Available online at www.sciencedirect.
com Current Opinion in
ScienceDirect
Oxidative stress during development:
Chemical-induced teratogenesis
Jason M. Hansen, Benjamin R. Jacob and Ted B. Piorczynski
Abstract
Oxidative stress has been shown to be an important contrib-
utor to birth defects, including structural malformation and
neurobehavioral deficits. At high levels, oxidative stress pro-
motes apoptosis but at lower levels that do not cause cell
death, redox-sensitive pathways can be disrupted. Chemicals
that cause birth defects usually provide a very distinct devel-
opmental outcome, dependent upon gestational periods of
exposure and level of exposure, but these observations also
suggest that there are specific pathways involved in the
manifestation of a given defect. Here, we review overarching
themes of oxidative stress and their effects during develop-
ment and provide specific examples of some of the most
notorious human teratogens that produce oxidative stress as
part of their teratogenic mechanism. Moving forward, future
studies should center on providing a more profound under-
standing of redox-sensitive elements during development to
develop potential preventative interventions.
Addresses
Department of Physiology and Developmental Biology, College of Life
Sciences, Brigham Young University, Provo, UT, 84602, USA
Corresponding author: Hansen, Jason M (jason_hansen@byu.edu)
Email address: ben.richard.jacob@gmail.com (B.R. Jacob),
ted.piorczynski@gmail.com (T.B. Piorczynski)
Current Opinion in Toxicology 2018, 7:110–115
This review comes from a themed issue on Oxidative Toxicology:
Role of ROS
Available online 7 November 2017
For a complete overview see the Issue and the Editorial
https://doi.org/10.1016/j.cotox.2017.11.003
2468-2020/© 2017 Elsevier B.V. All rights reserved.
Keywords
Glutathione, Birth defects, Oxidative stress, Redox, Signaling,
Apoptosis.
Abbreviations
ASK1, Apoptosis Signaling Kinase 1; Cys, Cysteine; D3T, 3H-1,2-
dithiole-3-thione; Eh, Redox Potential; FASD, Fetal Alcohol Spectrum
Disorder; Grx, Glutaredoxin; GSH, Glutathione; GSSG, Glutathione
Disulfide; H2O2, Hydrogen Peroxide; MAP, Mitogen-activated Protein;
NAC, N-Acetylcysteine; NF-kB, Nuclear Factor Kappa B; Nrf2, NF-
E2p45-related factor 2; ROS, Reactive Oxygen Species; -SOH, Sulfenic
Acid; -SSG, S-Glutathionylation; Trx1, Thioredoxin-1.
1. Introduction
Alarmingly, one in every 33 births present with a birth
defect, ranging from relatively minor, non-life-threatening
effects to severe, lethal developmental outcomes. Un-
fortunately, upwards of 70% of all birth defects occur
Current Opinion in Toxicology 2018, 7:110–115
Toxicology
through unknown etiologies [1]. Chemicals that produce
birth defects, known as teratogens, contribute only a small
amount to the total known causes of birth defects in
humans, but this may be an underestimate of environ-
mental influences in poor developmental outcomes. Of
the known human teratogens, many are known to produce
oxidative stress [1], suggesting an important mechanistic
link between oxidative stress, redox signaling and devel-
opment. Here, in this review, we outline the role of
oxidative stress in developmental toxicity and chemical-
induced embryopathy.
2. Oxidative stress and redox signaling
Oxidative stress has been classically defined as an
imbalance between oxidizing and reducing equivalents,
where the former predominates [2]. In severely pro-
oxidizing environments, cellular macromolecules are
damaged promoting apoptosis or necrosis [2]. With less
toxic levels of oxidative stress, redox states are simply
shifted but can disrupt or delay normal cell function. In
some cases, these redox-sensitive pathways are linked to
systems that support the restoration of functional cellular
redox states, prior to the oxidation-induced promotion of
cell death (Fig. 1). However, there are other redox-
sensitive pathways that are likely more closely tied to
developmental pathways, where untimely shifts in
cellular redox states could result in aberrant signaling of
redox-sensitive pathways, support untimely cellular
function and ultimately promote dysmorphogenesis.
Development is a mixture of different cellular actions,
such as proliferation and differentiation, which occur in
a well-coordinated manner, where disruption of these
events can result in poor developmental outcomes.
Proliferative, differentiative and apoptotic activities are,
in part, regulated by cellular redox states [3] and as
such, can be altered during periods of oxidative stress
and redox imbalance. Perhaps the most susceptible pe-
riods in the embryo are periods defined by transition
from an important developmental event to another (e.g.
proliferation/differentiation) in developing target
organs and systems (Fig. 2). Chemical-induced oxidative
stress can result in prolonged periods of redox imbalance
that alter developmental programming from regular
schedule events.
3. Redox regulation during development
The intracellular redox state has been shown to be an
integral part of many essential developmental processes.
The influence that redox states have on development is
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Fig. 1
Comparison of the activation of redox-sensitive pathways (green line) with
pro-cell death (red line) signaling. Under normal, usually pro-reducing,
intracellular redox states, compensatory redox signaling and cell death is
low. As redox states shift to a more oxidizing environment, as would occur
with chemical-induced oxidative stress, redox-sensitive elements and
pathways would be activated earlier in the redox spectrum and at more
moderate redox shifts. As redox states progress to more pro-oxidizing
potentials, various redox-sensitive signaling pathways could be deacti-
vated dependent on their redox sensitivity. As these corrective pathways
are either shut off or deactivated, apoptotic signaling will predominate to
promote cell death.
Fig. 2
Redox switches involved in cellular function. Under highly reducing con-
ditions, proliferation-related pathways are switched on (green line), but as
redox states transition to a more oxidizing condition, pro-proliferation
switches are deactivated and pro-differentiation switches (blue line) are
activated. Excessive shifts to extremely pro-oxidizing redox states switch
off pro-differentiation pathways and promote apoptosis (red line) and
necrosis (black line). During development, transitional periods (outlined in
yellow) may be the most susceptible periods to chemical-induced redox
signaling disruption. Untimely switching may prevent normal develop-
mental processes and cause poor developmental outcomes (structural
malformations, neurobehavioral deficits, etc.).
complex and far reaching, affecting a variety of cellular
systems. Because cellular processes affect the redox state
of the cell, the redox regulation of these processes can
involve feedback control [4]. Reactive oxygen species
(ROS) are understood to have beneficial as well as
deleterious effects on embryo development. However,
aberrant production of ROS to toxic levels can occur
through a variety of mechanisms including changes to
cellular metabolism, alterations to mitochondrial kinetics
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Oxidative stress and birth defects Hansen et al. 111
and the bioactivation of chemicals to more reactive,
oxidizing metabolites (e.g. ethanol is metabolized to
reactive acetaldehyde via alcohol dehydrogenase). Loss
of ROS regulation can be damaging during development
and thus, a tightly controlled redox state is optimal for
normal embryogenesis [5]. While there are many cellular
processes that rely on redox-dependent mechanisms, we
have highlighted only three in this review that are most
relevant to developmental toxicity-related processes.
3.1. Cellular signaling
Cellular signaling has been widely shown to incorporate
ROS, like H2O2, as a signaling intermediate and sec-
ondary messenger. For example, epidermal growth factor
signaling produces H2O2 to oxidize proteins in tyrosine
kinase cascades and promote DNA synthesis and
cellular proliferation [6]. Similar results were found with
platelet-derived growth factors when their tyrosine re-
ceptor signaling systems were blocked by the inhibition
of ROS production, indicating the use of redox shifts in
cellular signaling [7]. Furthermore, H2O2 is a necessary
intermediate for glucose-induced insulin secretion [8].
During development, the relative value of oxygen in
metabolism fluctuates as the preferential source for
cellular energy shifts from glycolysis to oxidative phos-
phorylation. This change shifts the redox state of the
cell when the embryo uses mitochondrial production of
ROS during metabolic switching [9,10].
Additionally, H2O2 has been shown to activate the
transcription factor NF-E2p45-related factor 2 (Nrf2)
during times of electrophilic and oxidative stress. Nrf2
then signals the increased gene expression of antioxi-
dant and phase II detoxification enzymes [11]. The
Nrf2-mediated response is an important element of the
antioxidant defense system in developing embryos. In
some models, embryos show distinct, inherent changes
to redox states during development, where cellular
redox states during periods of differentiation are
generally more oxidizing than those observed during
proliferation [12]. These changes may be an influencing
factor in how Nrf2 is regulated during development after
oxidant exposure [13]. There are a number of tran-
scription factors, like Nrf2, that are controlled by redox
states, many of which are involved in developmental
events, and thus, support redox regulation involvement
in development [14,15]. The specific mechanisms for
the redox-sensitive signaling methods are currently
under investigation, but may be directly or indirectly
tethered to intracellular redox states. While S-thiolation
has been suggested as a redox-control mechanism, S-
glutathionylation (-SSG) is seen as a direct control
regulator of redox-dependent responses [16]. Indirectly,
loss of reducing power may promote the increased
availability of ROS to cause protein oxidation (devel-
opment of sulfenic acids, -SOH). As such, through di-
sulfide exchange mechanisms, both indirect and direct
redox control of proteins can overlap [17].
Current Opinion in Toxicology 2018, 7:110–115
112 Oxidative Toxicology: Role of ROS
3.2. Differentiation
Cellular differentiation relies on some of the cellular
signaling mechanisms previously described and subse-
quently is also influenced by the redox potential of the
cell. Human stem cell differentiation into adipocytes
and osteocytes has been shown to be directly related to
the glutathione (GSH) redox potential (Eh); in both
processes, the overall GSH Eh shifted to a more
oxidizing state, albeit at different rates during the dif-
ferentiation period [18] and may highlight specific redox
regulation into certain phenotypes. Although redox
states were not the primary measure, studies show that
mitochondrial ROS seem to be involved in CD4þ and
CD8þ memory T cell differentiation [19]. Reactive
oxygen species have also been implicated as a signal of
adipocyte differentiation [20,21] and osteocyte differ-
entiation [22]. Reducing ROS levels in hematopoietic
stem cells promotes a more reducing environment
which correlated with a restriction in the cell’s ability to
differentiate [23]. These findings suggest a more
nuanced role for shifts in intracellular redox potentials
and indicate that, at different redox potentials and at
different stages of development, an embryo can be more
or less prone to differentiate.
3.3. Apoptosis
Redox state is also linked with the activation and
stimulation of apoptosis [24,25]. Reduced thioredoxin, a
protein oxidoreductase, can bind to and inhibit
apoptosis signaling kinase 1 (ASK1), a member of the
MAP3 kinase family [26]. However, upon oxidation,
Trx1 becomes unbound and allows ASK1 to become fully
active promoting apoptosis [27]. As such, changes in
cellular redox environments specific to Trx1 Eh can
directly influence ASK1 activity and stimulate related
downstream apoptotic activities.
As GSH becomes oxidized to glutathione disulfide
(GSSG), protein targets can become S-glutathionylated
and as a post-translational modification, protein function
can be changed. In relation to apoptosis, studies have
shown that in Fas-mediated death pathways, Fas can be
glutathionylated on a redox-sensitive cysteine residue
(Cys294) further promoting its downstream pro-
apoptotic signaling [28]. Fas-SSG increase FasL bind-
ing and accentuated apoptosis. Removal or addition of
GSH moieties to proteins can occur through the action
of glutaredoxins (Grx), but mostly de-glutathionylate
proteins under normal conditions. For de-
glutathionylation reactions, Grxs will reduce proteins
and become glutathionylated itself (Grx-SSG). Over-
expression of Grx prevented the formation of Fas-SSG
and reduced apoptosis. As such, the role of GSH Eh
requires further study to better understand the pro-
posed mechanisms here, especially in the context of
development.
Current Opinion in Toxicology 2018, 7:110–115
4. Disruption of redox control during
development through chemical exposures
Alterations in redox status influence multiple cellular
processes that may negatively affect embryonic devel-
opment. Consequently, embryonic cells are sensitive to
the direct action of certain drugs or to the environ-
mental changes produced by drugs that induce oxidative
stress [29]. While multiple teratogens have been shown
to increase ROS production and induce oxidative stress,
we will focus on only a few of the most prevalent ones for
this review.
4.1. Thalidomide
In the 1950s, this non-addictive sedative was widely
prescribed to pregnant women to ameliorate nausea
associated with morning sickness. Shortly thereafter,
thalidomide exposure during the first trimester of
pregnancy was shown to be responsible for a number of
deformities in newborns, including phocomelia and
amelia [30,31]. Recently, interest in thalidomide has
resurfaced as it has received FDA approval as an effec-
tive therapy for multiple myeloma and erythema nodo-
sum leprosum [32]. Multiple sources have shown that
thalidomide increases ROS production, induces oxida-
tive stress and disrupts the function of the redox-
sensitive transcription factor, Nuclear Factor Kappa B
(NF-kB), an important mediator of limb bud outgrowth,
and appear to contribute to limb reduction defects [33e
36]. Pretreatment with various antioxidants reduces the
associated thalidomide-induced terata in animal models
and restores redox states to preserve normal cellular
signaling and function [37,38], further suggesting the
role of oxidative stress, ROS generation and redox
imbalance in thalidomide teratogenesis.
4.2. Phenytoin
Phenytoin is a widely used anticonvulsant drug that
induces oxidative stress [39] and is associated with an
increased risk for isolated cleft palate in children
following maternal exposure during the first trimester of
pregnancy [40]. In addition, phenytoin results in
oxidative DNA damage and dysmorphogenesis, which
can be reduced by the antioxidant superoxide dismutase
[41]. Phenytoin-induced defects in animal models may
be reduced through pretreatment with N-acetylcysteine
(NAC), a precursor to GSH synthesis. Conversely, pre-
treatment with antioxidant depleting agents increased
the occurrence of defects [39]. Curcumin, a pigment
from plants known to have antioxidant properties, is
effective in preventing phenytoin-induced cognitive
impairment and oxidative stress in rats [42,43]. In other
studies, GSH levels in fetal organs were significantly
depleted when phenytoin was given from gestational
day 7e18, yet interestingly, antioxidant supplementa-
tion (vitamin E), in this case, failed to rescue changes to
GSH concentrations [44].
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 Oxidative stress and birth defects Hansen et al. 113

4.3. Ethanol 4.4. Mercury

Ethanol consumption during pregnancy can result in a
wide range of adverse effects in the developing fetus.
Fetal Alcohol Spectrum Disorder (FASD) comprises the
vast range of conditions that can occur when alcohol is
consumed during various periods of pregnancy. Fetal
Alcohol Syndrome (FAS), the most severe condition, is
characterized by facial abnormalities, growth retarda-
tion, and central nervous system impairment [45]. Evi-
dence from in vitro and in vivo models of prenatal ethanol
exposure suggest that oxidative stress contributes to
deficits seen in FASD, and that antioxidants are po-
tential candidates for the treatment of alcohol-induced
developmental disorders [46]. In In vitro culture, em-
bryos demonstrated a decrease in GSH concentrations
with ethanol exposure and similar GSH depletion was
observed with in utero exposure [47]. In the same study,
embryonic cysteine was also significantly decreased but
to an even greater extent than GSH with both in vitro
and in utero exposures. Ethanol caused an increase in
H2O2 and superoxide production in cultured fetal he-
patocytes, as well as an increase in malondialdehyde, a
marker of lipid oxidative damage [48,49]. The Nrf2-
inducer, D-L-sulforaphane, protects neural crest cells,
an ethanol-sensitive cell population implicated in
FASD, against ethanol-induced oxidative stress and
apoptosis [50]. Furthermore, in utero, administration of
the Nrf2 inducer, 3H-1,2-dithiole-3-thione (D3T),
improved antioxidant enzyme expression and activities
and prevented cranial apoptosis in the embryonic neural
folds [51].
Mercury is a naturally occurring element found in the
earth’s crust that has been released into the biosphere as
a consequence of natural processes including volcanic
activity, fires and erosion. Recently, anthropogenic
sources have greatly contributed to the environmental
distribution of mercury via coal mining and chemical
syntheses. While various types of mercury occur in
nature, perhaps the most detrimental, both develop-
mentally and otherwise, is methylmercury, the most
abundant organic mercury. Methylmercury has been
shown to bioaccumulate in organisms causing severe
health issues including irreversible brain damage and
even death [1]. Fetal methylmercury poisoning has been
well documented in Japan, where mothers consumed
fish contaminated by methylmercury resulting in
numerous children being born with neurobehavioral
deficits [52]. In mice, various in utero effects were
observed with methylmercury exposure, including cleft
palate, exencephaly, missing limbs and facial deformities
[53]. Microglial cells exposed to methylmercury showed
a concentration- and time-dependent increase in ROS
generation and a concomitant decrease in the ratio of
GSH and GSSG [54]. In a mouse model, administration
of NAC prevented methylmercury-induced malforma-
tions [55]. In mouse fetuses, methylmercury caused a
significant increase in GSSG and decrease in GSH,
supporting an environmental redox shift correlation with
its developmental toxicity [56]. Interestingly, mercury
exposure did not increase GSH synthesis pathways in
the fetus as the GSH synthesis enzyme activity was

Fig. 3

Overview of oxidative stress in developing tissues. Following chemical exposure, changes to cellular metabolism, mitochondrial kinetics or the bio-
activation of xenobiotics into reactive metabolites can promote an increase in ROS production increases and shift intracellular redox states. Excessively
high levels of ROS generation and/or highly oxidized redox states can promote apoptosis (black arrows), but under more moderate conditions, shifts in
redox state can promote disruption to redox-sensitive cell signaling (red arrows), including important developmental pathways. Outcomes can include
structural malformations and neurobehavioral deficits. However, redox shifts can also activate compensatory pathways that are designed to restore redox
imbalance and increase ROS detoxification (green arrows). Rapid and timely restoration of redox states may serve as a means to prevent prolonged
periods of signal disruption and support normal developmental patterning.

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114 Oxidative Toxicology: Role of ROS
unchanged, but increases in activity were observed in
the visceral yolk sac, which may suggest poor oxidant
pathway responses in the embryo/fetus during these
stages of development.
5. Conclusion
During development, cells are in flux, as demonstrated
by specified periods of proliferation, differentiation and
apoptosis. Oxidant exposure can increase ROS levels
resulting in variable effects. Dependent upon the
degree of ROS generation, cellular macromolecules can
be severely or irreversibly damaged to the point where
cells will undergo apoptosis, whereas under lower ROS
conditions, redox states can be altered to modify redox-
sensitive signaling pathways (Fig. 3). With the latter,
there are pathways that favor the correction and resto-
ration of redox states to reverse redox imbalanced
cellular environments. However, during periods of redox
imbalance, developmental stage specific redox-sensitive
pathways can still be perturbed, resulting in failed
developmental programming and poor developmental
outcomes such as structural malformations and/or
neurobehavioral deficits. Clearly, moving forward to
better understand environmental influences, both
physical and chemical, that act to disrupt timely
developmental signaling through dysregulation of redox
states is an area of great human health interest and
should be further studied to develop intervention and
prevention strategies.
Conflict of interest
The authors declare no conflict of interest.
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