Article summary with Environmental toxicology: Sensitive periods of development and neurodevelopmental disorders by Heyer & Meredith - 2017

Do environmental toxicants play a role in the emergence of neurodevelopmental disorders?

The development of the central nervous system is a delicate process and disrupting it can have severe and long-lasting consequences on brain structure and function, even causing neurodevelopmental disorders. Neurodevelopmental disorders often have a genetic cause, but there is increasing evidence that they can also be caused by environmental factors. Exposure to industrially applied or produced chemicals have been associated with neurotoxicity in humans and may pose a threat to public health, especially children who are still developing. In this review, the neurodevelopmental disorders autism, ADHD, and schizophrenia will be discussed in relation to environmental toxicology.

What is autism?

Autism Spectrum Disorder (ASD) 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 deficits in developing, understanding, and maintaining relationships, and abnormal and fixed interests and repetitive behavior. Potential mechanisms that contribute to ASD pathogenesis are immune dysregulation, hyperserotonemia, increased neural apoptosis, mitochondrial dysfunction and oxidative stress, and a disturbed between neuronal excitation and inhibition.

What is ADHD?

ADHD is a neurobehavioral disorder characterized by symptoms of inattention, hyperactivity, and impulsivity which often persists into adulthood. Individuals with ADHD show a reduction in brain volume and activity of the prefrontal cortex, caudate, and cerebellum. These areas are interconnected through dopaminergic and noradrenergic projections, and are involved in several aspects of cognition, attention, behavior, and emotion. Dysfunction of the dopamine and noradrenaline systems may underlie ADHD symptoms. Also, immune system dysregulation or thyroid hormone disruption may be involved in ADHD pathogenesis.

What is schizophrenia?

Schizophrenia is a brain disorder with both negative and positive symptoms. Negative symptoms such as impairments in executive functions, working memory and attention, social withdrawal, and apathy. Positive symptoms such as visual and/or auditory hallucinations, paranoia, and delusions. Schizophrenia is believed to be caused by aberrations during fetal development.

What are sensitive time-windows for brain development?

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 modification by intrinsic and extrinsic factors, which can produce long-lasting changes in brain and behavior. Harmful exposure during these periods could potentiate the emergence of distinct neurodevelopmental deficits. The sensitive time-windows may vary depending on the outcome measured, the affected brain regions and structures, and the underlying cause and its mechanisms.

Why are children at higher risk of environmental toxicant exposure?

Contaminated air, drinking water, soil, food, and house dust are all possible sources of exposure. These toxicants can enter the body through skin contact, ingestion, or inhalation. Children are more vulnerable to exposure because of several reasons:

• Many substances easily cross the placenta and the fetal blood brain barrier to reach the developing brain.
• Certain lipophilic chemicals accumulate in maternal adipose tissue and breast milk and can be transmitted by breast feeding.
• Children undergo higher contamination levels from environmental pollutants due to their relatively higher energy demands. Relative to bodyweight they breathe air more rapidly and ingest more water, fruit, and vegetables than adults.
• Children have an inherently higher risk to exposure due to their natural behaviors and activities. For example they crawl and play on the ground, and put many objects in their mouths.

Which environmental toxicants can affect neurodevelopment?

Based on a meta review of the available scientific information the following conclusions can be drawn with regards to different environmental toxicants on neurodevelopment:

• Polychlorinated biphenyls (PCBs) are classified as Persistent Organic Pollutants (POPs) and are used in industrial settings. The main source of human exposure to PCBs is due to accumulation in the food chain. Prenatal exposure to PCBs is linked to intellectual impairment, ADHD-related behaviors, attentional deficits, and increased impulsivity.
• Methylmercury (MeHg) is the most common form of organic mercury found in the environment where it accumulates in the aquatic food chain. MeHg can easily cross the fetal blood brain barrier (BBB) and placenta and predominantly accumulates in brain tissue. Observed deficits in exposed populations include deafness, blindness, cerebral palsy, low birth weight, and seizures. Prenatal exposure to MeHg is associated with increased attention problems, ADHD behavior, lower IQ, and intellectual disability.
• Lead is one of the most widely used neurotoxicants. Though its use is now mostly banned from industrial and consumer products, lead based paint in older buildings and contaminated soil near roads still prove major sources of exposure. Lead poisoning is related to intellectual impairment, hyperactivity and attention deficits, aggression, rule-breaking behavior, schizophrenia, and ASD.
• Arsenic is found in industrial pollution, and naturally occurs in ground water around the world. Contaminated wells and drinking water a source of chronic low-level exposure. Postnatal exposure to arsenic is associated with impairments in cognitive development and intellectual abilities. Environmental exposure to arsenic may be harmful throughout development, long-term postnatal exposure is more damaging to intellectual function.
• Pesticides are widely used and are present in food, water, and soil throughout the environment, especially in rural areas. Maternal residential proximity to organochlorine pesticide applications is linked to the risk for developing ASD. Exposure to other types of pesticides have also been linked to pervasive developmental disorder and ADHD-related behaviors.
• Bisphenol A (BPA) is an essential component of polycarbonate plastic, used in a wide range of products. BPA is found in water, food, dust, and air. It is a known endocrine disruptor. Studies report increased risk of ADHD, depression, anxiety, inattention, hyperactivity, and other externalizing behaviors. Though, the findings are mixed with regards to the timing of exposure (prenatal or postnatal).

How can PCBs affect neurodevelopment?

PCBs can affect neurodevelopment through thyroid hormones. Several PCBs are structurally similar to active thyroid hormones and could act as agonists or antagonists to thyroid hormones, by competing for binding sites on receptors or other proteins. PCBs can decrease levels of thyroid hormones and suppress thyroid hormone dependent development of neuronal dendrites. Also, PCBs could impair neurodevelopment by acting on neurotransmitter systems. E/I balance is important for cognition, and an imbalance between excitation and inhibition could be an underlying mechanism for autism.

How can methylmercury affect neurodevelopment?

The developing brain in utero has an increased sensitivity to MeHg exposure, leading to more generalized damage throughout the neocortex. At lower exposure levels, implicated underlying mechanisms involve impairments in neurotransmitter systems, neuronal excitability, and thyroid hormone disruption. At higher exposure levels, mechanisms may be oxidative stress, altered calcium homeostasis, and microtubule disruption.

How can lead exposure affect neurodevelopment?

Lead-induced damage preferentially occurs in the PFC, hippocampus, and cerebellum. It is known to impair neural differentiation, synaptogenesis, myelination, and BBB disruption. Lead can impair excitatory signaling and synaptic plasticity through its effects on glutamate release and NMDA receptor function. This could be related to lead´s ability to interfere with the regulatory functions of calcium. Lead can also alter dopamine systems and cause oxidative stress. Finally, lead has also been shown to negatively affect the immune system.

How can arsenic exposure affect neurodevelopment?

Different mechanisms have been identified through which arsenic exposure can affect neurodevelopment:

• Arsenic alters signaling of essential neurotransmitters by changing levels of glutamate, dopamine, serotonin, noradrenaline, and acetylcholine, as well as altering the expression of serotonin receptors and specific NMDA receptor subunits.
• Arsenic induces changes in synaptic strength and plasticity, possible causing cognitive and neurobehavioral impairments.
• Arsenic can dysregulate the HPA-axis, increase corticosterone levels and reduce the amount of glucocorticoid receptors, possibly causing cognitive and mood deficits.
• Arsenic promots apoptosis and necrosis, and inhibits neurogenesis, proliferation, and neurite growth, which may link to arsenic-induced alterations in DNA methylation and histone modifications as well as oxidative stress.

How can pesticides affect neurodevelopment?

Pesticides are linked to E/I balance disturbance in the brain, increasing serotonin levels, promoting apoptosis, inducing mitochondrial dysfunction and oxidative stress. Developmental exposure to atrazine, pyrethroids, and organophosphates can lead to immunosuppression and neuroinflammation. Also, certain pesticides reduce levels of maternal thyroid hormones, which are essential for normal neurodevelopment.

How can bisphenol A affect neurodevelopment?

Prenatal exposure to BPA is associated with reduced levels of thyroid hormones in newborns. BPA inhibits the TH-dependent dendritic development of Purkinje cells, implicating thyroid deficiency as a possible link between BPA and its neurotoxic effects. BPA can also cause neurodevelopmental deficits through immune system dysregulation. Finally, BPA induces mitochondrial dysfunction and oxidative stress.

How can maternal use of medication affect neurodevelopment?

Medication during pregnancy can severely affect the fetus in utero and at later postnatal stages. Different medications are identified:

• Thalidomide is a synthesized sedative related to children born with serious malformations. Thalidomide exposure during a sensitive period resulted in fetal deformities and sometimes infant death. Intake in the early sensitive period is associated with ear and upper limb malformations and cranial nerve and ocular deficits. Intake in later sensitive periods are associated with triphalangism of the thumbs and lower limb deformities. Autism is linked to thalidomide intake during the early sensitive period, coincident with neural tube closure.
• Valproic acid (VPA) is a medicine used to treat migraine, bipolar disorder, and prevent seizures. It increases the risk of fetal malformations, neural tube defects, ASD, and intellectual disability. It is related to altered gene expression, loss of N-cadherin expression in neural crest cells, increased apoptosis, reduced proliferation, increased levels of pro-inflammatory cytokines, and altered levels of enzymatic biomarkers for oxidative stress and mitochondrial dysfunction.
• Misoprostol is used to treat gastric ulcers, but in some countries it is used to induce abortion. As it often does not work, children who survive abortion are often born with Möbius sequence, a clinical condition associated with facial palsy and limb malformations. Möbius sequence is associated with increased risk of autism and intellectual disability. Misoprostol possibly causes hypoxia or ischemia in the fetus due to induced uterine contractions, which, during the development of the central nervous system could result in permanent damage.
• Selective Serotonin Reuptake Inhibitors (SSRIs) are used to treat anxiety and depression. They prevent the reuptake of serotonin at the plasma membrane, raising the level of extracellular serotonin which results in increased serotonin receptor activation. Serotonin fulfills additional roles during early development in regulating cell differentiation, migration, myelination, synaptogenesis, and pruning.

How can maternal infection affect neurodevelopment?

Maternal infection during pregnancy increased risk for neurodevelopmental disorders. Especially rubella infection, influenza, and other respiratory infections have been shown to increase schizophrenia and schizophrenia spectrum disorders. Rather than specific pathogens, the actual risk factor for neurodevelopmental deficits might be the maternal immune response in general. Maternal immune activation promotes the production of pro-inflammatory cytokines, in the mother and also in the fetus. This may lead to permanent dysregulation of the immune system of the child.

How can ionizing radiation affect neurodevelopment?

Ionizing refers to the amount of energy that can ionize atoms or molecules by freeing electrons. It includes gamma rays, X-rays, and the higher part of the ultraviolet electromagnetic spectrum. Ionizing is associated with schizophrenia and cognitive and behavioral deficits. Ionizing radiation suppresses cell division and synapse formation. Different areas of the brain are particularly vulnerable to exposure during their sensitive periods of proliferation and synaptogenesis. Also, ionizing radiation increases production of free radicals and dysregulates the immune system.

Through which common mechanisms do environmental factors exert their neurotoxic effects?

Many toxicants act through the same or similar common mechanisms. There are four common mechanisms by which toxicant effects disrupt the developing nervous system and potentially lead to neurodevelopmental disorders. These mechanisms are:

• Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) and the efficiency of antioxidant defenses. Excess amounts can cause severe damage to cellular structures.
• Immune system dysregulation.
• Altered neurotransmitter systems.
• Thyroid hormone disruption.