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Etiology Of Autism Spectrum Disorders - Genes, Environment, Or Both?

Several studies were already made to explore the cause or etiology of autism spectrum disorders. What could be the potential factors contributing to its development?

Dr. Cooney Blades
Dec 06, 20232928 Shares75083 Views
Three researchers affiliated with the University of British Columbia in Vancouver, Canada, conducted a study about the etiology of autism spectrum disorders.
The etiologies proposed for the spectrum of neurological disorders falling under the umbrella of autism spectrum disorders(ASD) shows the same range as those proposed for the well-known neurological disorders associated with aging.
The latter typically include:
  • Alzheimer’s disease
  • Parkinson’s disease
  • Lou Gehrig’s disease, aka amyotrophic lateral sclerosis(ALS)
The widespread but incorrect view regarding all these diseases is that most cases arise from genetic mutations or polymorphisms.
In reality, the large majority of these disorders that are not familial have no obvious genetic mutations associated with either the onset or progression of the disorder and fall into a category known as “sporadic.”
Moreover, an apparent increase in both prevalence and incidence of these disorders over a relatively short time span (i.e., several decades) rules out a purely genetic origin.


In ALS, for example, much of the literature of the last 20 years has focused sequentially on the search for genetic etiologies leading to motor neuron loss and the list of defective genes has grown larger over this time period.
These include a number of variations on the so-called “toxic gain of function” mutation in the gene coding for the antioxidant enzyme superoxide dismutase (SOD).
Additional mutations affect the genes coding for DNA binding protein TDP-43, FUS, or VEGF, or the newest player, C9orf72, and all have added to the complexity of the polygenic picture without necessarily increasing the total percentage of all ALS cases that are clearly gene mutation-derived.
Overall, the various mutations may account for about 10% of all ALS and mutant SOD may comprise about 25% of this or 2.5% of the total number of ALS cases.
In regard to Alzheimer’s disease, which remains one of the world’s most burdensome and disabling healthissues (affecting 24.3 million people with more than 4.5 million new cases/year), only a very small percentage are familial with early onset of symptoms, (less than 65 years).
In contrast, more than 95% are idiopathic (late onset, over 65 years) and most likely due to factors other than genetics.
Thus, the literature seems clear that the bulk of neurological disorders arise due to environmental factors, most still not identified.
None of this diminishes the putative role of susceptibility genes, also mostly unknown, whose interactions with the various environmental toxicants are highly likely to be crucially involved.
Keeping with this, experimentally it has proven possible to develop toxin-based animal models of ALS in outbred mice with no gene mutations and thus model the much higher fraction of ALS which is sporadic.
A very similar set of outcomes has been noted in the Parkinson’s disease literature, including the ability to generate Parkinsonian features in outbred rats using various toxins.
The bottom line is that apart from some neurological disorders such as Huntington’s disease, most cases of the various disorders do not arise from an obvious genetic mutation or polymorphism.
In spite of these observations, the dominance of a genetic causality perspective for the above disorders remains firmly in place.
There is insufficient space in the present review to go into the various scientific and sociological reasons why this may be so.
However, it is important to recognize that much the same perspective dominates the ASD field, a perspective that is likely to be as fundamentally incorrect as it is for ALS and the other age-related neurological disorders.
Indeed, the increase in the prevalence of autism has followed an even more dramatic upward curve than that of Alzheimer’s and is equally if not more so unlikely to be due to a change in population genetics.
The increase in ASD began after the early 1980s.
Prior to this, the prevalence of autism was relatively low and relatively stable (less than 5 in 10,000 children).
In 2011 to 2012, the U.S. Department of Health and Human Services and the U.S. Centers for Disease Control and Prevention (CDC) reported that 1 in 50 U.S. children aged 6 to 17 had been diagnosed with autism (200 per 10,000).
This prevalence estimate was significantly higher than the estimate for children in the same age group reported in 2007 (1 in 88), representing a 72% increase since 2007 alone.
In the United Kingdom, currently reported autism prevalence is 1 in 64 children (157 per 10,000).
It should be obvious that the cumulative 3,040 to 3,900% increase in ASD prevalence in two Western countries since the 1980s cannot be convincingly explained by genetic factors alone, nor by changes in diagnostic criteria, the latter often given as the reason.
Consistent with this, in a recent analysis comparing the prevalence of autism with that of other disabilities among successive birth cohorts of U.S. school-aged children, autism prevalence has been increasing with time, as evidenced by higher prevalence among younger birth cohorts.
That is according to a study published by the journal Pediatricsin 2005.
With the above as a general introduction, the present article will attempt to address the issue of ASD etiology, putting into perspective the likely roles of genes versus environment in the disorder and the interactions between the two.

Autism Features And Central Nervous System (CNS) Abnormalities

Autism and related disorders of the autism spectrum are neurodevelopmental disorders characterized by:
  • dysfunctional immune function
  • stereotypic behavior
  • various degrees of impairments in social skills and verbal communication (i.e., language delays)
Those related disorders include:
  • Asperger’s syndrome
  • Rett syndrome
  • pervasive developmental disorder not otherwise specified
Other neurological and medical conditions frequently co-occur with autism, including:
  • epilepsy(40% of cases)
  • mental retardation(30% of cases score mild to moderate; 40% score serious to profound retardation)
Comorbid behavioral and psychiatric conditions associated with the core symptoms include:
depressionsensory abnormalities
disruptionsleeping disturbances
The most frequent non-neurological comorbidities associated with ASD are:
  • food sensitivities
  • feeding difficulties
  • gastrointestinal abnormalities and underlying inflammation
Autistic symptoms normally appear before 36 months of age, and regression or loss of skills occurs in 30% of affected children, usually between 18 and 24 months.
Abnormal neural connectivity is one of the key pathological features of the autistic brain.
The term connectivity encompasses local connectivity within neural assemblies and long-range connectivity between brain regions.
Similarly, there is also:
a. Physical connectivity
  • “hard-wiring”
  • associated with synapses and tracts
b. Functional connectivity
  • “soft-wiring”
  • associated with neurotransmission
Physically, in the autistic brain, high local connectivity may develop in tandem with low long-range connectivity, potentially as a result of:
a. widespread alterations in synapse elimination; and/or
b. formation and or changes in inhibitory/excitatory synaptic ratios
There is now also abundant evidence supporting the notion that abnormal activity of immune signaling in the brain interferes with the establishment of appropriate neuronal circuitry during development.
Thus, contributing to the emergence of autistic phenotypes.
For example, mice deficient in MHC class I signaling and the classical complement cascade (C1q and C3) exhibit defects in synaptic pruning in specific areas of the brain as well as enhanced epileptic activity.
Cerebellar Purkinje cells, which are significantly reduced in autism, are a site of prominent MHC class I expression.
One hypothesis currently under investigation is that specifically timed changes in neuronal MHC class I expression could contribute to autism.
Notably, neuropathological examinations on autistic brains showed evidence of an active neuroinflammatory process in the cerebral cortex and the cerebellum with extensive loss of cerebellar Purkinje cells.
That is according to a study published in the journal Annals of Neurologyin 2005.
In particular, marked reactivity of the Bergmann’s astroglia in areas of Purkinje cell loss within the Purkinje cell layer, as well as marked astroglial reactions in the granule cell layer and cerebellar white matter were detected.
In the middle frontal gyrus and the anterior cingulate gyrus, astroglial reactions were prominent in the subcortical white matter.
In addition, in some cases, panlaminar astrogliosis was observed.
Moreover, cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-β1, derived from neuroglia, were the most prevalent cytokines in autistic compared to control brain tissues.
The cerebrospinal fluid derived from autistic patients likewise showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1.
Altogether these observations suggest that autistic brain is a result of a disease process that arises from altered activity of immune-related pathways in the brain.
Other evidence in support of this notion is the frequent finding of autoimmune manifestations, particularly those affecting the CNS, in autistic individuals, which do not appear to be limited to only a few nervous system antigens.
For example, in a study published in the Journal of Neuroimmunologyin 2002, its authors demonstrated elevated levels of immunoglobulins (Ig)G, IgM and IgA against nine different neuron-specific antigens in ASD children.
Additionally, more autistic children show serum autoantibodies to the human brain (especially the cerebellum and cingulate gyrus), compared to their unaffected control siblings (p less than 0.01).
The frequent findings of autoantibodies against neuronal antigens in autistic individuals has led many researchers to conclude that the blood-brain barrier (BBB) is breached in autism.
Indeed, such widespread manifestations of CNS-related autoimmunity may have arisen from BBB disruption which would then have enabled access of immunocompetent cells to many different CNS antigens.
Autoantibodies against fetal brain proteins have also been detected in mothers of ASD children, suggesting a disruption of BBB in utero.
It is important to emphasize that an in-utero initiation of ASD does not imply a genetic etiology.
Although it is currently not known how the BBB may become disrupted in autism, perinatal stressors and exposure to BBB-altering environmental stressors have been implicated as potential triggering factors.
These stressors include:
  • aluminum (Al)
  • mercury (Hg)
  • toxic metals (i.e., lead or Pb)
  • polychlorinated biphenyls (PCBs)
Of note, neuronal accumulation of immunoglobulins (IgGs) and CNS autoantibodies have also been detected in Alzheimer’s and Parkinson’s disease.
In addition, most recent studies show that the relevance of circulating anti-NMDA receptor autoantibodies in neuropsychiatric disease patients depends on BBB integrity.
In particular, seropositive schizophrenic patients with a historyof neurotrauma or birth complications (indicating at least temporarily compromised BBB), had more neurological abnormalities than seronegative patients with comparable history.
The above observations further suggest that a common immune-mediated mechanism underlies both neurodevelopmental and neurodegenerative disorders.
Immune abnormalities in ASD are not confined to the nervous system.
Indeed, a large body of data points to a role of systemic immune system dysregulation in the pathophysiology of ASD, which is likely to precede the inflammatory and autoimmune manifestations in the brain.
Concurrent with aberrant cytokine profiles, various studies have shown:
  • abnormal levels of blood lymphocytes
  • incomplete or partial activation of T-cells following stimulation
  • lower levels and decreased activity of circulating natural killer (NK) cells in ASD
Given the above, it has been proposed that the widespread manifestations of immune abnormalities in ASD stems from deleterious effects of immune insults that occur during a narrow window of postnatal development, which is characterized by extensive shaping of both the CNS and the immune system.

Evaluating The Evidence For A Genetic Etiology In Autism

Efforts to understand the etiology of ASD as a genetically-based disorder have been largely centered on three approaches:
1. whole genome scanning predicting the chromosomal localization of the disease by scanning families with more than one affected member, especially twin studies;
2. cytogenetic and molecular studies which have sought de novo chromosomal anomalies and inherited mutations, including gene copy number variations; and
3. candidate genes studies which examine the relationship between those genes known to be associated with abnormal brain development and phenotype of the disease.
Using these approaches, these chromosomes have shown to have some linkage to ASD:
Duplications, inherited maternally, on the 15q11-q13 region of chromosome 15 have been particularly associated.
Deletions on chromosome 16p11 have also shown to be associated with ASD, mental retardation and other developmental disabilities.
Replicated copy number variations from genome wide studies are located on the following chromosomes:
1q2115q11-13 (UBE3A, OR4M2, OR4N4)
2p16.3 (NRXN1)16p11.2 (MAPK3, MAZ, DOC2A, SEZ6L2, HIRIP3, IL6)
3p25-26 (CNTN4)22q11.2
7q36.2 (DPP6)--
However, some of these are also shown to be more frequently present in patients with schizophrenia and mental retardation than controls; thus, raising questions about specificity to ASD.
Several studies have demonstrated that ASD reflects heterogeneous disorders whose etiology is linked with several rare monogenic disorders, such as fragile X syndrome and mutations in:
Synaptic cell adhesion and associated molecules, which indicate glutamatergic abnormalities in ASD, have also been cited. These molecules include:
  • neurexin 1
  • neuroligin 3 and 4
  • the SHANK3
A key problem with genetic investigations into ASD origins has been the lack of reproducibility and overlap in genetic linkage studies.
Although to date, ten full genome screens have been reported and have indeed identified numerous regions of suggestive linkage, only a small subset of these overlap across studies.
Similarly, although more than 100 candidate ASD genes have been studied, there is no consistent replication of positive results.
What we can conclude from the above is that while there are some genetic associations, it is quite clear that the mode of inheritance of autism is not Mendelian.
Rather, it must reflect a polygenic, multifactorial etiology with multiple gene-gene and/or gene-environment interactions.
Indeed, rapidly accumulating evidence appears to support a model of autism as a multisystem disorder with genetic influence, environmental contributors, and a distinct immune component.
Studies of animal models have suggested that genetic variations in ASD, rather than being causal to the disorder, instead confer an altered vulnerability to exposure to environmental stressors.
In this regard, an epidemiological study on ASD that included a comparison amongst siblings suggested that individuals with ASD may react with less tolerance to the same environmental stressors.
One of the reasons why autism is considered to be a clear example of a heritable neurodevelopmental disorder is the large difference in concordance rates between monozygotic and dizygotic twins.
In particular, three studies of twins ascertained from clinical samples with a total of 36 monozygotic pairs (concordance rate of 72%) and 30 dizygotic pairs (concordance rate of 0%) have estimated the heritability of autism, or proportion of liability attributable to genetic factors, at about 90%.
However, a recent study on identical and fraternal twin pairs with autism published in the journal JAMA Psychiatryin 2011 showed that genetic susceptibility to ASD was lower than estimates from prior twin studies.
In particular, environmental factors common to twins accounted for 55% of their risk for developing autism, while genetic heritability explained only 37% of the risk of ASD.
The findings in the aforementioned 2011 study indicate that the rate of concordance in dizygotic twins may have been seriously underestimated in previous studies and the influence of genetic factors on the susceptibility to develop autism, overestimated.
Its authors noted that because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers.
Because the prenatal environment and early postnatal environment are shared between twin individuals and because evidence is accumulating that overt symptoms of autism emerge around the end of the first year of life, the study has concluded that at least some of the environmental factors impacting susceptibility to autism exert their effect during this critical period of life.

Evidence For An Environmental Etiology In Autism

Extensive research has underscored the tight connection between development of the immune system and that of the CNS.
Thus, substantiating the notion that disruption of critical events in immune development may play a role in neurobehavioral disorders including those of the autism spectrum.
Indeed, early-life immune insults (both perinatal and postnatal) have been shown to produce long-lasting, highly abnormal cognitive and behavioral responses, including:
  • increased fear and anxiety
  • impaired social interactions
  • deficits in object recognition memory
  • sensorimotor gating deficits
These symptoms are typical of ASD and results from the heightened vulnerability of the developing immune system to disruption by immuno-modulating environmental pollutants.
Neuroinflammatory processes and immune dysfunction associated with autism can result following early-life exposure to various xenobiotics, that is:
  • aluminum (Al)
  • bisphenol A (BPA)
  • mercury (Hg)
  • lead (Pb)
  • polychlorinated biphenyls (PCBs)
Of the latter, although Hg and Al in particular can come from various sources, the one common source to which infants and pregnant women are universally exposed is through vaccinations.
The burden of pediatric vaccines received in the first two years of life (i.e., currently in the U.S., 27 doses of vaccines) has been blamed the most by some proponents of environmental etiologies as being the key factor driving the upward trend of autism prevalence worldwide.
Mercury has historically been used in some vaccines in the form of an ethyl mercury compound, trademarked as Thimerosal, a bacteriostatic agent.
It is no longer in widespread use in most Western countries, although it is still routinely in use in the Third World with older vaccine stocks.
The evidence that Thimerosal may be involved in ASD remains controversial.
Certainly, compelling data exist on the capacity of low-dose Thimerosal (in vaccine-relevant exposures) to harm the developing nervous system in animal models in a manner consistent with the pathology of autism, and because of this, the safety of TCVs appears to stand on uncertain grounds.
However, the fact that a significant reduction of Thimerosal from vaccines in use in the Western world implemented in 2001 was not accompanied by a correspondingly dramatic reduction in the reported rate of autism suggests that mercury (Hg) alone cannot be the main culprit behind the increased autism rates.
Nonetheless, it should be noted that Thimerosal was subsequently re-introduced to vaccines administered to pregnant women as well infants of 6 months of age (and then yearly throughout childhood) in the form of multi-dose flu vaccines.
This recommendation to reintroduce Thimerosal at the same time when the U.S. medical authorities recommended its removal from routine childhood vaccines has created a false overall impression that the impact of Thimerosal has been reduced, when in actuality, the administration during the gestational period has increased the potential to damage the developing CNS.
In contrast to mercury, aluminum continues to be used in most pediatric and adult vaccines as an adjuvant, as it has been for almost 90 years (since 1926).
The highly effective and currently indispensable adjuvant properties of aluminum, make its removal from vaccines problematic since without the various aluminum salts, most vaccines would fail to stimulate the immune system to a sufficient extent to produce acceptable antibody titers.
Aluminum’s adjuvant-mediated immune-enhancing effect is accomplished via mechanisms that impinge on both the innate and adaptive immune systems.
While the potency and toxicity of aluminum adjuvants should be adequately balanced so that the necessary immune stimulation is achieved with minimal side effects, such balance can be difficult to accomplish in practice.
This is because the same mechanisms that drive the immune-stimulatory effects of adjuvants have the capacity to provoke a variety of autoimmune and/or inflammatory adverse reactions.
Moreover, as we will demonstrate below, the evidence for a role, direct or indirect, of aluminum in ASD, perhaps in concert to certain susceptibility genes as cited above, is increasing.
We note that for many in the medical community, the notion that any compound in vaccines might be involved in the changing rates of ASD is sometimes taken as a form of apostasy.
It is not our intention in the following to incite this concern.
Rather, it is merely to show that aluminum has the neurotoxic capability and ubiquity to contribute to ASD in humans and that some of the features of the disorder can be demonstrated in animals treated with aluminum by injection.

Aluminum As A Neurotoxicant And Its Impact In The CNS

There is now an abundant literature on aluminum and its ubiquity in the modern “age of aluminum” and widespread use in a variety of materials, as well as in:
  • food
  • water
  • various medicinal products
Much of this was suspected as early as 100 years ago and repeatedly confirmed.
Indeed, in spite of rather ill-informed views that aluminum is non-toxic and inert and may even be beneficial for a developing human fetus, since the seminal work of William J. Gies in 1911, epidemiological, clinical and experimental data have clearly identified the CNS as the most sensitive target of aluminum’s toxic effects regardless of mode of exposure (i.e., oral, injectable as adjuvant in vaccines, etc.).
The neurotoxicity of aluminum typically manifests in:
learningspeech deficits
memoryincreased seizure activity
concentrationimpaired psychomotor control
It likewise shows in altered behavior, that is:
  • anxiety
  • confusion
  • sleep disturbances
  • sleep disturbances
One hundred years of general ignorance of Gies’ concerns and recommendations (that aluminum should be excluded from human consumption), has brought us to the need of re-evaluating our increased intake of aluminum from whatever source.
This need is highlighted in burgeoning evidence that links aluminum to the spectrum of neurological diseases which plague the 21st century, including:
The extent of the aluminum’s neurotoxic impacts may depend in large part on the:
  • form(s) of aluminum
  • route of administration
  • concentration and duration of exposure
Included in this latter category is the issue of dietary versus injected aluminum.
It should be obvious that the route of exposure, which bypasses the protective barriers of the gastrointestinal tract and/or the skin, will likely require a much lower dose to produce a toxic outcome.
In the case of aluminum, only ~0.25% of dietary aluminum is absorbed into systemic circulation and then rapidly filtered by the kidneys in those with mature and patent kidney function.
In contrast, aluminum hydroxide (the most common adjuvant form) injected intramuscularly may be absorbed at nearly 100% efficiency over time and follow a completely different route in the body.
Namely, intramuscularly or subcutaneously injected aluminum (mimicking vaccine exposure) may accumulate in other organs including the spleen and the brain, where it is still detected up to one-year post-injection.
Notably, research on human subjects suffering from post-vaccination syndromes showed retention of aluminum adjuvants up to 8 to 10 years following exposure.
The prolonged hyperactivation of the immune system and chronic inflammation triggered by repeated exposure and unexpectedly long persistence of aluminum adjuvants in the human body are thought to be the principal factors underlying the toxicity of these compounds.
One of the reasons for this long retention of aluminum adjuvants in bodily compartments including systemic circulation is most likely due to its tight association with the vaccine antigens or other vaccine excipients (i.e., DNA residuals), which makes such aluminum complexes resistant to both kidney excretion and enzymatic degradation.
Even dietary aluminum has been shown to accumulate in the CNS over time, producing Alzheimer type outcomes in experimental animals that feed equivalent amounts of aluminum to what humans consume through a typical Western diet.
With respect to aluminum in the vaccine adjuvant form, in the last decade, studies on animal models and humans have indicated that aluminum adjuvants have an intrinsic ability to inflict adverse neurological and immuno-inflammatory manifestations.
This research culminated in delineation of ASIA or “autoimmune/inflammatory syndrome induced by adjuvants.”
ASIA encompasses the wide spectrum of adjuvant-triggered medical conditions characterized by a dysregulated immune response.
Notably, a large portion of adverse manifestations experimentally triggered by aluminum in animal models, and those associated with administration of adjuvanted vaccines in humans are neurological and neuropsychiatric.
The ability of aluminum adjuvants to cross the blood-brain and blood-cerebrospinal fluid barriers may in part explain the reason the adverse manifestations following vaccinations tend to be neurological with an underlying immuno-inflammatory component.
Thus, it appears that aluminum impacts on the CNS and immune system are not disparate actions but rather are reciprocally linked.
CNS damage has been directly linked to the immunostimulatory properties of aluminum (Al) adjuvants in mice and sheep, where in both cases damage to the motor system was noted at both behavioral and cellular levels.
In particular, the “sheep ASIA syndrome” mimics in many aspects human neurological diseases linked to aluminum adjuvants.
The adverse chronic phase of this syndrome affects 50 to 70% of flocks and up to 100% of animals within a flock.
It is characterized by severe neurobehavioral outcomes all of which are consistent with aluminum toxicity:
ataxialoss of response to stimuli
comamuscle tremors
compulsive wool bitingrestlessness
generalized weaknesstetraplegia
Two more outcomes are inflammatory lesions in the brain and the presence of aluminum in central nervous system tissues.
The main histopathologic change of the chronic phase of the “sheep ASIA syndrome” is located at the spinal cord and consists in multifocal neuronal necrosis and neuron loss in both dorsal and ventral column of the grey matter.
In humans, the best studied condition linked to adjuvant aluminum is the neuromuscular disorder macrophagic myofasciitis (MMF) syndrome and associated cognitive impairment.
MMF is a condition characterized by highly specific myopathological alterations at deltoid muscle biopsy due to long-term persistence of vaccine-derived aluminum hydroxide nanoparticles within macrophages at the site of previous vaccine injections.
Patients diagnosed with MMF tend to be female (70%) and middle-aged at time of biopsy (median age 45 years), having received 1 to 17 intramuscular aluminum-containing vaccines (mean 5.3) in the 10 years before MMF detection.
Clinical manifestations in MMF patients include:
  • arthralgia
  • chronic fatigue
  • diffuse myalgia
  • muscle weakness
  • cognitive dysfunction
Overt cognitive alterations affecting memory and attention are manifested in 51% of cases.
In addition to chronic fatigue syndrome, 15-20% of patients with MMF concurrently develop an autoimmune disease, the most frequent being:
  • Hashimoto’s thyroiditis
  • diffuse dysimmune neuromuscular diseases
  • multiple sclerosis-like demyelinating disorders
Some examples of diffuse dysimmune neuromuscular diseases:
  • dermatomyositis
  • myasthenia gravis
  • inclusion body myositis
  • necrotizing autoimmune myopathy
Even in the absence of overt autoimmune disease, the following are commonly detected:
  • abnormal iron status
  • low titers of various autoantibodies
  • increased inflammatory biomarkers
The pathological significance of the MMF lesion has long been ill-understood because of the lack of an obvious link between persistence of aluminum agglomerates in macrophages at sites of previous vaccination and delayed onset of systemic and neurological manifestations.
However, recent studies from these same investigators have demonstrated in experimental animals a clear pathway for injected aluminum hydroxide from muscle in which the aluminum particles are transported via the draining lymph nodes by circulating macrophages into the brain.
Once there, aluminum’s unusual physical and biophysical properties and its ability to bind to and disrupt normal biochemical reactions render it capable of altering normal signaling at every level of the CNS and also able trigger autoimmune reactions.
In spite of the observation that long-term cumulative exposure from aluminum adjuvants in adults can result in adverse autoimmune and neurological outcomes, children worldwide continue to be exposed to a much greater aluminum burden from vaccines.
While an adult MMF patient may have received up to 17 vaccines in 10 years prior to diagnosis, an average U.S. child would have received the same number of aluminum-adjuvanted vaccines in their first 18 months of life according to the latest U.S. CDC vaccination schedule.
Of note, in humans, important aspects of brain development (i.e., synaptogenesis) occur during the first 2 years after birth, a period in which the immature brain is extremely vulnerable to neurotoxic and immunotoxic insults, and in which children receive the majority of their pediatric vaccinations.
Yet another factor that is universally overlooked in the design of routine vaccination schedules is that simultaneous administration of as little as two to three immune adjuvants, or repeated stimulation of the immune system by the same antigen, can overcome genetic resistance to autoimmunity.
The lax view about the potential toxicity of aluminum is perhaps best exemplified by its historical and routine use as a placebo in vaccine safety trials, a practice that puts in doubt all widely held assumptions about aluminum safety in vaccines.

Aluminum As A Candidate Risk Factor In Autism

The ability of aluminum to adversely affect both the immune and the nervous system as described above make it a plausible candidate risk factor for triggering disorders of the autism spectrum.
Indeed, the two principal components of ASD are neurological malfunction and immune system dysfunction.
Aluminum is also a known BBB toxin and there is increasing evidence that the widespread manifestationof CNS-related autoimmunity in autistic patients is partially due to disruption of the BBB.
The mechanism by which peripheral (systemic) immune stimulation affects responses in the brain is critical to understanding the potential role of aluminum adjuvants in neurodevelopmental disorders of the autism spectrum.
An important advance in understanding of the function of the normal and the diseased brain was the recognition that there is an extensive communication between the immune system and cells in the CNS.
As a result of this neuro-immune cross-talk, neural activity can be dramatically altered in response to a variety of immune stimuli.
Such peripheral immune stimuli lead to de novo production of proinflammatory cytokines within the brain by the activated microglia, the brain’s resident immune cells.
It should be emphasized that repeated activation of once resting microglia sometimes induces an irreversible shift of these cells to a neurodestructive proinflammatory and excitotoxic phenotype.
That adjuvant aluminum can induce proinflammatory responses in the brain including a dramatic activation of glial cells has been repeatedly shown in the literature.
Moreover, two studies on autistic brain samples suggest that neuroglial activation and neuroinflammation could be critical in initiating and maintaining some of the CNS abnormalities present in autism.
Both of those studies were published in 2005: one in the journal Annals of Neurology; the other in International Review of Psychiatry.
Proinflammatory responses arising from peripheral immune stimuli early in the postnatal period are further detrimental because they result in accumulation of proinflammatory cytokines and excitotoxic levels of the neurotransmitter glutamate within the brain.
Thus, promoting inflammation and disrupting neural development.
Moreover, such immune stimuli can increase CNS vulnerability to subsequent immune insults and the latter can then permanently impair CNS function.
For example, in rodents, peripheral immune stimuli with either bacterial antigens or viral mimetics within the first two postnatal weeks are sufficient to cause:
  • anxiety-like behaviors
  • impairments in memory
  • deficits in social interactions
  • abnormal immune cytokine profiles
  • altered responses to novel situations
  • long-lasting increase in seizure susceptibility
  • increase extracellular glutamate in the hippocampus
All these abnormalities are to various degrees observed in autistic children.
Repeated administration of bacterial and viral antigens (most of which are adsorbed to aluminum adjuvants) through present vaccination schedules is clearly analogous both in nature and timing to peripheral immune stimulation with microbial mimetics in experimental animals during early periods of developmental vulnerability of the CNS.
If administered during these periods (including early postnatal), such potentiated immune stimuli have the intrinsic capacity to produce adverse neurodevelopmental outcomes, and also to permanently impair immune responses to subsequent immune challenges later in life.
In spite of these clear analogies, pediatric vaccinations have been historically dismissed as a plausible cause for the growing burden of neurodevelopmental and immune abnormalities in children.
With this background in mind, we undertook an ecological study of ASD incidence in seven Western countries, including the U.S., in relation to aluminum-adjuvanted vaccine use in each country’s recommended pediatric vaccination schedule.
The results showed a clear, and statistically significant correlation between the number of aluminum adjuvants administered (and the estimated total aluminum body burden) and the rate of ASD over the period examined.
Moreover, the rate, which varied by country, changed in synchrony to the number of aluminum-adjuvanted vaccines in any country’s schedule.
Recognizing that correlation does not demonstrate causality, we applied Hill’s criteria and found that 8 of the 9 criteria could reasonably be satisfied.
Further recognizing that even this was not sufficient, we undertook detailed behavioral studies on newborn male and female outbred mice given an “equivalent” to high and low exposure to aluminum from vaccines (according to the U.S. and Scandinavian vaccination schedules, respectively).
The results of the light/dark box test showed that aluminum injections in the neonatal period significantly increased anxiety-like behaviors and reduced exploratory activities in mice when they were tested as adults approximately four months later.
These adverse behavioral outcomes were long-lasting and persisted throughout the two-month period of testing.
In particular, mice of both sexes injected according to the “high aluminum” schedule showed a highly significant increase in anxiety (p=0.0001 males; p<0.0001 females) and a highly significant reduction in exploratory activities (p<0.0001 males; p<0.0001 females) compared to saline controls.
Females however were more severely affected, showing significant increase in anxiety even at “low aluminum” exposure (p<0.034).
In addition, males but not females receiving “high aluminum” were significantly more lethargic and less active in the open field test than control males or those on the “low aluminum” schedule (p<0.0001).
In particular, the young male CD-1 mice exposed to high doses of aluminum adjuvant traveled shorter distances (p<0.0001), spent significantly less time moving (p<0.0001) and moved more slowly (p<0.0001) than the control animals.
These mice also showed reduced rearing frequency compared to controls (p<0.0004).
Overall, the adverse effects of high aluminum adjuvant exposure on locomotor activities in male mice were also long-lasting and persisted throughout the period of testing.
The various behavioral outcomes noted, and the differences between male and female mice treated with aluminum point to sex difference in sensitivity to neurotoxic/neurodisruptive action of aluminum.
For example, while locomotor activity seemed to be disrupted in males treated with “high aluminum,” in females under the same treatment no impairments were observed.
Of note, while investigating the neurotoxic potential of Thimerosal in vaccine relevant exposures in young adult Wistar rats, the researchers of a study published in the journal Behavioral Brain Researchin 2011 reported similar outcomes in locomotor activity.
Namely, male rats were more sensitive to Thimerosal disruption in the locomotor parameters measured in the open field while the anxiety parameters were altered in both sexes even at the lowest doses of Thimerosal, a result which may reflect the higher intrinsic acute neurotoxic potential of mercury when compared to aluminum.
At least two other studies in the current literature support the role of aluminum in neurological and neurodevelopmental disorders.
A study published in the journal Entropyin 2012 made a comprehensive analysis of the data from the U.S. Vaccine Adverse Event Reporting System (VAERS).
The analysis showed that reports of autism in VAERS increased steadily at the end of the last century during a period when mercury was being phased out of U.S. vaccines, while aluminum adjuvant burden was being increased.
Using standard log-likelihood ratio techniques, the aforementioned 2012 study also identified several signs and symptoms that were significantly more prevalent in vaccine reports after 2000, including:
These signs and symptoms were also significantly associated with aluminum-containing vaccines.
Finally, a study published in the journal Clinical and Experimental Pharmacology and Physiologyin 2013 found that autistic patients have higher than normal blood serum levels of aluminum and other toxic metals - like arsenic (As) and chromium (Cr) - while having lower levels of essential metals including:
  • copper (Cu)
  • magnesium (Mg)
  • zinc (Zn)
Aluminum is well known to displace essential metals from bio-enzymes, especially magnesium and this property of aluminum is linked to its role in triggering neurodegenerative disorders.
In the aforementioned 2013 study, several important factors regarding exposure to toxic metals were identified:
  • in 80% of the cases, the autistic children had used or made use of controlled drugs
  • 90% of them had taken all recommended vaccines
In addition, 70% of mothers of ASD children received vaccines and 80% of them ate canned food and fish during pregnancy.

Aluminum Alters Gene Expression

The ability of aluminum to bind to DNA and change gene expression patterns has been established in two studies: one published in the journals FEBS Lettersin 1989 and the other one in Elsevier Sciencein 2001.
At nanomolar concentrations, aluminum inhibits brain-specific gene transcription from selected AT-rich promoters of human neocortical genes.
Aluminum’s repressive action on gene transcription is linked to its ability to:
1. decrease the access of transcriptional machinery to initiation sites on DNA template by enhancing chromatin condensation; or
2. interfere with ATP-hydrolysis-powered separation of DNA strands either indirectly (by binding to phosphonucleotides and increasing the stability and melting temperature of DNA) or directly (by inhibiting the ATPase-dependent action of RNA polymerase).
These effects were experimentally demonstrated at physiologically-relevant aluminum concentrations (10-100 nm.), and at levels that have been reported in Alzheimer diseasepatients’ chromatin fractions.
Furthermore, aluminum content expressed per gram of DNA was found to be significantly increased in nuclear and heterochromatin fractions in pre-senile Alzheimer's disease patients when compared to age-matched controls.
It is particularly interesting to note that in spite of its overall repressive action on some gene expression, aluminum can also promote transcription.
Aluminum promotes lipid peroxidation and oxidative stress and, in this way, activates the ROS-sensitive transcription factors, hypoxia inducible factor-1 (HIF-1) and nuclear factor (NF)-κB and augments specific neuroinflammatory and pro-apoptotic signaling cascades by driving the expression from a subset of HIF-1 and NF-κB-inducible promoters.
Out of eight induced genes up-regulated in cultured human neurons by 100 nm. aluminum sulfate (the same compound that is used as a flocculant in water), seven showed expression patterns similar to those observed in Alzheimer’s, including:
  • HIF-1/NF-κB-responsive AβPP
  • interleukin-1β (IL-1β) precursor
  • NF-κB subunits
  • cytosolic phospholipase A2 (cPLA2)
  • cyclooxygenase (COX)-2 and DAXX (a regulatory protein known to induce apoptosis and repress transcription)
Both HIF-1 and NF-κB are up-regulated in Alzheimer’s disease, where they fuel the proinflammatory cycle which leads to further exacerbation of oxidative stress and inflammation, culminating in neuronal death.
In light of the above data, we selected 18 candidate genes which have implied functions in both ASD and macrophage-initiated innate immune response.
We measured the expression levels of these 18 genes using semi-quantitative RT-PCR in brain samples from three male control and three aluminum-injected mice from the study cited above.
In total, seven genes showed changes in expression.
Some of the activators and effectors of immuno-inflammatory response were significantly up-regulated, including:
  • interferon gamma (IFNG)
  • tumor necrosis factor (TNF)
  • chemokine CCL2
  • lymphotoxin beta (LTB)
The inhibitors of the immune reaction NF-κBIB (inhibitor of NF-κB) complement component C2.
Also, a gene controlling the regulation of the degradative enzyme for the neurotransmitter acetylcholine (acetylcholinesterase or AChE) were significantly down-regulated.
In 5 out of these 7 genes, the analysis of the corresponding protein levels showed significant changes in expression:
  • IFNG, TNF, and CCL2 - up-regulated
  • NF-κBIB and ACHE - down-regulated
Although it is still premature to make definitive conclusions given the still small sample size (the data are currently being collected on other samples), these results suggest that an immuno-inflammatory response was activated and the neural activity decreased by aluminum injection.
Moreover, our results are in agreement with a study published in Journal of Inorganic Biochemistryin 2005.
Its authors demonstrated upregulation of NF-κB responsive and proinflammatory genes by nanomolar aluminum.
Altogether, the gene expression studies following aluminum treatment point to a greater complexity than perhaps previously anticipated: not only can aluminum evoke direct neural damage and trigger activation of adverse immune-mediated signals, it can also directly influence gene expression.
Thus, triggering more complex interactions between genes and toxins.
Insofar as the latter may be correct, it will be highly important in the future to determine where in the lifespan aluminum can impact gene expression and how long such changes might last.


It should be clear by now that the etiology of ASD is not a simple process involving only genetic factors, but rather involves a multiple “hit” etiology.
This is not particularly surprising given the existing literature on neurodegenerative disorders associated with aging (e.g., Alzheimer’s disease, Parkinson disease, and ALS) have reached much the same conclusions.
Based on the likelihood of gene-environment interaction, we propose that some combination of genetic predispositions can sensitize the developing CNS of some individuals to a secondary toxic insult.
That second insult could conceivably be that aluminum from various sources including pediatric vaccines, although clearly other toxicants may also be involved.
Aluminum salts are the most widely used adjuvants in current use.
The fact that they can trigger pathological immunological responses and a cascade of adverse health effects is now well documented, albeit still not widely recognized in the medical community.
As detailed in this article, the risks associated with vaccine-derived aluminum are four-fold:
First, aluminum can persist in the body.
Second, aluminum can trigger pathological immunological responses.
Third, aluminum can make its way into the CNS, where it can activate deleterious immuno-inflammatory and excitotoxic processes.
Fourth, aluminum can alter expression of numerous genes involved in the immuno-inflammatory responses and cell-to-cell signaling.
Further, given that a strong adjuvant effect can overcome even genetic resistance to autoimmunity, it is likely that an increasing number of individuals, regardless of their genetic background, will react adversely if exposures to compounds with immune adjuvant properties exceed a certain threshold.
Prior genetic susceptibilities may in such cases only determine the degree of severity of manifestations of the disease spectrum, rather than being the principal driving factor in their increase.
The fact that as many as 2% of people aged 6 to 17 years old in the U.S. currently show some form of autism (representing over a 70% increase since 2007), argues in favor of this hypothesis.
No genetic susceptibility can account for such a dramatic increase in such a short time span as genes in a population are highly unlikely to change that rapidly.
Notably, studies on twins have now shown that common environmental factors account for 55% of their risk for developing autism while genetic susceptibility explains only 37% of cases.
It is reasonable that at least some of the environmental factors contributing to the risk of autism exert their deleterious neurodevelopmental effect during this early period of life because:
a. the prenatal environment and early postnatal environment are shared between twins; and
b. overt symptoms of autism emerge around the end of the first year of life.
Indeed, important aspects of human brain development take place during the first two postnatal years, when the immature brain is extremely vulnerable to neurotoxic and immunotoxic insults.
This is also a period during which children worldwide are routinely exposed to the majority of aluminum-adjuvanted vaccines.
Aluminum is both a neurotoxin and an immunotoxin.
There is now sufficient evidence from both human and animal studies that cumulative exposure to this adjuvant is not as benign as previously assumed.
Because infants represent the most vulnerable population that is universally and routinely exposed to aluminum adjuvants, a more rigorous evaluation of its potentially adverse neurodevelopmental impacts is needed.
Further research should be conducted about the etiology of autism spectrum disorders.
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