell 165: 1081–1091.
Oh Y, Zhang F, Wang Y, et al. (2017) Zika virus directly infects
peripheral neurons and induces cell death. Nature Neuroscience 20
(9): 1209–1212. DOI: 10.1038/nn.4612.
Rasmussen SA, Jamieson DJ, Honein MA and Petersen LR (2016)
Zika virus and birth defects – reviewing the evidence for causality.
New England Journal of Medicine 374 (20): 1981–1987.
Sadler T (2012) Langmans Medical Embryology, 13th edn. Philadel-
phia, PA: Wolters Kluwer.
Schardein JL (2000) Chemically Induced Birth Defects, 3rd edn. New
York: Marcel Dekker.

Schuler-Faccini L, Ribeiro EM, Feitosa IM, et al. (2016) Pos-
sible association between Zika virus infection and micro-
cephaly – Brazil, 2015. Morbidity and Mortality Weekly Report 65
(3): 59–62.
Smithells RW and Newman CG (1992) Recognition of thalidomide
defects. Journal of Medical Genetics 29 (10): 716–723.
Stern RS, Rosa F and Baum C (1984) Isotretinoin and pregnancy.
Journal of the American Academy of Dermatology 10 (5 Pt1):
851–854.
Sylvain NJ, Brewster DL and Ali DW (2010) Zebrafish embryos
exposed to alcohol undergo abnormal development of motor
neurons and muscle fibers. Neurotoxicology and Teratology 32:
472–480.
Therapontos C, Erskine L, Gardner ER, et al. (2009) Thalidomide
induces limb defects by preventing angiogenic outgrowth during
early limb formation. Proceedings of the National Academy of
Sciences of the United States of America 106 (21): 8573–8578.
Vargesson N (2009) Thalidomide-induced limb defects: resolving a
50-year old puzzle. BioEssays 31: 1327–1336.
Vargesson N (2013) Thalidomide embryopathy: an enigmatic chal-
lenge. ISRN Developmental Biology 2013, Article ID 241016, 18
pages. Available from: 10.1155/2013/241016.
Vargesson N (2015a) Thalidomide: The Drug with a
Dark Side but an Enigmatic Future. Available from:
https://theconversation.com/thalidomide-the-drug-with-a-dark-
side-but-an-enigmatic-future-50330
Vargesson N (2015b) Thalidomide-induced teratogenesis: history
and mechanisms. Birth Defects Research. Part C, Embryo Today
105 (2): 140–156.
Vargesson N (2016) Is Primodos ‘The Forgotten Thalidomide’?
Available from: https://theconversation.com/is-primodos-
the-forgotten-thalidomide-50673
Vargesson N and Schuler-Faccini L (2016) Proving that
the Zika Virus Causes Microcephaly. Available from:
https://theconversation.com/proving-that-the-zika-virus-causes-
microcephaly-53716
Vargesson N and Hootnick DR (2017) Arterial dysgenesis and limb
defects: clinical and experimental examples. Reproductive Toxicol-
ogy 70: 21–29.
eLS © 2017, John Wiley & Sons, Ltd. www.els.net
View publication stats
Teratogenesis
Vianna F, Schuler-Faccini L, Leite JC, et al. (2013) Recognition of
the phenotype of thalidomide embryopathy in countries endemic
for leprosy: new cases and review of the main dysmorphological
findings. Clinical Dysmorphology 22: 59–62.
Whitsel AI, Johnson CB and Forehand CJ (2002) An in ovo chicken
model to study the systemic and localized teratogenic effects of
valproic acid. Teratology 66: 153–163.
Wilson JG (1973) Handbook of Teratology, 1st, vols. 1–3 edn. New
York: Plenum Press.
Yamamoto FY, Filipak Neto F, Freitas PF, et al. (2012) Cadmium
effects on early development of chick embryos. Environmental
Toxicology and Pharmacology 34 (2): 548–555.
Further Reading
Colborn T, vom Saal FS and Soto AM (1993) Developmental effects
of endocrine-disrupting chemicals in wildlife and humans. Envi-
ronmental Health Perspectives 101 (5): 378–384.
van Gelder MM, de Jong-van den Berg LT and Roeleveld N (2014a)
Drugs associated with teratogenic mechanisms Part II: a literature
review of the evidence on human risks. Human Reproduction 29
(1): 168–183.
van Gelder MM, van Rooij IA, de Jong-van den Berg LT and
Roeleveld N (2014b) Teratogenic mechanisms associated with
prenatal medication exposure. Thérapie 69 (1): 13–24. DOI:
10.2515/therapie/2014003.
Hazelden KP (2013) The developmental toxicity testing of
biologics. Methods in Molecular Biology 947: 31–36. DOI:
10.1007/978-1-62703-131-8_3.
Zeller R (2010) The temporal dynamics of vertebrate limb
development, teratogenesis and evolution. Current Opin-
ion in Genetics and Development 20 (4): 384–390. DOI:
10.1016/j.gde.2010.04.014.
Zuniga A, Zeller R and Probst S (2012) The molecular basis of human
congenital limb malformations. Wiley Interdisciplinary Reviews:
Developmental Biology 1 (6): 803–822. DOI: 10.1002/wdev.59.
7