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Causes of Autism

Michael Cervantes

Anna Kelley

Cornerstone 2

March 28th 2017

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Abstract

Autism could be called an epidemic because of the increase, of 1:10,000 to about 1:100,

of children getting diagnosed with autism spectrum disorder. Autism spectrum disorder (ASD)

is a “broad range of behavioral and cognitive manifestations” (Grossberg & Seidman 2006 483-

525). Looking at the range of people with autism, about “one fourth to one third of autistic

individuals have an IQ in the normal range, or even above” (Grossberg & Seidman 2006 483-

525). The actual cause of autism is still not known today, and much research is currently

underway. There are many genes that have been located that are said to be a cause of autism or

at least play a part in the cause of autism. But the argument that genetics is not the only cause of

autism is strong because there have been many cases that people were diagnosed with autism but

had no genetic problems. This was the start of the research in the environmental causes of

autism. To this day, the research of these two types of causes are researching separately which is

getting them nowhere. Research on causes of autism has been found that not all people with

autism have any genetic problems which shows that there are many different causes of autism.

The research in both areas looks into the symptoms of autism, and how autism affects the

behavioral features, social and communicative features, and cognitive features for someone who

has ASD. One thing to understand is that someone who has autism does not have to have all

three deficits. Individuals who are diagnosed with autism could just have behavioral deficits and

not the other two. The goal of this research paper is to reveal that there are multiple causes of

autism that range from environmental factors, to genetic factors, all the way to immune

dysregulation.
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Introduction

Thesis:

There are many common diseases that are not fully understood. Autism is one of these

diseases in a way. There is many research that had happened to find the cause of autism and

many research that is still going on today, but the cause is still unknown. The two main areas of

research are the genetic factors and causes and the environmental factors and causes. There is a

third type of research that puts together both genetic and environmental factors to explain the

effect of immune dysregulation on autism. All these factors of autism could be considered

causes of autism too, but how do we know what the main cause of autism is.

Background:

The neuroscience of autism is examined through MRI imaging, showing many

abnormalities in the brain. The first abnormality that the researchers found was early brain

enlargement. The research showed that children with autism were found to have increased total

brain volume (Buxbaum & Hof 2013). Looking closer into brain enlargement, the brains of

individuals with autism had gray and white matter abnormalities. Through all the parts of the

brain that had abnormalities in the gray and white matter, the largest amount of changes was

connected to the frontal lobe volume. While looking at the frontal lobe, they also found an

increased dorsolateral prefrontal cortex and medial prefrontal cortex (Buxbaum & Hof 2013).

These two are not anatomical parts of the brain, but functional parts. You find both of these in

the prefrontal cortex, which is in the frontal lobe. The dorsolateral prefrontal cortex’s main

function is in executive functions. This covers cognitive processes all the way to decision
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making. The medial prefrontal cortex functions in response flexibility, empathy, insight, fear.

These are the functions that relate to autism, while there are still about five more (Buxbaum &

Hof 2013). The gray matter also showed differences in many brain regions. The regions that

showed a difference was the “superior temporal sulcus, fusiform gyrus, insula, inferior parietal

lobe” (Buxbaum & Hof 2013). The white matter also showed differences in several areas of the

brain. The two main parts of the brain that showed differences were the cerebellum and the

corpus callosum. The abnormalities were mostly found in the more outer radiate compartments

of these parts of the brain” (Buxbaum & Hof 2013). Another part of the brain that they had

explain which also had abnormalities was the cerebellum. This part of the brain is involved in

motor coordination, but the cerebellum also has a role in modulation language, emotion and

executive function (Buxbaum & Hof 2013). Although the research on the cerebellum has been

inconsistent, there has been findings that there is a decreased volume of cerebellar vermal

lobules six and seven in people diagnosed autism. The amygdala is another region of the brain

that is affected. This is a region of the brain that has an integral role in emotional and social

behavior (Buxbaum & Hof 2013). There has been an increased amygdala volume found in

children with autism. This enlargement of the amygdala has been linked to social and

communication deficits, which one deficit of autism (Buxbaum & Hof 2013). The thalamus is

also involved in implication of language and emotional processing, as well as some aspects of

executive function. There was a study of children with autism and what they found was that

there was a positive correlation between thalamic volume and TBV in both the control group and

the children with autism (Buxbaum & Hof 2013). The last area to have major differences in

people with autism is the corpus callosum. This is a white matter tract that connects the cerebral

hemispheres, which facilitates interhemispheric connectivity. Knowing this, they found that the
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corpus callosum volume was decreased in children with autism. Looking at specifics, they used

a meta-analysis to identify that the anterior regions of the corpus callosum had the largest

volumetric deficits in people with autism (Buxbaum & Hof 2013). There are many parts of the

brain that are affected by autism, not just the ones that I explained. Some of the other parts of

the brain affected is the hippocampus, insula, brainstem, inferior frontal gyrus, superior temporal

gyrus, and the fusiform gyrus. Overall, from all the information above, both white and gray

matter have been identified to have volumetric differences.

Main Point 1

Genetics is possibly the main cause of autism. Genetic research has found that there are

many different genes that are affected by autism. There is research in de novo mutations, which

are genetic mutations not transmitted by parents. Up to five to eight percent of all ASD cases

could possibly be caused by various types of de novo mutations (Meek, Lemery-Chalfant,

Jahromi, & Valiente 2013 pp. 497-521). Meek et al. (2013) introduced the study of epigenetics,

which is a new area in autism genetics research. This revealed a different genetic mechanism

that highly affects ASD which is different from the novo mutations in genetic research. Studies

showed hypermethylation implicated in several candidate genes in ASD affected individuals

(Meek et al. 2013 pp. 437-521). This also affected the oxytocin receptor gene, the relin gene, the

methyl CpG binding protein 2 gene, and the brain-derived neurotrophic factor gene (Meek et al.

2013 pp. 437-521). Looking at this study more, the lower levels of the designated proteins and

mRNA were found in multiple regions of ASD affected individuals (Meek et al. 2013 pp. 437-

521). Knowing this shows that all these proteins seem to play a big role in the effects of ASD

throughout the entire brain. There is likely to be multiple genetic influence involved in the

development of ASD.
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Multiple research groups have reported a connection between oxytocin-related genes and

autism, which is another reason to believe that this could be one of the causes of autism. The

oxytocin receptor gene is the gene responsible for oxytocin receptor synthesis (Meek et al. 2013

pp. 437-521). Oxytocin is a neuropeptide that is produced in the hypothalamus and also

circulated to multiple regions of the brain. Looking at the aspects of the oxytocin system,

oxytocin synthesis and the oxytocin receptors are partially estrogen dependent (Meek et al. 2013

pp. 437-521). This backs up the research that oxytocin is more abundant in some regions of the

female brain, when comparing it to a male brain. There are many social behaviors that oxytocin

is involved with. Some of the social behaviors are maternal behavior, social

recognition/response to threat, social initiations, social responsivity, and social motivation (Meek

et al. 2013 pp. 437-521). Looking at some previous research that was done, the results show that

children with autism have a significantly lower level of oxytocin in plasma samples than their

typical peers (Meek et al. 2013 pp. 437-521). With knowing this you can look at neurotypical

children and see that a lower concentration of oxytocin is associated with lower social and

cognitive functioning. Multiple research groups have reported a connection between oxytocin-

related genes and autism, which is another reason to believe that could be one of the causes of

autism. Looking at some biological explanations for oxytocin, you can see that oxytocin’s role

in social development is linked to brain functioning (Meek et al. 2013 pp. 437-521). This role of

oxytocin is linked in the amygdala. When there are lower levels of oxytocin, the higher the

amygdala activates in individuals with ASD. This is one process that could be contributing to

social anxiety and social withdrawal.

Arginine Vasopressin (AVPR1a) and oxytocin have shown to have similar sequences.

AVPR1a is a neuropeptide that is produced in the hypothalamus, stria terminalis and the
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amygdala. A neuropeptide is a small protein like molecules that are used by neurons to

communicate with each other. This neuropeptide is distributed throughout the regions of the

“social brain” including the amygdala, parts of the prefrontal cortex and the anterior cingulate

cortex (Meek et al. 2013 pp. 437-521). Studies have shown that this neuropeptide also has sex

differences like oxytocin. AVPR1a is found to have enhanced functioning in males when

comparing it to females (Meek et al. 2013 pp. 437-521). Five studies have found a link between

AVPR1a and autism. Looking at the most recent analysis of AVPR1a and ASD, the study used

the biological implications of allelic variation length in parent-child triads (Meek et al. 2013 pp.

437-521). Looking at specific allele lengths in genes that are a part of AVPR1a showed that

people with autism are more likely to have a short allele variant of RS1. With this shortened

allele, transcription of AVPR1a is reduced, which shows a lower density of this neuropeptide in

multiple regions of the brain, including the amygdala. This increases the rate of activation of the

amygdala which then increases social anxiety (Meek et al. 2013 pp. 437-521). This can be

crossed back to the social communicative deficit that people with autism could possibly have.

Researchers also found a connection between dopamine and autism. Dopamine is a

neurotransmitter which is produced and released in many parts of the brain which include the

amygdala, hippocampus, and the ventral striatum. This neurotransmitter is said to be highly

relevant in establishing reward value and motivation which are some of the effects of autism

(Meek et al. 2013 pp. 437-521). There are five dopamine receptors, but DRD1 and DRD2 are

the genes that encode for D1 and D2, which are subtypes of the dopamine receptor family (Meek

et al. 2013 pp. 437-521). D1 and D2 are said to play an important role in social development,

but specifically in social behavior and reward value. These receptors pair these two social

development aspects together to show that dopamine plays a role in reward value. Knowing how
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dopamine works and how increases of D1 receptors affect certain areas of the brain, specifically

the parts that are linked to social functioning and repetitive behaviors (Meek et al. 2013 pp. 437-

521). This increase could have detrimental effects on the social parts of the brain and lead to less

social behavior.

All these genes interact in some way with each other and work codependently to

influence social behavior. Some researchers have suggested that oxytocin and vasopressin

augment the value of social stimuli by activating regions highly populated with dopamine

receptors which are also known to influence reward perception (Meek et al. 2013 pp. 437-521).

This shows how interconnected these three genes are. One region that is known to show this

phenomenon is the ventral striatum. This part of the brain focuses on reward system (Meek et al.

2013 pp. 437-521). Looking at the sex differences in oxytocin and vasopressin, there is some

research that shows the activation of dopamine receptors and oxytocin facilitates “pair bond

formation” in females and that dopamine receptors and vasopressin similarly “facilitate pair

bonding” in males. Looking at the high density of oxytocin in the female brain, research have

suggested that oxytocin could possibly serve as a protective factor, which backs up the evidence

that males are more likely to be diagnosed with autism.

Main Point 2:

The medical model showed that there has been a rather large increase in the number of

diagnoses of autism. While looking more deeply, they had categorized autism as a disease, but

also as an epidemic, not just because of the number of diagnoses, but because in the causal

environmental factors (Kapp, Gillespie-Lynch, Sherman, & Hutman, 2013 59-71). There are

many different hypotheses for the cause of autism. For example, one hypothesis is that an
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increase in fetal testosterone which correlates with increased prevalence of autism and male

vulnerability. The one thing that these hypotheses fail to explain is the major increase in the

diagnosis of autism.

Researchers went in a different approach and started to investigate if the development of

autism could be caused by fragrances, which are complex mixtures of chemicals. This includes

hormone disruptors as well. Bagasra, Gene Pace, Hughes, Pestaner, Sealey, and Steinemann

(2015) analyzed over 90 fragrances. The researchers found that commonly used fragrances have

the potential to cause neurological damage to a developing fetus by introducing different

mutations and or depleting certain neuronal subtypes. When neuronal subtypes and or mutations

are introduced, there could be an interference with normal brain development. Bagasra et al.

(2015) looked into certain fragrances that were identified to have significant cytotoxic effects on

neural cells and known to also impart significant neuromodifications at morphological and

immunological bases. While only testing three, there are many fragrances that affect the brain of

a fetus.

There is environmental evidence that also backs up genetic factors. Basgasra et al.

(2015) had done numerous studies which all showed that children with autism usually have

significantly lower levels of both oxytocin and arginine vasopressin when testing samples of

their plasma. The researchers also looking into mothers who had autistic children and what they

found gave them more evidence to support their hypothesis. Mothers of ASD children had low

levels of both oxytocin and arginine vasopressin, but they also had higher levels of testosterone.

Looking at the amount of research that these researchers had done, they had concluded that

fragrances may have different effects on the human neural development and differentiation.
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There was another group that looked into cytokine dysregulation in ASD and the possible

role of the environment. Goines and Ashwood (2012) looked into the growing body of evidence

that was immunological disturbances. They believed that people with autism and their family

members demonstrate increased autoimmunity, altered cellular immunity and skewed expression

of soluble mediators such as cytokines. The researchers explained many different environmental

factors, some were heavy metals and pesticides. The heavy metals that were explored was lead

and mercury. Lead is a toxic mechanism that shares structural features with calcium which

allows it to compete for binding sites (Goines et al. 2012, pp 67-81). Lead does have neurotoxic

activity, but it also is immunotoxic. At high levels, this metal is immunosuppressive, which

leads to the increase production of regulatory cytokines and increase the chance of infection.

Mercury is the other heavy metal associated with autism. This metal is said to alter calcium

signaling and cytokine production (Goines et al. 2012, pp 67-81). This metal is still on the

boarder of being a factor of autism and not being a factor of autism because of the lack of

evidence.

There are three pesticides that are said to be a factor of autism, they are organochlorines,

organophosphates, and pyrethroids. “Organochlorine pesticides (OCs) are structurally and

functionally variable toxic compounds” (Goines et al. 2012, pp 67-81). OCs interferes with

calcium signaling, voltage sensitive sodium channels and GABA receptors, leading to neuro and

immunotoxicity. Immunologically, these compounds have an impact on both humoral and cell-

mediated processes, and it also reduces the host response to infectious challenges (Goines et al.

2012, pp 67-81). This is important because it reveals that this affects cytokines, which have a

major effect on the brain. So in turn, this pesticide has the possibility to have an immunological

impact. The next pesticide is organophosphates (OPs). OPs are esters of phosphoric acid that
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were introduced as replacements for various banned OC pesticides (Goines et al. 2012, pp 67-

81). These pesticides ten to act primarily through acetylcholinesterase inhibition, which leads to

altered cholinergic signaling, parasympathetic and sympathetic perturbations, seizers and

possibly even respiratory arrest. This shows that with this one pesticide, many server things

could happen to the person’s brain who is exposed toOPs. The researchers also found that some

OPs development effects are more server in males than females, which is interesting when

looking at the fact that autism has a heavy male bias. The third pesticide is pyrethroids. This

pesticide is a group of insecticides and repellants derived from natural compounds in the

Chrysanthemum genus of plants (Goines et al. 2012, pp 67-81). Exposure to any of these

compounds is associated with a wide range of neurodevelopmental problems when tested in

mammalian models. Researchers had also found that immunological abnormalities are also

linked to pyrethroids.

Pathogenic exposures in autism can change fetal development which leads to aberrant

neural and immune activity. Some researchers, who have a focus in finding the cause of autism,

found that this caused is increasingly implicated in autism (Goines et al. 2012, pp 67-81). They

found that there are several infections that are said to be associated with autism. The infections

include measles, cytomegalovirus, and rubella. Looking at the overall aspect of environmental

exposure, and looking at the prevalence rates for ASD is important (Goines et al. 2012, pp 67-

81). Some compounds, such as lead and chlorinated pesticides have decreased in our population

but there has been an increase in OPs. With some of the factors of autism having a decrease in

our population, you need to ask yourself why? Why is there still an increase in autism and what

is causing it? One more cause that brings together both environmental and genetic research is

the idea that immune dysregulation contributes.

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Main Point 3:

Immune dysregulation is a possible contributor to the cause of autism. This factor uses

both, environmental and genetic causes, to explain the way the immune system could be a cause

of autism. Immune dysregulation reveals many genetic associations and most of the

environmental factors linked to autism spectrum disorder. These all converge on immune

dysregulation through alterations in immune-related genes and also in immune responses to

environmental stimuli (McAllister 2017, pp. 380-382). One chromosome that is linked to autism

is chromosome 6, but specifically the aberrations on this chromosome. This chromosome is

densely packed with genes for immune molecules, but specifically haplotypes of immune genes

(McAllister 2017, pp. 380-382). Looking at the expression of many immune-related genes in the

brain, research shows that some immune-related genes are altered in individuals with autism.

This shows that there is a link to autism when looking at specific immune-related genes.

Looking at the genetic associations, both with and without the combinations of the

environmental exposures, contribute to the ongoing immune dysregulation in autism spectrum

disorder.

When looking at immune dysregulation, researchers are able to define the many autism

spectrum disorders subtypes. This reveals that not all immune-related genes can be connected to

autism but that many different subtypes of ASD are also related to immune dysregulation. One

group of researchers used neonatal blood spots from the childhood Autism Risks from Genetics

and the Environment study found that levels of serval cytokines are elevated at birth in people

with ASD when comparing to typically developing controls (McAllister 2017, pp. 380-382).

One cytokine that was shown to have an increase was interleukins. The importance of this

increase was because they had specifically found that elevated interleukins were associated with
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a much high likelihood of having a more server ASD. Researchers also found that males at birth

who had elevated levels of interleukins were more likely to have nonverbal cognitive abilities

(McAllister 2017, pp. 380-382). This suggests that the immune system does play a big role in

diagnosing an individual with autism. They have already figured out ways to look at the

different cytokines that are active and or elevated at birth.

The immune system can have effects on behavior. Onore, Careaga and Ashwood (2012)

explained that there are many immune proteins which function within the nervous system. These

proteins act as mediators for normal neurodevelopment. In individuals with Autism Spectrum

Disorder, they have abnormal neurodevelopment. In addition, there has also been observations

of ongoing neuroinflammation in individuals diagnosed with autism. This inflammation reveals

an increased inflammatory cytokine, and prominent microglia activation in the brain tissue and

cerebral spinal fluid (Onore et al. 2012). Microglia are mononuclear phagocytic cells of the

central nervous system. The Microglia cells participate in immune surveillance while also

participating as “synaptic pruning” in normal neurodevelopment. When Onore et al. (2012) used

the method of expression profiling of a postmortem brain of an individual with ASD, they found

increased levels of RNA transcription of many immune system genes. Looking at the findings of

the research, it revealed changes in microglia and immune activation. This suggested a role for

immune dysregulation in ongoing neurological dysfunction in the brains of people who had

ASD.

Another study looked into immune cell infiltration. Stigler, Sweeten, Posey, and

McDougle (2009) revealed that one out of six brains of patients with autism had shown signs of

immune cell infiltration when looking at postmortem studies. A hypothesis stated that autism

could be caused by an antibody attack against one or more brain proteins. Using the hypothesis,
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Stigler et al. (2009) conducted a study and found that nineteen out of thirty three autistic

individuals had antibodies against brain proteins. When the researchers looked at mothers of

autistic children, they found that six of eleven mothers had plasma antibodies that were found to

react against their child’s lymphocytes (Stingler et al. 2009). When connecting findings, the

authors concluded that while exploring their data they found a potential relationship between

genetic and environmental factors with placental transfer of maternal antibodies in autism.

Conclusion:

Individuals with and ASD disorder are affect in many different ways. The brain is

affected in about 6 mains parts of the brain and about 7 other smaller parts of the brain. The

main cause of is still unknown. All the research can only go so far to explain the different

possible causes or factors of autism. When looking at all cases of autism, there is not one cause

or factor that is the same in all cases. This means that the research is on the right path but are

researching the wrong area. To find the cause of autism, the environmental and genetic

researchers need to come together and conduct their research so that the possible cause of autism

could be found. Each researcher has come close, but has always hit a dead end. Looking at how

immune dysregulation research took both genetic and environmental factors to help explain how

the immune system also plays a major role in autism shows that by just putting the types of

research together, it is possible to come closer to finding the cause of autism.

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References

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