Heyer Et Al - 2017

NeuroToxicology 58 (2017) 2341
Contents lists available at ScienceDirect
NeuroToxicology
Review
Environmental toxicology: Sensitive periods of development and

neurodevelopmental disorders
Djai B. Heyer, Rhiannon M. Meredith*
Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, De Boelelaan 1085, 1081 HV
Amsterdam, The Netherlands
A R T I C L E I N F O
Article history:
Received 4 August 2016
Received in revised form 25 October 2016
Accepted 31 October 2016
Available online 4 November 2016
Keywords:
Neurodevelopmental disorders
Autism
ADHD
Schizophrenia
Toxicant
Prenatal
A B S T R A C T
Development of the mammalian central nervous system is a complex process whose disruption may have
severe and long-lasting consequences upon brain structure and function, potentially resulting in a
neurodevelopmental disorder (NDD). Many NDDs are known to be genetic in origin, with symptom onset
and their underlying mechanisms now known to be regulated during time-dependent windows or
critical periods during normal brain development. However, it is increasingly evident that similar
disturbances to the developing nervous system may be caused by exposure to non-genetic,
environmental factors. Strikingly, at least 200 industrially applied or produced chemicals have been
associated with neurotoxicity in humans and exposure to these modifying compounds, through
consumer products or environmental pollution, therefore poses serious threats to public health. Through
a combination of human epidemiological and animal experimental studies, we identied developmental
periods for increased vulnerability to environmentally-modifying compounds and determined whether
and how exposure during specic sensitive time-windows could increase the risk for the NDDs of autism,
ADHD or schizophrenia in the developing organism. We report that many environmental toxicants have
distinct sensitive time-windows during which exposure may disrupt critical developmental events,
thereby increasing the risk of developing NDDs. The majority of these time-windows occur prenatally
rather than postnatally. We propose four underlying mechanisms that mediate pathogenesis, namely
oxidative stress, immune system dysregulation, altered neurotransmission and thyroid hormone
disruption. Given the complexity of underlying mechanisms and their prenatal inception, treatment
options are currently limited. Thus, we conclude that preventing early exposure to environmental
toxicants, by increasing public awareness and improving government and industry guidelines, may
ultimately lead to a signicant reduction in the incidence of NDDs.
2016 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
Neurodevelopmental disorders and environmental toxicants

Early onset of neurodevelopmental disorders . . . . . . . . . . . .
Sensitive time-windows for brain development . . . . . . . . . . .
Environmental toxicant exposure . . . . . . . . . . . . . . . . . . . . . .
Literature search & analysis . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Environmental toxicants . . . . . . . . . . . . . . . . . . . . . . . .
6.1.
Polychlorinated biphenyls (PCBs) . . . . . . . . .
6.1.1.
Methylmercury (MeHg) . . . . . . . . . . . . . . . . .
6.1.2.
Lead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1.3.
Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1.4.
Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1.5.
* Corresponding author.
E-mail address: r.m.meredith@vu.nl (R.M. Meredith).
http://dx.doi.org/10.1016/j.neuro.2016.10.017
0161-813X/ 2016 Elsevier B.V. All rights reserved.
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24
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24
D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341
6.1.6.
Bisphenol A (BPA) . . . . . . . . . . . . . . . . . . . . . . . . . . .
Maternal use of medication . . . . . . . . . . . . . . . . . . . . . . . . . .
Thalidomide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.1.
Valproic acid (VPA) . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.2.
Misoprostol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.3.
Selective Serotonin Reuptake Inhibitors (SSRIs) . . .
6.2.4.
Other environmental factors . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.
Maternal infection . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.1.
6.3.2.
Ionizing radiation . . . . . . . . . . . . . . . . . . . . . . . . . . .
Maternal malnutrition . . . . . . . . . . . . . . . . . . . . . . .
6.3.3.
Sensitive time-windows for toxicant exposure and NDD risk
6.4.
Common pathophysiological mechanisms . . . . . . . . . . . . . . . . . . . .
Oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1.
Immune system dysregulation . . . . . . . . . . . . . . . . . . . . . . . .
7.2.
Altered neurotransmitter systems . . . . . . . . . . . . . . . . . . . . .
7.3.
7.4.
Thyroid hormone disruption . . . . . . . . . . . . . . . . . . . . . . . . .
Limitations of this study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Competing nancial interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.
7.
8.
9.
1. Neurodevelopmental disorders and environmental toxicants

The development of the central nervous system is an extremely
intricate process, and its disruption may have severe and longlasting consequences on brain structure and function, potentially
resulting in neurodevelopmental disorders (NDDs). While many
disturbances underlying NDDs are genetic in origin, it is
increasingly evident that such disturbances can also be created
by environmental factors. Strikingly, no less than 200 industrially
applied or produced chemicals have been associated with
neurotoxicity in humans (Grandjean and Landrigan, 2006), and
exposure to these compounds, through consumer products or
environmental pollution, may therefore pose a serious threat to
public health, particularly of children (Miodovnik, 2011). This
review discusses several chemicals whose presence in the
environment and negative impact on neurodevelopment are
well-established. In addition, we address the use of medication
during pregnancy, as well as other environmental factors shown to
negatively affect neurodevelopment. Through combining evidence
from human epidemiological and experimental animal studies, we
identied periods of increased vulnerability during development,
and addressed whether exposure during these sensitive timewindows could increase the risk of NDDs.
2. Early onset of neurodevelopmental disorders
This review focuses primarily on autism, Attention Decit/
Hyperactivity Disorder (ADHD), and schizophrenia, since these are
the only three NDDs extensively discussed in the pre-existing
literature regarding environmental toxicology and early exposure.
Autism Spectrum Disorder (ASD), as dened by DSM-V, is a
neurobehavioral disorder with an onset before the age of three. It is
characterized by persistent impairments in communication and
social interaction, manifesting as decits in developing, understanding and maintaining relationships, and abnormal and xed
interests and repetitive behavior (American Psychiatric Association, 2013). While most symptoms become evident after 12
months of age, behavioral studies in children later diagnosed with
autism have revealed that some symptoms can even be observed as
early as in the rst six months of life. Moreover, blood samples
from newborns later diagnosed with autism have shown altered
levels of several neuropeptides and neurotrophins compared to
typically-developing children (Arndt et al., 2005). These ndings
suggest pathogenesis of autism and ASD early in development.
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36
Several potential mechanisms have been suggested to contribute

to autism/ASD pathogenesis, including: immune dysregulation
(Goines and Ashwood, 2013; Rossignol and Frye, 2012), increased
blood levels of serotonin, also known as hyperserotonemia
(Whitaker-Azmitia, 2005), mitochondrial dysfunction and oxidative stress (Rossignol and Frye, 2012), increased neural apoptosis
(Wei et al., 2014), and a disturbed balance between neuronal
excitation and inhibition (E/I balance) (Rubenstein and Merzenich,
2003).
ADHD is one of the most common childhood neurobehavioral
disorders, and is characterized by symptoms of inattention,
hyperactivity, and impulsivity which often persist into adulthood
(Sharma and Couture, 2014). Brains from individuals with ADHD
showed a reduction in the volume and activity of the prefrontal
cortex (PFC), caudate, and cerebellum. These areas are interconnected through dopaminergic and noradrenergic projections, and
are involved in several aspects of cognition, including attention,
emotion, and behavior. It is suggested that dysfunction of these
dopamine and noradrenaline systems may underlie ADHD
symptoms. This is supported by the fact that drug treatment
using stimulants, which block the reuptake of these neurotransmitters, has been shown to effectively reduce symptoms of
ADHD patients (Sharma and Couture, 2014). In addition, there are
also indications that immune system dysregulation or thyroid
hormone disruption may be involved in ADHD pathogenesis
(Andersen et al., 2014; Portereld, 2000; Verlaet et al., 2014).
Affecting approximately 1% of the population, schizophrenia
causes both negative symptoms (e.g. impairments in executive
functions, working memory and attention, apathy, alogia, and
social withdrawal), and positive symptoms (e.g. visual and/or
auditory hallucinations, delusions, and paranoia) in affected
individuals (Fatemi and Folsom, 2009; Loganovsky et al., 2005).
While disease onset typically occurs in late adolescence or early
adulthood, several lines of evidence suggest that schizophrenia
results from aberrations during fetal development. For instance,
children who later developed schizophrenia were already mildly
impaired in cognitive, behavioral, and neuromotor function tests
years prior to diagnosis. Moreover, subtle craniofacial malformations and brain abnormalities, known to result from developmental aberrations during the rst or second trimester, are more
prevalent among schizophrenic patients than controls (Fatemi and
Folsom, 2009). Further evidence for early pathogenesis is that
children born between January and March have an increased risk of
developing schizophrenia, with one underlying explanation being
a seasonally varying infection such as inuenza, which peaks

during the winter. Accordingly, schizophrenia is more prevalent in
cities, as opposed to rural areas where infectious pathogens are
less easily transmitted (Brown and Susser, 2002).
3. Sensitive time-windows for brain development
While these three disorders exhibit early onset, there may be
specic developmental periods that if disrupted, increase risk for
NDDs. In the most general sense, critical and sensitive periods are
restricted time-windows during which the development of an
organism is most prone to change. During these periods, the
developing system is most susceptible to modication by both
intrinsic and extrinsic factors, which can lead to permanent
changes on various levels ranging from physiology to morphology
and behavior (Kroon et al., 2013; Marco et al., 2011; Meredith,
2015). These transient periods enable several essential developmental changes to occur in the central nervous system. At the same
time however, they present windows of heightened vulnerability
of the developing system to deleterious stimuli, and harmful
exposure during these periods could potentiate the emergence of
distinct neurodevelopmental decits (Adams et al., 2000; Leblanc
and Fagiolini, 2011; Rice and Barone, 2000; Selevan et al., 2000).
Even though historically there are some conceptual differences,
the terms critical and sensitive periods/time-windows have
been used interchangeably throughout the literature. Here, we use
sensitive time-windows to refer to developmental periods of
increased vulnerability of the nervous system, during which
exposure to internal or environmental factors can produce longlasting changes in brain and behavior. These sensitive timewindows may vary depending on the outcome measured, the
affected systems/brain regions/structures, and the underlying
cause and its mechanism(s) of action.
4. Environmental toxicant exposure
When assessing environmental factors and NDDs, contaminated air, (drinking) water, soil, house dust, and food are all possible
sources of exposure. These toxicants can enter the body through
skin contact, inhalation or ingestion. Children are particularly
vulnerable to exposure for a number of reasons: First, many
substances easily cross the placenta and the fetal blood brain
barrier (BBB) to reach the developing brain (Grandjean and
Landrigan, 2006; Koger et al., 2005). Secondly, certain lipophilic
chemicals are shown to accumulate in maternal adipose tissue and
breast milk and can be transmitted by breast feeding (Grandjean
and Landrigan, 2006; Weiss et al., 2004). Thirdly, children may
undergo higher contamination levels from environmental pollutants: Children have relatively greater energy demands than adults
due to development and therefore, relative to bodyweight they
breathe air more rapidly and are reported to ingest a higher
proportion of water, fruit, and vegetables in their diet than adults
based on dietary analysis patterns (Koger et al., 2005; National
Research Council, 1993; Weiss et al., 2004). Finally, children are
inherently at an increased risk of exposure due to their natural
behavior and activities. For example, they spend more time in- and
outdoors crawling and playing on the ground, thereby increasing
levels of contact with potentially contaminated dust and soil or
toxic residues on toys and other objects. Furthermore, young
children tend to explore their surroundings by sticking objects or
soil in their mouth (Koger et al., 2005; Weiss et al., 2004). Thus, due
to differences in physiology, diet, and behavior, levels of
environmental toxicants in the blood and brains of babies and
young children may be many times higher than those of adults
living in the same environment (Miodovnik, 2011).
25
To evaluate the potential neurodevelopmental toxicity of

certain chemicals in humans, epidemiological studies have applied
several different methods to estimate the frequency, timing, and/or
exposure level. Determining prenatal exposure, studies rely on
measuring maternal urine, blood, or hair samples throughout
pregnancy, as well as umbilical cord blood just after birth.
Contrastingly, postnatal exposure can be measured directly in
urine, blood, and hair samples of children themselves. Furthermore, levels of heavy metals in childrens teeth can be used as a
measure of long-term exposure to these elements, and life-time
accumulation of toxic substances in the brain can be determined by
measuring levels in post-mortem brain tissue. Unfortunately, such
long-term estimates do not provide information on the exact
timing of exposure. Environmental exposure can be estimated
indirectly, for instance, based on maternal or childhood residency
in areas with contaminated ground water, near sites of pesticide
application or during environmental disasters. In some cases,
parental reports may sufce to assess the neurodevelopmental
effects of toxicants, given that the source, timing, and amount of
exposure are known e.g. with maternal use of medication during
pregnancy.
5. Literature search & analysis
The rst author conducted an initial search using Google
Scholar and PubMed databases. Search terms for different
chemicals (e.g. PCBs, BPA, pesticides, organochlorides, organophosphates, chlorpyrifos, lead, MeHg, arsenic, VPA, thalidomide,
and misoprostol, amongst others) were used in combination with
terms relevant to NDDs and associated symptoms (e.g. Autism,
ASD, PDD, ADHD, Schizophrenia, (in)attention, hyperactivity,
antisocial behavior). Additional information was acquired by
combining these search terms with those relating to environmental pollution and pre-/postnatal exposure, sensitive time-windows,
critical periods, (neuro)toxicology/toxicity, (neuro)development,
(patho)physiology, and possible underlying mechanisms of oxidative stress, immune system dysregulation, hyperserotonemia,
dopamine dysfunction, E/I balance, thyroid hormone disruption,
apoptosis, and dysgenesis. Cited references of the identied
relevant publications were also searched for additional articles.
Only peer-reviewed data and review articles up to and including
publication in 2016 were considered for inclusion. Articles were
excluded based on content irrelevant to this review, inadequate
sample sizes, or insufcient clarity of methods, design, or
conclusion. Both human and animal studies were included. The
nal selection was estimated to consist of roughly 210 publications.
To compare developmental stages between humans and animals
and estimate sensitive time-windows for human development, a
validated model based on cellular changes such as neurogenesis
and myelin formation, protein expression and other neurological
biomarkers was used to translate both pre- and postnatal
neurodevelopmental time across different mammalian species
(Clancy et al., 2007; Workman et al., 2013). This model is available
at www.translatingtime.net.
6. Results
6.1. Environmental toxicants
6.1.1. Polychlorinated biphenyls (PCBs)
Until their classication as Persistent Organic Pollutants (POPs)
in 1979, Polychlorinated Biphenyls (PCBs) were used in industrial
settings worldwide. The main source of human exposure to PCBs is
due to accumulation in the food chain, resulting from the high
chemical stability of these compounds (Winneke, 2011).
26
Several prospective cohort studies have found associations

between prenatal exposure to PCBs from contaminated food
sources and intellectual impairment (Jacobson and Jacobson, 1996;
Lai et al., 2002; Ribas-Fit et al., 2001). Furthermore, links have
been identied between prenatal PCB exposure and ADHD-related
behaviors (De Cock et al., 2012; Sagiv et al., 2010), attentional
decits (Jacobson and Jacobson, 2003; Ribas-Fit et al., 2001), and
increased impulsivity (Jacobson and Jacobson, 2003; Stewart et al.,
2003). Despite these ndings, other studies, often with smaller
sample size, found no signicant associations between PCBs and
intellectual impairment (Ribas-Fit et al., 2001) or ADHD
(Symeonides et al., 2014). A recent pilot study discovered an
increased risk for autism with high maternal serum levels of PCBs.
However, again likely due to the small sample size, these results
were not signicant (Cheslack-Postava et al., 2013). Interestingly, a
comparison of human post-mortem brains from healthy subjects
and subjects with NDDs detected signicantly higher levels of PCB
95 in brains of subjects with 15q11-q13 duplication autism
spectrum disorder (Mitchell et al., 2012).
Further evidence for prenatal PCB exposure in intellectual
disability and ADHD is provided by rodent studies, reporting
hyperactivity and impaired learning after pre/perinatal exposure
to PCBs (Agrawal et al., 1981; Rice and Barone, 2000; Tilson et al.,
1990). However, in Rhesus monkeys, ADHD-related symptoms and
learning impairments occurred after PCB exposure during the rst
20 postnatal weeks (Rice and Hayward, 1999; Rice, 2000, 1999,
1997). These ndings suggest that the teratologic effects of PCBs
may not be restricted to the prenatal period, and exposure to these
compounds can negatively impact the brain throughout early
development. Nevertheless, most studies emphasize the impact of
prenatal PCB exposure over that of postnatal exposure (Symeonides et al., 2014; Winneke, 2011).
One potential mechanism by which PCBs could affect neurodevelopment is through thyroid hormones. Several PCBs are
structurally similar to active thyroid hormones (TH), and could
therefore act as agonists or antagonists to TH, by competing for
binding sites on receptors or other proteins (Portereld, 2000).
PCBs can decrease levels of TH in humans and animals (Wise et al.,
2012) and suppress TH-dependent development of neuronal
dendrites (Kimura-Kuroda et al., 2007). Furthermore, maternal
TH dysfunction is associated with Intellectual Disability (ID),
(Portereld, 2000) ASD and ADHD (Andersen et al., 2014). In
support, a meta-analysis combining results from PCB exposure, TH
levels, and neurological outcomes in one model, revealed a doseresponse decrease in IQ after prenatal PCB exposure and reduced
TH levels (Wise et al., 2012). In addition to TH disruption, PCBs
could impair neurodevelopment by acting on neurotransmitter
systems. E/I balance is important for cognition, and an imbalance
between excitation and inhibition has been suggested as an
underlying mechanism for autism (Rubenstein and Merzenich,
2003). PCB exposure impairs excitatory synaptic transmission and
short-term plasticity (Gilbert, 2003), potentially by damaging
dopaminergic (Agrawal et al., 1981; Fonnum et al., 2006) and
glutamatergic systems (Gafni et al., 2004). Finally, limited evidence
exists for PCB-induced formation of Reactive Oxygen Species (ROS)
and oxidative stress (Fonnum et al., 2006; Rossignol and Frye,
2012), as well as hyperserotonemia (Quaak et al., 2013) underlying
some autistic disorders.
6.1.2. Methylmercury (MeHg)
Methylmercury (MeHg) is the most common form of organic
mercury found in the environment, where it bioaccumulates in the
aquatic food chain. Consequently, consumption of contaminated
sh is a major source of human exposure. MeHg can easily cross the
BBB and placenta and predominately accumulates in brain tissue
(Grandjean et al., 2014).
In the 1950s/60 s in Japan, MeHg pollution of shing waters in

Minamata and Niigata led to poisoning of the local communities
through contaminated sh consumption. Children exposed in
utero exhibited severe neurodevelopmental decits, even when
their mothers showed little or no symptoms. Another poisoning
episode with similar effects took place in the early 1970s in Iraq,
where MeHg-treated seed grain intended for planting was
accidentally consumed by local villagers. Observed decits in
these exposed populations included ID, deafness, blindness,
cerebral palsy, seizures, and low birth weight (Mendola et al.,
2002; Myers and Davidson, 2000). Following these catastrophes,
several cohort studies were initiated to determine the effects of
low-level MeHg exposure from sh consumption. In a north
Quebec Inuit cohort, prenatal MeHg exposure was associated with
increased attention problems and ADHD behavior (Boucher et al.,
2012), as well as lower IQ and increased risk of ID (Jacobson et al.,
2015). This association between ADHD symptoms and prenatal
MeHg exposure was also reported in other New Bedford and Faroe
Isles cohorts (Sagiv et al., 2012; Symeonides et al., 2014) but not for
neurodevelopment in a Seychelles cohort, after adjusting for
postnatal exposure (Myers et al., 2003). None of these cohort
studies detected effects of postnatal MeHg exposure, in agreement
with a longitudinal study on MeHg exposure in children (Cao et al.,
2010). Using structural equation modelling to determine effects of
pre- and postnatal MeHg exposure in the Faroese birth cohort,
prenatal exposure contributed most to neurodevelopmental
decits, although postnatal exposure also exerted neurotoxic
effects, mainly with respect to visuospatial processing and
memory (Grandjean et al., 2014).
These studies suggest an increased sensitivity of the developing
brain in utero to MeHg exposure. In support, adult exposure to
MeHg leads to damage in restricted areas of the visual cortex and
granule cell layer of the cerebellum in both humans and rodents,
while pre-/perinatal exposure leads to more generalized damage
throughout the neocortex (Costa et al., 2004; Johansson et al.,
2007). Furthermore, despite continuous pre-/postnatal MeHg
exposure during gestational day(GD)0-postnatal day (PND)30,
brain Hg levels decreased 20-fold from PND7 to PND30 in young
rats (Johansson et al., 2007), suggesting an increased vulnerability
to MeHg during pre-/perinatal development.
Several molecular and cellular mechanisms have been implicated in the neurotoxicity of MeHg. At lower exposure levels,
implicated underlying mechanisms involve impairments in
neurotransmitter systems, neuronal excitability, and TH disruption. The more severe cellular pathology, such as apoptosis,
observed after high levels of exposure is proposed to be induced
through oxidative stress, altered calcium homeostasis, and
microtubule disruption (Castoldi et al., 2001; Johansson et al.,
2007; Newland et al., 2015).
6.1.3. Lead
Lead is one of the oldest known yet most widely used
neurotoxicants, its previous usage ranging from birth control to
wine sweetener, paint and petrol additive to manufacture of water
pipes and food cans (Gilllan, 1965). As the true extent of leads
neurotoxicity became more evident, its use was nally banned
from industrial and consumer products. Despite the huge
reduction in environmental and human lead levels since, lead
based paint in older buildings and contaminated soil near roads
still prove major sources of exposure today (Grandjean and
Landrigan, 2006; Mendola et al., 2002).
Acute lead poisoning often results in severe intellectual
disability, and can be lethal at high concentrations (Grandjean
and Landrigan, 2006; Mendola et al., 2002). However, the more
subtle effects of longer term low level exposure associated with
contaminated soil and paint pose an even greater threat to public
health. These low level effects include intellectual impairment,

hyperactivity and attention decits, as well as aggression and rulebreaking behavior (Caldern et al., 2001; Costa et al., 2004;
Jacobson and Jacobson, 1996; Jacobson et al., 2015; Koger et al.,
2005; Symeonides et al., 2014; Williams and Ross, 2007; Winneke,
2011). Remarkably, in line with these ndings, the rise and fall of
environmental lead over the past decades is associated with a
similar increase and decrease in intellectual disabilities and violent
crimes respectively (Nevin, 2009; Reyes, 2007). Exposure to lead is
strongly associated with clinically-conrmed ADHD (Braun et al.,
2006; Froehlich et al., 2009) and Conduct Disorder (CD) (Braun
et al., 2008). Furthermore, second-trimester lead exposure has
been linked to schizophrenia (Opler et al., 2004), and lead air
pollution associated with ASD (Roberts et al., 2013).
Evaluating sensitive time windows for lead exposure, both pre-/
and postnatal exposure contribute to negative behavioral outcomes (Dietrich et al., 2001; Wasserman et al., 1998), while other
reports showed an association for current blood lead levels
(Bellinger et al., 1994; Boucher et al., 2012; Chen et al., 2007;
Plusquellec et al., 2010). Overall, while there is plenty of evidence
supporting the involvement of prenatal lead exposure in cognitive
and behavioral decits, most studies emphasize the effects of
postnatal lead exposure (Symeonides et al., 2014; Williams and
Ross, 2007).
In the developing brain, lead-induced damage preferentially
occurs in the PFC, hippocampus, and cerebellum (Finkelstein et al.,
1998) and is known to impair neural differentiation, synaptogenesis, and myelination (Costa et al., 2004), as well as disrupting
the BBB (Finkelstein et al., 1998). At the molecular level, several
mechanisms contribute to the neurotoxicity of lead. For example,
lead can impair excitatory signaling and synaptic plasticity
through its effects on glutamate release and NMDA receptor
function (Adams et al., 2000; Costa et al., 2004), which in turn
could be related to leads ability to interfere with the regulatory
functions of calcium (Costa et al., 2004). Furthermore, similar to
PCBs and MeHg, lead can also alter dopamine systems (Dietrich
et al., 2001; Froehlich et al., 2009), and induce the formation of ROS
resulting in oxidative stress (Flora et al., 2004). Finally, in addition
to its neurotoxicity, lead has also been shown to negatively affect
the immune system (Chen et al., 2004; Miller et al., 1998).
6.1.4. Arsenic
Aside from industrial pollution, naturally occurring arsenic is
present in ground water around the globe, and contaminated wells
and drinking water are a major source of chronic low-level
exposure, raising great concerns for public health. The clearest case
for arsenic exposure and NDD risk arose from the consumption of
contaminated powdered milk in Japan in 1955 causing over 12000
cases of poisoning and 131 deaths. Several years later, a follow-up
study of exposed and non-exposed adolescents born during the
incident reported a tenfold increase in the prevalence of
intellectual disability in the exposed group (Yamashita et al.,
1972). In more recent studies, postnatal exposure to arsenic is
associated with impairments in cognitive development and
intellectual abilities (Caldern et al., 2001; Tolins et al., 2014; Tsai
et al., 2003; Tyler and Allan, 2014; Wasserman et al., 2004). In
rodents, arsenic causes decits in various learning and memory
tasks associated with hippocampal functions (Tyler and Allan,
2014). Unfortunately, the effects of arsenic exposure on NDDsother
than intellectual disability are less clear. For instance, while some
reports show an association between arsenic exposure and
increased risk for ADHD and ADHD symptoms, others fail to
replicate these results (Rodrguez-Barranco et al., 2015; Tolins
et al., 2014; Tyler and Allan, 2014). Similar inconsistencies are
observed in studies regarding ASD (Rossignol et al., 2014), anxiety,
and depression (Tolins et al., 2014; Tyler and Allan, 2014).
27
In contrast to the strong associations observed between

postnatal arsenic exposure and intellectual impairment, studies
assessing the impact of prenatal exposure on cognition fail to
produce consistent results, suggesting that prenatal exposure may
contribute less (Tolins et al., 2014; Tyler and Allan, 2014). Further
evidence supporting this notion arises from animal studies
examining different routes of prenatal exposure. While intravenous and intraperitoneal injections of arsenic at high doses cause
fetal malformations such as neural tube defects, these methods of
administration are not representative of environmental exposure.
More relevant repeated oral or respiratory administration, even at
doses that are toxic or lethal to the mother, did not produce
structural malformations (Jacobson et al., 1999). Furthermore,
follow-up studies on chronic arsenic exposure in children and
adolescents have revealed age-dependent effects on intellectual
function, i.e. greater impairment with increasing age, suggesting
cumulative effects of arsenic exposure on cognitive development
(Tolins et al., 2014; Tyler and Allan, 2014). Together, these ndings
suggest that while environmental exposure to arsenic may be
harmful throughout development, long-term postnatal exposure is
most devastating to intellectual function.
The neurotoxic effects produced by arsenic can act on or
interfere with a range of cellular and molecular systems and
pathways, offering several possible mechanisms that may underlie
or contribute to the observed decits in cognition. Arsenic alters
signaling of essential neurotransmitters, both by changing levels of
glutamate, GABA, dopamine, serotonin, noradrenaline, and acetylcholine, as well as altering the expression of serotonin receptors
and specic NMDA receptor subunits, (Tolins et al., 2014; Tyler and
Allan, 2014). Consequently, arsenic induces changes in synaptic
strength and plasticity (Tyler and Allan, 2014), which may underlie
some cognitive and neurobehavioral impairments associated with
exposure. Aspects of cognitive and mood decits may also be
explained by arsenics ability to dysregulate the HPA-axis,
increasing corticosterone levels and reducing the amount of
glucocorticoid receptors (Tyler and Allan, 2014). In addition,
arsenic promotes apoptosis and necrosis, and inhibits neurogenesis, proliferation, and neurite growth (Tolins et al., 2014; Tyler
and Allan, 2014), which may link to arsenic-induced alterations in
DNA methylation and histone modications (Tyler and Allan,
2014), as well as to oxidative stress resulting from mitochondrial
dysfunction and reduced removal of ROS (Prakash et al., 2015).
6.1.5. Pesticides
Pesticides destroy or repel organisms that pose a threat to
human food supplies, health, or comfort and their widespread use
has led to great economic and public health benets (Weiss et al.,
2004). Due to widespread usage, pesticides are present in food,
water and soil throughout the environment, with highest
concentrations in rural areas near agricultural sites. Several classes
of chemicals with varying properties are used to target specic
organisms including specic insect, fungi or plant species and
rodents. Many pesticides act by interfering with nervous system
function, suggesting that pre- or postnatal exposure could have
detrimental effects on neurodevelopment (Weiss et al., 2004).
In humans, the risk for developing ASD is consistently
associated with maternal residential proximity to organochlorine
pesticide applications across a number of studies (Roberts et al.,
2007; Shelton et al., 2014; Cheslack-Postava et al., 2013). Based on
timing and location of maternal residency and pesticide applications, predominantly dicofol or endosulfan, the risk for ASD was
increased with the amount of organochlorines applied, and
decreased with residential distance from the sites of application.
The highest estimated risk of developing ASD arose when pesticide
application occurred between 26 and 81 days postconception,
around the time of central nervous system (CNS) embryogenesis
28
(Roberts et al., 2007). A later study, using Bayesian modelling on

the same data, proposed an extension of this prenatal sensitive
period from 38 days pre- to 163 days postconception (Roberts and
English, 2013). Furthermore, a postnatal sensitive period between
346 and 529 days postconception was also identied (Roberts and
English, 2013), roughly corresponding to the period of highest
growth rate and maturation of the brain (Rice and Barone, 2000).
Similar prenatal exposure risks for ASD are reported in children
whose mothers resided near applications for the organochlorine
DDE (dichlorodiphenyldichloroethylene) (Cheslack-Postava et al.,
2013) and for chlorpyrifos applications during the second
trimester and organophosphate or pyrethroid applications during
the third trimester (Shelton et al., 2014).
Prenatal exposure to chlorpyrifos and other organophosphates
has been further associated with increased risk of pervasive
developmental disorder (PDD) (Eskenazi et al., 2007; Rauh et al.,
2006) Impaired social behavior has also been observed in mice,
following perinatal exposure to atrazine (Belloni et al., 2011) and
ADHD-related behaviors have also been associated with prenatal
exposure to DDE (Sagiv et al., 2010), chlorpyrifos (Rauh et al.,
2006), and organophosphates (Marks et al., 2010). Similar ndings
to prenatal exposure were reported for postnatal organophosphate
exposure in 8 to 19 year olds (Abdel Rasoul et al., 2008; Bouchard
et al., 2010), although one further study found no association
between ADHD and postnatal exposure in the rst ve years of life
(Marks et al., 2010).
Organochlorines/pyrethroid compounds and organophosphosphates inhibit GABAergic neurotransmission and acetylcholinesterase (AChE) action respectively, suggesting that environmental
exposure to pesticides may disturb the E/I balance in the brain
(Shelton et al., 2012). Furthermore, altered monoamine neurotransmission occurs in rats, with prenatal exposure to chlorpyrifos
increasing dopamine turnover (Eaton et al., 2008) and prenatal
exposure to endosulfan, chlorpyrifos or other organochlorines and
organophosphates increasing serotonin levels (Quaak et al., 2013).
Chlorpyrifos and other organophosphates also promote apoptosis
(Eaton et al., 2008; Rice and Barone, 2000; Shelton et al., 2012),
which may relate to their shared ability with organochlorines to
induce mitochondrial dysfunction and oxidative stress (Eaton
et al., 2008; Shelton et al., 2012). Developmental exposure to
atrazine, pyrethroids, and organophosphates can lead to immunosuppression and neuroinammation (Eaton et al., 2008; Rooney
et al., 2003; Shelton et al., 2012). Equally relevant, organochlorines,
organophosphates, and atrazine have been shown to reduce levels
of maternal thyroid hormones (TH), which are essential for normal
neurodevelopment (Rooney et al., 2003; Shelton et al., 2012).
6.1.6. Bisphenol A (BPA)
BPA is an essential component of polycarbonate plastic, used in
a wide range of products from bottles and cardboard to medical
devices. Consequently, BPA is detected in food, water, dust, air, as
well as human blood and urinary samples (Vandenberg et al.,
2010). This poses a risk to public health, since BPA is a known
endocrine disruptor (Vandenberg et al., 2010).
Previous studies on BPA exposure and childhood behavior
consistently reported increased risks of ADHD, anxiety, depression,
inattention, hyperactivity, and other externalizing behaviors.
However, these ndings contradict each other with regard to
the timing of exposure; while one report only found an effect for
prenatal BPA, another emphasized the impact of postnatal
exposure (Braun et al., 2011; Harley et al., 2013). One event
spanning both the pre- and postnatal period in humans is the brain
growth spurt (BGS), a period of rapid growth and maturation
during which the brain may be particularly vulnerable to
disruption (Dobbing and Sands, 1979). In mice, the BGS peaks
around postnatal day 10, and a single dose of BPA administered on
this day resulted in behavioral decits and hyperactivity in mice

(Viberg et al., 2011). Moreover, the BGS of rhesus macaques takes
place approximately two months before birth (Dobbing and Sands,
1979), and BPA exposure during the nal two months of gestation
in these animals led to a decrease both in midbrain dopaminergic
neurons and hippocampal dendritic spines (Elsworth et al., 2013).
However, these effects were not observed after postnatal exposure
(Elsworth et al., 2013), further suggesting the BGS as a period of
vulnerability to the disruptive effects of BPA.
Prenatal exposure to BPA, measured by maternal urinary
samples, is associated with reduced levels of TH in newborn
children, and this association was strongest for BPA measured
during the third trimester (Chevrier et al., 2013; Romano et al.,
2015). Moreover, BPA inhibits the TH-dependent dendritic
development of Purkinje cells (Kimura-Kuroda et al., 2007),
implicating thyroid deciency as a possible link between BPA
and its observed neurotoxic effects. BPA could additionally result in
neurodevelopmental decits via immune system dysregulation,
interfering with the function of a variety of immune cells (for a
review, see Rogers et al., 2013). Finally, BPA induces mitochondrial
dysfunction and oxidative stress: while low-level prenatal exposure is already sufcient to increase fetal oxidative stress, at higher
doses, prenatal BPA exposure is also associated with increased
oxidative stress in adult sheep and rats (Veiga-Lopez et al., 2015).
6.2. Maternal use of medication
In addition to exposure in the external environment, medication during pregnancy can severely affect the fetus in utero and at
later postnatal stages.
6.2.1. Thalidomide
Thalidomide was a newly synthesized sedative introduced in
the 1950s with global usage due to its effectiveness and, seemingly,
few side-effects. However, reports rapidly showed children born
with serious malformations associated with maternal use of
thalidomide during pregnancy. Worldwide, over 10.000 children
were affected by the time the drug was withdrawn from the
market (Ito et al., 2011; Strmland et al., 1994).
From detailed medical records, it was estimated that thalidomide exposure during a sensitive period from 20 to 36 days
postconception resulted in fetal deformities, proving lethal in early
infancy in roughly one third of the cases. The type of malformation
was dependent on the timing of thalidomide ingestion; intake in
the early sensitive period was associated with ear and upper limb
malformations as well as cranial nerve and ocular decits, while
intake later in the sensitive period resulted in triphalangism of the
thumbs and lower limb deformities (Ito et al., 2011; Miller et al.,
2005; Strmland et al., 1994). In a Swedish population study, ve
out of the 100 thalidomide affected individuals met the full criteria
for autism, considerably more than would be expected based on
prevalence in the general population (Strmland et al., 1994).
Furthermore, besides also suffering from intellectual disability, all
individuals displayed ear malformations, facial nerve, ocular, and
hearing decits. Based on these ndings, an association was
suggested between autism and thalidomide intake during the early
sensitive period spanning 2024 days postconception, coincident
with neural tube closure (Strmland et al., 1994).
Since rodents are resistant to the neurotoxic effects of
thalidomide, experimental studies on the behavioral effects and
underlying mechanisms are limited. Nevertheless, in rabbits,
inhibition of ROS suppressed thalidomide-induced oxidative stress
and limb defects, supporting the notion that oxidative stress might
play a role in thalidomide neurotoxicity (Ito et al., 2011).
Furthermore, exposure to thalidomide around the time of neural
tube closure in rats has shown to increase blood and brain levels of
serotonin (Narita et al., 2002).
6.2.2. Valproic acid (VPA)
While also being used to treat migraine and bipolar disorder,
the main function of VPA is to prevent seizures in patients with
epilepsy and other seizure disorders. Since seizures during
pregnancy are associated with a higher rate of miscarriages and
lower birth weight (Chen et al., 2009), many epileptic women
continue their medication during pregnancy. However, antiepileptic drugs, especially VPA, increase the risk of fetal malformations
(Kozma, 2001; Moore et al., 2000).
Children prenatally exposed to VPA are often born with
craniofacial anomalies, neural tube defects and limb malformations (Kozma, 2001; Moore et al., 2000). Despite being generally
less severe, these deformities bear a strong resemblance to those
resulting from thalidomide (Arndt et al., 2005) and accordingly, an
increase is observed in the prevalence of ASDs and intellectual
disability amongst the VPA-exposed children also (Kozma, 2001;
Moore et al., 2000; Roullet et al., 2013). In a study of children with
fetal anticonvulsant syndrome, of whom the majority were
exposed to VPA, 60% displayed two or more autistic symptoms,
with inattention and hyperactivity observed in 39% of the cases
(Moore et al., 2000).
Since antiepileptic drugs are typically taken throughout
pregnancy, trying to determine a sensitive time-window for VPA
exposure using only epidemiological data is extremely challenging.
Nevertheless, the occurrence of neural tube defects and craniofacial abnormalities (Kozma, 2001; Moore et al., 2000) similar to
those associated with thalidomide suggest that the neurodevelopmental decits ascribed to VPA exposure may also originate
during early CNS development. Further evidence supporting this
notion is provided by several studies on rats showing that VPA
exposure at embryonic day 12 (ED12), during the time of neural
tube closure, resulted in cranial nerve, brainstem, and cerebellar
anomalies similar to those observed in post-mortem brains of
autism patients (Ingram et al., 2000; Rodier et al., 1997, 1996).
Moreover, rats exposed to VPA at ED12-12.5, but not at ED7-9 or
ED14-15, display autism-like behaviors and are therefore often
used as an animal model for autism (Kataoka et al., 2013; Kim et al.,
2011; Schneider and Przewocki, 2005).
VPA is known to inhibit histone deacetylase and prenatal
exposure at ED12.5 can cause a transient increase in acetylated
histone levels, suggesting an involvement of altered gene
expression in VPA neurotoxicity. Indeed, the akt/mTOR pathway
is downregulated in VPA-exposed rats, which is important for
synaptic protein synthesis and spine density and morphology.
Similar changes have been observed in postmortem brains of
idiopathic autism patients (Nicolini et al., 2015). Furthermore, in
vitro VPA exposure resulted in loss of N-cadherin expression in
neural crest cells, an effect that may underlie the observed neural
tube defects, since N-cadherin is essential for neural crest cell
migration (Roullet et al., 2013). VPA exposure at ED12.5 increased
apoptosis and reduced proliferation in rat brains (Kataoka et al.,
2013). In addition, prenatal VPA neurotoxicity increased levels of
pro-inammatory cytokines and altered levels of enzymatic
biomarkers for oxidative stress and mitochondrial dysfunction
in adolescent rat brains (Hegazy et al., 2015). Finally, similar to
thalidomide, prenatal VPA exposure in rats increases brain
serotonin levels and hyperserotonemia (Narita et al., 2002).
6.2.3. Misoprostol
While misoprostol is commonly used to treat gastric ulcers, this
cheap and easily accessible drug also causes uterine contractions
and vaginal bleeding, making it a popular abortifacient amongst
women in Brazil and other developing countries were abortion is
29
illegal. Unfortunately, misoprostol is not very effective at

terminating pregnancy, especially when administered in the rst
trimester. Children surviving these failed rst trimester abortion
attempts are often born with Mbius sequence (Bandim et al.,
2003).
Mbius sequence is a clinical condition associated with facial
palsy and limb malformations, whose main diagnostic criteria is
involvement of the 6th and 7th cranial nerve. Etiological factors
underlying this condition include genetic predisposition as well as
early developmental insults including misoprostol-induced abortion attempts (Bandim et al., 2003). Mbius sequence of unknown
etiology is associated with signicantly increased risks of autism
and intellectual disability (Miller et al., 2005). Based on the
literature and a small group of ASD patients exposed to
misoprostol during the rst trimester, the sensitive period for
misoprostol-induced Mbius sequence is proposed to lie between
the 4th and 6th week postconception, just after neural tube closure
(Bandim et al., 2003).
One possible explanation for the increased autism and ID risk of
misoprostol exposure is that the induced uterine contractions
cause hypoxia or ischemia in the fetus, which, during the suggested
sensitive period of CNS development could result in permanent
damage or dysgenesis of the developing nervous system (Bandim
et al., 2003).
6.2.4. Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs are a class of drugs frequently prescribed to treat anxiety
and depression disorders. Their primary mechanism of action is to
prevent the reuptake of serotonin at the plasma membrane,
thereby raising the level of extracellular serotonin which, in turn,
results in increased serotonin receptor activation (Homberg et al.,
2009). SSRIs are considered safe for use during pregnancy, since
there are no known reports of gross fetal dysmorphology following
prenatal SSRI exposure. However, SSRIs are capable of crossing the
placenta and have been shown to increase fetal serotonin levels.
Serotonin acts mainly as a modulatory neurotransmitter in the
mature brain, but fullls additional roles during early development
in regulating cell differentiation, migration, myelination, synaptogenesis, and pruning (Oberlander et al., 2009). Moreover, increased
serotonin levels during brain development may be involved in the
pathogenesis of autism (Whitaker-Azmitia, 2005). Recent systematic reviews and a meta-analysis of existing literature indicate that
prenatal exposure to SSRIs increases ASD risk (Gentile, 2015; Man
et al., 2015). While one study suggests that the developing embryo
is particularly vulnerable during the rst trimester (Croen et al.,
2011), the usually continuous and long-term intake of SSRIs makes
it difcult to replicate these ndings.
6.3. Other environmental factors
6.3.1. Maternal infection
The neurodevelopmental consequences of maternal infection
during pregnancy point towards increased NDD risks. Following a
rubella virus epidemic in the United States in 1964, a high
incidence of neurological abnormalities and CNS dysfunction
including increased prevalence of intellectual disability and autism
occurred amongst preschool children with congenital rubella
(Chess, 1971). An independent study cohort revealed that children
of mothers who contracted rubella were more likely to be schoolimmature, suggesting developmental delays, and were often
assigned as poorest performers in class. This was most evident for
those infected during the second month of pregnancy (Lundstrom
and Ahnsjo, 1962). Congenital rubella infection also increased later
risk of non-affective psychosis at age 2123 in the 1964 study
cohort. Moreover, using a more comprehensive diagnostic assessment when the subjects where 3335 years old, approximately
30
20% of subjects met the criteria for schizophrenia or other

schizophrenia spectrum disorders (SSD). Again, the effect was
strongest for rubella infection during the rst two gestational
months (Brown and Susser, 2002). In addition to rubella, inuenza
and other respiratory infections during the rst and/or second
trimester have also been shown to increase schizophrenia and
SSDs risk in several follow-up cohort studies (Brown and Susser,
2002; Brown, 2006; Brown et al., 2004). Furthermore, a Danish
population study revealed an increased ASD risk for children
whose mothers had been hospitalized during pregnancy due to
either viral infections in the rst trimester, or bacterial infections
in the second trimester (Atladttir et al., 2010). These ndings
suggest that, rather than specic pathogens, the actual risk factor
for neurodevelopmental decits might be the maternal immune
response in general.
In support, several longitudinal cohort studies found associations between elevated maternal cytokine levels during pregnancy
and schizophrenia and ASD in the offspring (Brown, 2012, 2006;
Buka et al., 2001). In rodents, maternal immune activation using
polyinosinic:polycytidylic acid (poly I:C) produces behavioral signs
associated with schizophrenia and ASD, including decits in
acoustic startle and social interaction and differences in responses
to antipsychotic and psychomimetic medicationafter prenatal
exposure in mice at ED9.5 (Shi et al., 2003),and decits in latent
inhibition and altered antipsychotic medication responses in rats
at ED15 (Zuckerman et al., 2003). In addition, these rats showed
decit neuronal morphology and cell loss in the hippocampus and
entorhinal cortex, akin to morphological anomalies displayed by
schizophrenic patients (Zuckerman et al., 2003). Schizophrenicand autistic-like behaviors have also been observed in rats
prenatally exposed to the cytokine-inducing bacterial endotoxin
lipopolysaccharide (LPS) (Borrell et al., 2002; Fortier et al., 2004).
The timing of exposure in these rodent studies roughly corresponds to the human late rst to second trimester (Workman et al.,
2013).
Maternal immune activation promotes the production of proinammatory cytokines, not only in the mother, but also in the
developing brain and body of the fetus (Meyer et al., 2011), leading
to permanent dysregulation of the immune system in the offspring
(Hsiao et al., 2012). There are multiple ways in which these changes
could affect neurodevelopment, discussed later in more detail.
6.3.2. Ionizing radiation
Radiation with enough energy to ionize atoms or molecules by
freeing electrons is considered ionizing and includes gamma rays,
X-rays, and the higher part of the ultraviolet electromagnetic
spectrum. Potential sources of exposure are either manmade (e.g.
nuclear weapons and power plants), or naturally occurring
background radiation (World Health Organization, 2016). Particularly high levels of background radiation have been observed in
rural areas in India (Loganovsky et al., 2005). It has been suggested
that this may be one of the reasons why India has the highest
incidence of schizophrenia worldwide. Specically, since the
incidence of schizophrenia in India is higher in rural than in
urban areas, which is in stark contrast with the usual pattern of
incidence observed in other countries, where schizophrenia is
more common in larger cities (Loganovsky et al., 2005). However,
stronger evidence for timed links to NDDs arise from nuclear
disasters, namely the atomic-bombing of Japan during the second
world-war, and the 1986 Chernobyl nuclear power plant disaster in
Ukraine.
30 years after the Second World War, the prevalence of
schizophrenia among the atomic bomb survivors in Nagasaki was
considerably higher in comparison to the general Japanese
population (Loganovsky et al., 2005). Furthermore, an increased
incidence of schizophrenia was reported in workers employed for
at least 5 years in the cleanup of the Chernobyl nuclear power plant

after the disaster. These schizophrenia cases were associated with
observed EEG abnormalities, namely a left frontotemporal
dysfunction thought to be characteristic of schizophrenic brains
(Loganovsky and Loganovskaja, 2000). The incidence of schizophrenia only started to increase 34 years after the disaster, either
because it took several years before symptoms manifested after the
initial exposure, or alternatively because symptoms resulted from
prolonged exposure to radiation (Loganovsky and Loganovskaja,
2000). Further evidence suggests that radiation exposure during
dened early periods of development also leads to cognitive and
behavioral decits. For example, children whose mothers were
pregnant and residing near Chernobyl during the disaster were at
higher risk of developing moderate to severe intellectual disability
(Nyagu et al., 1998). Moreover, similar ndings were reported in
Hiroshima and Nagasaki, where children prenatally exposed to
atomic bomb radiation between 8 and 15 weeks postconception
were most likely to be intellectually disabled (Otake et al., 1996).
This illustrates that during CNS development, the effects of
ionizing radiation are dependent on the time of exposure.
Moreover, due to the fact that ionizing radiation effectively
suppresses cell division and synapse formation, different regions of
the developing brain are particularly vulnerable to exposure
during their respective critical periods of proliferation and
synaptogenesis. During the second trimester, synaptogenesis
occurs mostly in the hippocampus, while the highest proliferation
rates take place in hippocampus, cerebellum, neocortex, limbic
cortex, and amygdala (Rice and Barone, 2000). Interestingly,
reductions in the volume of these brain areas as well as GABAergic
and glutamatergic dysfunction in the hippocampus have been
associated with schizophrenia (Fatemi and Folsom, 2009). These
ndings suggest a possible link between second trimester
exposure to ionizing radiation and schizophrenia. In support of
this notion, Imamura et al. showed that among Nagasaki survivors,
schizophrenia prevalence was highest for those exposed during the
second trimester (Imamura et al., 1999). Furthermore, a follow-up
study of children prenatally exposed to radiation from Chernobyl
reported that these children, and especially those exposed in the
second trimester, show schizophrenia-associated EEG abnormalities (Nyagu et al., 1998) similar to those observed in adult
Chernobyl workers (Loganovsky and Loganovskaja, 2000).
Possible factors that could contribute to the pathogenesis of
schizophrenia induced by ionizing radiation include oxidative
stress damage resulting from increased production of free radicals
(Azzam et al., 2012), and dysregulation of the immune system
(Loganovsky et al., 2005).
6.3.3. Maternal malnutrition
The neurodevelopmental consequences of maternal malnutrition have been studied following two
great famines in the 20th century, namely the Dutch Hunger
Winter from October 1944 until May 1945 in the Nazi-occupied
Netherlands and the 19591961 Chinese famine following the
Communist Party Great Leap forward campaign for rapid
industrialization across the country. Children conceived just
before or during the Hunger Winter had an increased risk of
congenital neural defects. Furthermore, later follow-up of these
and surrounding birth cohorts revealed an increase in the
prevalence of schizophrenia, especially among those conceived
or in early gestation at the height of the famine (Susser et al., 1996).
Similarly in China, an increased risk of schizophrenia was found for
those conceived or in early gestation at the height of the famine.
Moreover, this risk increased with the severity of famine
conditions across different regions (Xu et al., 2009). These
epidemiological ndings are further supported by experimental
research. In rats, prenatal protein deprivation triggers structural
and functional hippocampal decits, increases in striatal NMDA

receptor levels, and behavioral abnormalities, all associated with
schizophrenia (Brown et al., 1996; Palmer et al., 2004). Some
changes may be explained by an increased release and turnover of
serotonin and dopamine in response to prenatal maternal
malnutrition. Dysfunction of these monoamine systems could
disrupt neuronal migration potentially underlying some of the
observed morphological abnormalities and consequent behavioral
decits (Brown et al., 1996).
6.4. Sensitive time-windows for toxicant exposure and NDD risk
All relevant ndings from the studies presented in this review
were combined in order to estimate, for each environmental
toxicant, the period during which exposure to one is most likely to
increase the risk of developing NDDs (see Fig. 1). While these
sensitive time-windows, specically represent human neurodevelopment, they are estimated based on ndings from both
human and animal studies using a published and validated model
to translate neurodevelopmental stages from animals to humans
(Workman et al. (2013). It is clear that the sensitive time- windows
for the majority of toxicants occur between conception and birth.
Key neurodevelopmental processes for brain formation take
place during this period, which could explain why exposure during
prenatal stages of development is associated with the highest risks.
7. Common pathophysiological mechanisms
Several potential mechanisms exist through which these
environmental factors could exert their neurotoxic effects.
Remarkably, it appears that many toxicants act through the same
or similar common mechanisms, summarised in Box 1. The data
propose 4 common mechanisms whereby toxicant effects disrupt
the developing CNS and potentially lead to NDDs.
31
7.1. Oxidative stress

Oxidative stress is caused by an imbalance between the
production of ROS and the efciency of antioxidant defenses
(Emiliani et al., 2014). While low levels of ROS are required for
normal cellular function (e.g. by regulating gene expression and
participating in signaling pathways), excess amounts can cause
severe damage to cellular structures (Azzam et al., 2012).
Oxidative stress has consistently been associated with NDDs.
Namely, biomarkers for increased oxidative stress have been
observed in patients with autism (Ornoy et al., 2015; Wei et al.,
2014), schizophrenia (Emiliani et al., 2014; Flatow et al., 2013), and
ADHD (Ceylan et al., 2012). A predominant physiological source of
ROS are the mitochondria, where they are created as a natural
byproduct of energy generation. Correspondingly, mitochondrial
dysfunction may lead to an overproduction of ROS and increased
oxidative stress (Emiliani et al., 2014; Frye and Rossignol, 2011).
This is especially interesting given the high prevalence of
mitochondrial dysfunction in autism, and that many autism
patients display abnormalities in mitochondrial DNA (Frye and
Rossignol, 2011; Ornoy et al., 2015). In addition, proteomic analysis
of human postmortem PFC tissue revealed that nearly half of the
altered proteins in schizophrenic vs control brains are involved in
mitochondrial function and/or oxidative stress responses. Moreover, these alterations were accompanied by similar changes at the
transcriptomic and metabolomic level (Prabakaran et al., 2004).
There are several ways in which oxidative stress could alter
neuronal development and/or injure the developing structures. For
instance, increases in ROS production can lead to changes in gene
expression and even cause direct damage to DNA. If DNA repair
proves unsuccessful, this can result in mutations in nuclear and
mitochondrial DNA, or eventually even promote cell death.
Oxidative stress has also been shown to impair neuronal
proliferation and to mediate apoptosis (Azzam et al., 2012; Floyd,
1999; Wei et al., 2014). These effects could underlie some of the
Fig. 1. Sensitive time-windows for exposure to environmental toxicants and susceptibility to neurodevelopmental disorders (NDDs). The colored bars indicate the
developmental period during which exposure to the corresponding toxicant is associated with an increased risk of developing NDDs. Increases in opacity are used to indicate
the periods of the highest risk, with different colors representing different NDDs. These sensitive time-windows are estimated based on ndings from both epidemiological
and experimental research. Abbreviations: OCs, organochlorines; SSRIs, selective serotonin reuptake inhibitors; inf, infection; OPs, organophosphates; PCBs, polychlorinated
biphenyls; MeHg, methylmercury.
32
Box 1. Potential pathophysiological effects shared between neurotoxicants.

Oxidative stress
PCBs
MeHg
Lead
Arsenic
Organophosphates
Organochlorines
BPA
VPA
Thalidomide
Immune system dysregulation
Lead
Atrazine
Organophosphates
Pyrethroids
BPA
VPA
Thalidomide
Misoprostol
Hyperserotonemia
PCBs
Organophosphates
Organochlorines
VPA
SSRIs
Thalidomide
Dopamine dysfunction
PCBs
MeHg
Lead
Arsenic
Chlorpyrifos
BPA
E/I balance
PCBs
Lead
Organophosphates
Organochlorines
Pyrethroids
Thyroid hormone disruption
PCBs
MeHg
Organophosphates
Organochlorines
BPA

Fonnum et al. (2006); Rossignol and Frye (2012)

Shenker et al. (1999); Johansson et al. (2007); Castoldi et al. (2001)
Flora et al. (2004)
Prakash et al. (2015)
Shelton et al. (2012)
Veiga-Lopez et al. (2015)
Hegazy et al. (2015)
Ito et al. (2011)

Miller et al. (1998); Chen et al. (2004)

Rooney et al. (2003)
Rogers et al. (2013)
Hegazy et al. (2015)
Kim et al. (2015)
Haynes et al. (1992)

Quaak et al. (2013)

Quaak et al. (2013)
Quaak et al. (2013)
Narita et al. (2002); Dufour-Rainfray et al. (2010); Oyabu et al. (2013)
Oberlander et al. (2009)
Narita et al. (2002)

Agrawal et al. (1981); Fonnum et al. (2006)

Johansson et al. (2007); Castoldi et al. (2001); Newland et al. (2015)
Froehlich et al. (2009); Dietrich et al. (2001)
Tyler and Allan (2014); Tolins et al. (2014)
Eaton et al. (2008)
Elsworth et al. (2013)

Gilbert (2003); Gafni et al. (2004); Quaak et al. (2013)

Adams et al. (2000)
Shelton et al. (2012); Quaak et al. (2013)
Shelton et al. (2012); Quaak et al. (2013)

Wise et al. (2012); Kimura-Kuroda et al. (2007)

Johansson et al. (2007)
Romano et al. (2015); Chevrier et al. (2013); Kimura-Kuroda et al. (2007)
specic decits observed in NDDs, depending on the timing and

location of oxidative stress damage.
7.2. Immune system dysregulation
Prenatal viral and bacterial infections are correlated to
increased incidences of autism and schizophrenia and the majority
of toxicants associated with autism and/or schizophrenia are able
to interfere with the immune system. Many genes involved in the
immune and/or inammatory response can be mapped to autism
linkage regions (Herbert et al., 2006), and altered cytokine levels
have consistently been detected in the blood and brains of ASD
subjects (Goines and Ashwood, 2013). The nervous and immune
systems are known to interact in many ways with cytokines, which
regulate the intensity and duration of the immune response,
forming the basis of this interaction. Cytokines share structural and
functional similarities with neurotrophins and other neuronal
growth factors. During development, cytokines are involved in

neuronal proliferation, differentiation, migration, and synaptogenesis (Goines and Ashwood, 2013). Accordingly, elevated levels
of fetal pro-inammatory cytokines IL-6, IL-1b, and TNF-a in
response to maternal infection can produce pathological changes
in brain morphology akin to those observed in ASD and
schizophrenia (Fatemi and Folsom, 2009; Goines and Ashwood,
2013). Additionally, maternal immune activation can also affect
neurodevelopment indirectly through the placenta: an increase in
maternal IL-6 in the placenta lead to a reduction in growth
hormone and insulin-like growth factor, while simultaneously
activating the Janus kinase (JAK)-signal transducer and activator of
transcription 3 (STAT3) pathway, resulting in the expression of
acute phase genes. These placental changes in gene expression
mediated by maternal IL-6 can have downstream effects on fetal
(neuro) development (Patterson, 2011). In line with these ndings,
altered morphology of pyramidal neurons is observed in the PFC
and hippocampus following maternal immune activation in rats. In

addition, there is also evidence suggesting neuroanatomical
abnormalities in the main dopaminergic, GABAergic, and glutamatergic systems after prenatal infection (Baharnoori et al., 2009).
The increase in pro-inammatory cytokine levels in response to
maternal immune activation may also promote oxidative stress
and apoptosis, and the resulting damage hereof could contribute to
the development of ASD and/or schizophrenia (Bitanihirwe and
Woo, 2011; Floyd, 1999). Furthermore, such an increase in proinammatory cytokines has also been shown to upregulate the
activity of serotonin transporter (SERT), leading to hyperserotonemia during early development (Jaiswal et al., 2015) and
consequently, a decrease in brain serotonin levels of adolescent
mice (Winter et al., 2008).
7.3. Altered neurotransmitter systems
The main purpose of neurotransmitters is to enable synaptic
communication between cells. During development however, they
fulll additional roles in CNS morphogenesis and neuronal
proliferation, migration, and differentiation. Therefore, any toxicants that interfere with neurotransmitter systems have the
potential to produce acute and/or long-lasting decits in CNS
structure and function, offering a possible explanation as to how
exposure to these substances might contribute to the pathogenesis
of NDDs (Costa et al., 2004; Rice and Barone, 2000).
For example, it is noticeable that many neurotoxicants
associated with ADHD have been shown to reduce brain dopamine
levels and/or cause damage to dopaminergic neurons. This is of
particular interest since dysfunction of the dopaminergic and
noradrenergic systems of the PFC, caudate, and cerebellum is
commonly believed to underlie ADHD symptoms. This is supported
by the fact that brains from ADHD patients show a reduction in the
volume and activity of these brain areas, which are involved in
regulating attention, emotion, and behavior. Moreover, drug
treatment using stimulants, which block dopamine and noradrenaline reuptake, has been shown to effectively reduce ADHD
symptoms (Brennan and Arnsten, 2008; Sharma and Couture,
2014).
In the case of ASD, one neurotransmitter that clearly stands out
is serotonin. Up to 30% of ASD subjects reportedly have large
increases in blood serotonin levels, frequently referred to as
hyperserotonemia (Anderson, 2002). While some cases of hyperserotonemia may be explained by genetic predispositions,
additional ndings suggest that it could also be the result of
prenatal infection or exposure to certain neurotoxicants, which
have also been associated with an increased risk of developing ASD
(Jaiswal et al., 2015; Quaak et al., 2013). Since serotonin cannot
cross the BBB and is made either in the gastrointestinal system or
the central nervous system (Janusonis, 2014), the high blood levels
dening hyperserotonemia may not be representative of the level
of serotonin in the brain. With respect to development and early
ASD symptom onset, it was hypothesized that the fetal BBB may be
permeable to high levels of serotonin (Whitaker-Azmitia, 2005).
One consequence of such a mechanism would be that high levels of
serotonin could reach the developing brain, potentially resulting in
a loss of serotonin terminals due to an early negative regulatory
feedback mechanism (Rumajogee et al., 2004). Evidence from
experimental animal studies does suggest the loss of serotonergic
projections from the dorsal raphe nuclei to the amygdala and
hypothalamus could be involved in the social and emotional
behavioral decits observed in autism (Whitaker-Azmitia, 2005).
However,
hyperserotonemia may also arise directly from local synthesis
alterations in the CNS: using labelled tryptophan and positron
emission tomography, the capacity for serotonin synthesis in
33
neurotypical children was transiently higher until around 5 years

of age before decreasing to adult values. Such a developmental
decrease was not observed in autistic children in the same study:
rather, a gradual increase in synthesis capacity occurred from 2 to
15 years age (Chugani et al., 1999). Irrespective of the direct cause
underlying altered CNS serotonin levels, serotonergic signaling can
modulate GABAergic inhibition in the prefrontal and temporal
cortices, thereby regulating the level of neuronal excitability in
these regions (Yan, 2002).
The level of neuronal excitability is determined by the balance
between excitation and inhibition, or E/I balance (Takesian and
Hensch, 2013). A well-maintained E/I balance is essential to normal
cortical function, and an excessive shift towards excitation could
lead to a wide range of decits in perception, cognition, memory,
and motor function (Froemke, 2015). Combining evidence from
genomic and clinical studies, as well as experimental studies at the
molecular, cellular, and neuronal network level, Rubenstein &
Merzenich proposed a model of autism where the E/I balance in the
cortical regions regulating language and social behavior is shifted
towards hyperexcitability (Rubenstein and Merzenich, 2003). The
main inhibitory and excitatory neurotransmitters in the mature
brain are GABA and glutamate, respectively. It may come as no
surprise therefore that many environmental toxicants and genetic
mutations that have been associated with autism can interfere
with GABAergic and/or glutamatergic signaling, either directly, or
indirectly through other neurotransmitter systems (Quaak et al.,
2013; Rubenstein and Merzenich, 2003; Shelton et al., 2012).
7.4. Thyroid hormone disruption
A fourth common mechanism potentially underlying the
developmental neurotoxicity of environmental chemicals is a
disruption of the thyroid hormone system. Thyroid hormones are
crucial for normal neuronal development, and any disruption may
lead to structural or functional changes that could predispose an
individual to an increased risk of neurodevelopmental disorders
(Andersen et al., 2015). In fact, it has been observed that the
prevalence of ADHD is higher in families with resistance to thyroid
hormones, a genetic condition caused by a mutation in the thyroid
receptor-b gene (Andersen et al., 2015). Furthermore, a Danish
population-based cohort study revealed that children born to
mothers suffering from thyroid dysfunction had an increased risk
of developing ASD and ADHD (Andersen et al., 2014).
In the developing brain, thyroid hormones regulate the
expression of many genes, including nerve growth factor, brainderived neurotrophic factor, neurotrophin-3, neurotrophin-4/5,
and myelin basic protein (Koibuchi and Iwasaki, 2006; Portereld,
2000). This may explain why TH disruption can have such a
profound effect on brain development. For example, thyroid
deciency can lead to impaired neuronal outgrowth and cellular
migration. These processes are highly dependent on normal actin
polymerization and microtubule synthesis and assembly, which
are in turn regulated by thyroid hormones (Koibuchi and Iwasaki,
2006; Portereld, 2000). The developmental process of synaptogenesis is also likely dependent upon TH-regulated gene expression since TH deciency is shown to impair synapse formation and
proper development of neurotransmitter systems. Several brain
regions/systems that have been associated with ADHD are those
that are particularly vulnerable to the effects of TH deciency on
synaptogenesis. These include the cerebellum, the cholinergic
projections from hippocampus to basal forebrain, and certain
dopaminergic systems (Koibuchi and Iwasaki, 2006; Portereld,
2000). In addition, dopamine metabolism in the caudate putamen
and nucleus accumbens is reportedly decreased in a TH-decient
mouse model for ADHD (Ookubo et al., 2015).
34
The developing fetus starts to produce thyroid hormones from

the second trimester, once the thyroid gland is sufciently
developed. However, since TH are required for normal neurodevelopment signicantly earlier, the fetus also relies on
maternally derived TH throughout pregnancy. This, together with
the observation that different defects are observed depending on
whether the thyroid dysfunction is maternal or congenital in
origin, suggest that the timing of thyroid dysfunction is an
important contributor to the eventual neurodevelopmental
outcome (Andersen et al., 2015). TH are required for several
developmental processes from cell migration to synaptogenesis.
However, since these processes occur at differing periods across
development, and these periods also differ between brain regions,
it is difcult to determine a single dened sensitive time-window
for TH disruption (Morreale De Escobar et al., 2004; Zoeller et al.,
2002).
8. Limitations of this study
There are important points that should be kept in mind when
interpreting the ndings and conclusions presented in this review
regarding ndings in the elds of environmental toxicology and
neurodevelopment.
Firstly, there are several problems facing epidemiological
research. Primarily, it is not always possible to reliably estimate
the precise level or timing of exposure to environmental toxicants.
While this is most apparent in cases where one has to rely on
participants self-report of exposure (e.g. on the intake of
contaminated food, water, or medication), careful consideration
should also be taken when evaluating ndings based on measures
of biological samples. For instance, maternal toxicant levels may
not always be representative of the amount of fetal exposure, nor
do blood measures necessarily give an accurate indication of brain
levels for certain substances. Accordingly, using different measures
of exposure across studies may result in inconsistent ndings.
Similarly, discrepancies between studies could also be due to
differences in their denition of, or diagnostic criteria for NDDs.
Arguably however, the most important drawback of human
epidemiological research is that their ndings are mainly based
on correlational evidence. From this type of evidence alone, it is not
possible to determine causation. In other words, a correlation
merely implies that there is some sort of relationship between two
variables, while no inferences can be made regarding whether one
causes the other. In order to establish a causal relationship, an
experimental study with toxicological application is required. For
obvious, ethical reasons, an experimental study focusing on
environmental neurotoxicants can only be performed on animals,
which raises additional issues to be addressed.
While animal research has proven invaluable to advancing the
knowledge on human (neuro)physiology, the fact remains,
however, that species can differ considerably in brain and
behavioral markers. This is particularly problematic when
attempting to study human NDDs like autism and ADHD in animal
models, since diagnosis of these disorders is mostly based on
human behavioral symptoms. It is therefore difcult to determine
as to how far the observed alterations in animal behavior upon
exposure to environmental toxicants form an accurate representation of the human NDDs under study. In addition, a chemical that
is toxic to animals does not necessarily have the same effect in
humans, or vice versa e.g. as has been shown for thalidomide. Such
variation in sensitivity across species could arise from differences
in their metabolism, for example, when it is not the chemical itself
but a metabolite thereof that is toxic. This chemical may then seem
harmless in experimental animals which are unable to produce
this metabolite, while it could prove disastrous to humans. The
nal issue regarding cross-species comparisons is specic to the
study of sensitive time-windows of heightened vulnerability

during neurodevelopment. Namely, that human neurodevelopment does not run synchronously to that of animals. For example,
while the general order in which different neurobiological
processes of brain development take place is highly preserved
across species (Workman et al., 2013; Clancy et al., 2007), there is
great variation in their absolute duration, as well as differences in
the timing of birth along this developmental timeline. The latter is
especially important considering that birth is characterized by
extreme changes in the fetus environment and, consequently, in
the possible pathways of exposure. Therefore, it may not always be
easy to make inferences about sensitive time-windows in human
neurodevelopment based on animal experimental ndings alone.
Another major problem is a large gap in the existing knowledge
regarding environmental toxicants. There are over 1000 industrial
chemicals which have been found to be neurotoxic in experimental
studies. While more than 200 of these are documented to produce
neurotoxic effects in humans, so far only 11 have been proven to be
toxic to human neurodevelopment. However, this does not mean
that exposure to any of the remaining chemicals is harmless to the
developing fetus. Rather, it is more likely that for most of these
chemicals there is either no data available on human exposure, or
their potential toxic effect on neurodevelopment has simply not
been studied. To make matters even worse, due to a lack of
systematic testing, the same is likely to be true for the majority of
all industrially applied chemicals, which is currently estimated to
surpass 80.000 (Grandjean et al., 2014; Grandjean and Landrigan,
2014, 2006). An additional issue is that most of the previous
research has focused primarily on single chemicals, while in reality
concurrent exposure to multiple chemicals may be common.
Moreover, it has become increasingly evident that mixtures of
chemicals can produce neurotoxic effects, even though the single
concentration of each chemical in those mixtures is below the
individual no observed effect concentration (NOEC) (Meijer et al.,
2014; Silva et al., 2002; Walter et al., 2002). Since chemical toxicity
risk assessment and management are also based on these
presumed safe NOECs, the actual risk posed by environmental
exposure to industrial chemicals may be severely underestimated.
9. Conclusions
Nevertheless, despite these limitations, we believe that
combining evidence from both human epidemiological and animal
experimental studies does allow conclusions to be drawn. We
propose three models for how the common underlying mechanisms might interact and eventually lead to autism, ADHD, or
schizophrenia, respectively. These conclusions are drawn based on
the literature presented in this review. While there is variation in
the timing of sensitive time-windows for the different toxicants
associated with autism, several of them are centered around or just
after the closing of the neural tube, particularly, to the medications
thalidomide, misoprostol, VPA, and the OC pesticides (Fig. 1). These
toxicants are all able to cause damage through apoptosis induced
by hypoxia, oxidative stress, or a pathological increase in proinammatory cytokines (Box 1; Fig. 2A). During these early stages
of development, this would be most harmful to the earliest
developing brain structures, such as those in the brainstem. This is
consistent with a large body of evidence supporting the common
occurrence of brainstem injuries in autistic brains (Rodier, 2002;
Rodier et al., 1997, 1996). One way in which a brainstem injury may
lead to autism is when the injury also extends to the serotonergic
cells of the raphe nuclei, which in turn could result in an autistic
phenotype by disrupting the E/I balance in the cortex (Fig. 2A).
Furthermore, the E/I balance can be disturbed directly by toxicants
acting on neurotransmitter systems. Moreover, a decrease in
serotonin could also result from a negative feedback effect
A
Misoprostol
OCs
OPs
PCBs
Thalidomide
VPA
Lead
Hypoxia
Oxidative stress
35
Lead
Misoprostol
OPs
Pyrethroids
VPA
Infection
Lead
OCs
OPs
PCBs
Pyrethroids
SSRIs
Serotonin levels
during development
Pro-inflammatory
cytokine production
Apoptosis
Injury to brainstem structures
during early development
Serotonin terminals
in mature brain
Disturbed
E/I balance
Autism spectrum disorders
PCBs
MeHg
Lead
Arsenic
OPs / OCs
BPA
Oxidative stress
Lead
OPs
BPA
PCBs
MeHg
OPs / OCs
BPA
Pro-inflammatory
cytokine production
Thyroid hormone
disruption
Apoptosis
PCBs
MeHg
Lead
Arsenic
Chlorpyrifos
BPA
Dysregulated
brain development
Persistent structural / functional deficits in

prefrontal cortex, caudate & cerebellum
Dopaminergic system
dysfunction
Attention-Deficit / Hyperactivity Disorder
Lead
Infection
Radiation
Oxidative stress
Malnutrition
Pro-inflammatory
cytokine production
Apoptosis
Release / turnover of
dopamine & serotonine
Impaired neuronal migration
Persistent structural / functional deficits in

hippocampus, prefrontal cortex & cerebellum
Schizophrenia
Fig. 2. Shared effects between environmental toxicants: possible mechanisms underlying neurodevelopmental disorders. Connecting arrows represent potential pathways
from environmental toxicant exposure to an increased risk of developing (A) autism spectrum disorders (ASDs), (B) attention-decit/hyperactivity disorder (ADHD) and (C)
schizophrenia. Abbreviations: OCs, organochlorines; OPs, organophosphates; PCBs, polychlorinated biphenyls; VPA, valproic acid; SSRIs, selective serotonin reuptake
inhibitors; E/I, excitation/inhibition; BPA, bisphenol A; MeHg, methylmercury.
36
following increased serotonin levels during early development,

either by toxicants acting directly on serotonin levels, or via proinammatory cytokines. This shows that there are numerous ways
in which exposure to an environmental toxicant could ultimately
lead to autism, which might explain some of the variety observed
in the timing of sensitive-time windows.
Compared to autism, the sensitive time-windows for ADHD risk
are less clearly dened (Fig. 1). While most of them span the entire
duration of pregnancy, there are some exceptions. Lead, for
instance, has a sensitive time-window for ADHD risk that extends
well into postnatal life, while that of bisphenol A roughly covers
the period of rapid growth and maturation known as the Brain
Growth Spurt (BGS). The biggest outlier is arsenic, in which case
the risk appears to increase in a cumulative manner following
long-term exposure. The fact that there are no clear short sensitive
time-windows for ADHD risk suggests that the underlying
mechanisms are probably also not reliant on brief temporal
events. Accordingly, the brain areas most associated with ADHD
are the PFC, caudate, and cerebellum (Sharma and Couture, 2014),
whose development is spread out over most of the prenatal and
early postnatal stages of development (Rice and Barone, 2000).
During this time, exposure to certain environmental toxicants
could lead to neuronal loss or dysgenesis in these structures,
possibly through the ability of these substances to increase
oxidative stress, pro-inammatory cytokine levels, and/or disrupt
the thyroid hormone system (Box 1; Fig. 2B). These mechanisms
could contribute to the dopaminergic dysfunction that is
characteristic of ADHD. In addition, environmental toxicants
may also act directly on the dopaminergic system at specic
periods during development to similarly disrupt neurotransmission (Fig. 2B).
For schizophrenia, the highest risk from environmental
exposure is during the rst and second trimester of pregnancy
(Fig. 1). Maternal malnutrition during this time could impair
neuronal migration due to increases in the release and turnover of
dopamine and serotonin. Exposure to lead, maternal infection, or
ionizing radiation can increase oxidative stress and pro-inammatory cytokine production, which could also disrupt neuronal
development or even promote apoptosis (Box 1; Fig. 2C). This may
ultimately lead to functional and structural decits in the
hippocampus, PFC, and cerebellum, thereby increasing the risk
of developing schizophrenia later in life (Fatemi and Folsom, 2009).
In summary, many environmental toxicants have distinct
sensitive time-windows during which exposure may disrupt
critical developmental events, thereby increasing the risk of
developing NDDs. Overwhelming evidence from human and
animal studies points towards prenatal exposure as the highest
risk period for the majority of compounds where neurodevelopmental toxicity data exists. Considering that most of these
toxicants have multiple effects in the nervous system, it seems
unlikely that a single underlying mechanism is generally
responsible for the increased risk for developing NDDs. Rather,
in most cases it is probably a combination of several parallel and
interrelated pathways/chain reactions which ultimately predisposes an individual to NDDs. Due to this complexity it may prove
difcult, if at all possible, to successfully counteract these
pathological mechanisms especially since some developmental
abnormalities or neuronal injuries sustained during these sensitive
time-windows may be irreversible. Given the rapid increase in
diagnoses for many NDDs, particularly autism, and the escalating
socioeconomic costs (Vos et al., 2015), these data emphasize the
importance of not only general toxicology testing but that of
developmental neurotoxicology for both individual and groups of
compounds. Ultimately, prevention of fetal and infant exposure to
environmental toxicants may lead to a signicant reduction in the
incidence of NDDs in future generations.
Competing nancial interests

No interests to declare.
Acknowledgements
RMM was funded by NWO ZonMW VIDI grant (#917.10.372).
The funder had no involvement in the collection, analysis and
interpretation of data; in the writing of the report; and in the
decision to submit the article for publication.
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NeuroToxicology 58 (2017) 2341

Contents lists available at ScienceDirect

Environmental toxicology: Sensitive periods of development and

Neurodevelopmental disorders and environmental toxicants

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

1. Neurodevelopmental disorders and environmental toxicants

Several potential mechanisms have been suggested to contribute

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

a seasonally varying infection such as inuenza, which peaks

To evaluate the potential neurodevelopmental toxicity of

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

Several prospective cohort studies have found associations

In the 1950s/60 s in Japan, MeHg pollution of shing waters in

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

health. These low level effects include intellectual impairment,

In contrast to the strong associations observed between

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

(Roberts et al., 2007). A later study, using Bayesian modelling on

this day resulted in behavioral decits and hyperactivity in mice

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

illegal. Unfortunately, misoprostol is not very effective at

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

20% of subjects met the criteria for schizophrenia or other

at least 5 years in the cleanup of the Chernobyl nuclear power plant

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

and functional hippocampal decits, increases in striatal NMDA

7.1. Oxidative stress

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

Box 1. Potential pathophysiological effects shared between neurotoxicants.

Fonnum et al. (2006); Rossignol and Frye (2012)

Miller et al. (1998); Chen et al. (2004)

Quaak et al. (2013)

Agrawal et al. (1981); Fonnum et al. (2006)

Gilbert (2003); Gafni et al. (2004); Quaak et al. (2013)

Wise et al. (2012); Kimura-Kuroda et al. (2007)

specic decits observed in NDDs, depending on the timing and

growth factors. During development, cytokines are involved in

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

and hippocampus following maternal immune activation in rats. In

neurotypical children was transiently higher until around 5 years

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

The developing fetus starts to produce thyroid hormones from

study of sensitive time-windows of heightened vulnerability

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

Autism spectrum disorders

Persistent structural / functional deficits in

Attention-Deficit / Hyperactivity Disorder

Impaired neuronal migration

Persistent structural / functional deficits in

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

following increased serotonin levels during early development,

Competing nancial interests

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

in school-aged children. Environ. Res. 126, 4350. doi:http://dx.doi.org/10.1016/

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

D.B. Heyer, R.M. Meredith / NeuroToxicology 58 (2017) 2341

J. Neurosci. 33, 73687383. doi:http://dx.doi.org/10.1523/JNEUROSCI (574612.2013).

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