APPENDIX II-AT: Truitt, The Role
of Genetic and Xenobiotic Factors in the Etiology of Autism ,
This appendix is copied from:
http://autisticconjectureoftheday.blogspot.com/2005/10/environmental-toxins.html
In autism, as in education, the argument of nature versus
nurture collects emotional adherents on both sides. Is it what you are born
with, or where you are born that determines the outcome? It certainly appears
that in autism AND education, this is not an either/or question. Translation:
it is both.
The following is a college paper that examines the roles of genetic susceptibility
and exposure to environmental toxins in the epidemic of autism.
AUTISTIC CONJECTURE OF THE DAY
The Role of Genetic and Xenobiotic
Factors in the Etiology of
Abstract
Autism is a pervasive neurodegenerative disease that is behaviorally defined by
a broad constellation of symptons. The diverse symptomatology of autism has made it difficult to pinpoint
the etiology of autism. A genetic component compounded with
prenatal toxic exposures (teratogens) are
found to be consistent with autism symptomology
(Kidd, 2002). This suggests that perinatal central
nervous system infection, impaired detoxification and disturbed neuroimmune networks are factors in the pathogenesis of
autism spectrum disorders. Both innate and adaptive immune responses have been
studied and results found that autistic individual’s portray adverse reactions
to environmental factors such as vaccination, pesticides, childhood infection
and dietary proteins. This is consistent with the proposal that environmental
agents have a causal role in autism.
Introduction
In 1943 Leo Kanner published
the first case histories of a childhood developmental disorder that he called
autism. He defined three sets of behavioral patterns that categorize the
disorder: (1) failure to use language for communication, (2) abnormal
development of social reciprocity and (3) a desire for sameness, as seen in
repetitive rituals or intensly limited interests (Kanner, 1943). Individuals with autism portray an extreme
difficulty in learning from experience as well as modifying their behavior to
accommodate varying situations.
The statistics on the occurrence of autism (AD) and autism spectrum disorders
(ASD) strongly suggests that these disorders have become epidemic. Surveys
conducted prior to the 1990’s found that the nationwide prevalence was 5 per
10,000 for AD and 20 per 10,000 per ASD (Fombonne,
1999). By 1997, the prevalence rate has increased and is estimated to be 45-50
per 10,000. A landmark study done on Brick Township in New Jersey suggested
that the frequency of ASD may have reached 1 in 150 (London, 2000).
Furthermore, from 1987 to 1998 The California Health and Human Services Agency
reported that the number of children being treated for autism in
There are conflicting hypotheses suggesting what has led to this increase. Some
experts claim that the increased prevalence of AD and ASD is only apparent due
to the changes in diagnostic criteria and the improvements in early detection
(Kidd, 1997). Although a feasible argument, the tripling or quadrupling of
prevalence in little more than a decade seems to overwhelming to support this
hypothesis. Sidney M. Baker and Richard A. Kunin have
independently listed factors that have become more prominent in developed
countries, such as
Today, most accepted hypotheses for the etiology of autism claim a genetic
component that is triggered by xenobiotic factors. Edelson and Cantor proposed that there is a chronic
toxicological mechanism that is occurring in autism. They posited that autism
may begin as early as the fetal development period, some even say as early as
days 20-24 in the womb (1998). This is the time that the Central Nervous System
is exceptionally vulnerable to influences from the external environment due to
the lack of the protective blood brain barrier. This vulnerable time of
development becomes pertinent to potentially autistic individuals when
considering the proposed genetic defect in autism. Research has consistently
found that autistic individuals have a defect in liver detoxification (Kidd,
2000), due to this consistentcy
many have posited that it is a genetic component that plays a vital role in the
etiology of autism. In these individuals, the liver cannot effectively detoxify
the chemicals of lipophilic character that enter the
fetus’ body, thus xenobiotic agents have easy access
to neurons and dendritic processes. The impairment of
the detoxification system has serious consequences in light of the increased levels
of ordinary toxins in our environment. For individuals with a dysfunctional
liver detoxification system, exposure to chemicals such as paints, plastics,
glues, carpets, pastes, and pesticides can be devastating. This could
potentially explain why the brains of autistic individuals develop microscopic
pathology (Eigsti & Shapiro, 2003).
During the fetal development stage, exposure to xenobiotic
agents is devastating to the growing central nervous system. Researchers have
proposed that it is lipophilic compounds that are not
properly metabolized. Due to this, the lipophilic
compounds are able to pass directly to the CNS during the developmental period
that the blood brain barrier cannot protect the developing brain structures.
These chemicals cause damage to neurons, dendritic
processes, receptors and mitochondrial RNA (mRNA). Recent research indicates
that when mRNA is deficient, the cells don’t manufacture proteins, which can
potentially lead to a failure in the CNS to produce certain structures such as Tubulin, axial fibrillary
proteins, and dendrites. This impaired development leads to dysfunctional cerebral and cerebellar functions which
has been suggested to create the variety of behaviors seen in autism and
autism spectrum disorders (Bailey, Luthert &
Dean, 1998).
Due to impaired ability of the liver to detoxify, toxins are consistently
compounding within autistic individuals, thus propagating further destruction
to the central nervous system by xenobiotic agents.
Numerous researchers have isolated different mechanisms that may play distinct
roles in originating autistic symptoms:
Sulfation and its role in endogenous and exogenous
detoxification
Kidd recently explored the likelihood of linkages between the variety of toxins
present in our modern environment and the correlation with increased childhood
abnormalities (2000). Today’s environment is covered with xenobiotics.
Heavy metals, herbicides, organohalide pesticides,
fumigants and a wide range of aromatic as well as aliphatic (carbon based) solvents
have been linked to abnormalities in cognition, behavior, perception and motor
ability during the early developmental stages (ages 1-4). Research has also
found that children exposed intensely or chronically to lead, aluminum,
cadmium, mercury or arsenic often have permanent
neurological damage. Lead has long been studied for its causality in
developmental delay and mental retardation (Schwartz, 1994). These
environmental factors correspond with the abnormally high heavy metal burden
that has been found in autistic individuals (Edelson
& Cantor, 1998).
This excessive accumulation of xenobiotic pollutants
becomes important as one begins to look at the proposed detoxification impairements in AD and ASD individuals. Amongst the
unending number of theories proposing causes to autism, one category of
abnormalities occurs close to 100 percent frequency and that is abnormal liver
detoxification (Kidd, 2002). The liver uses sulfation
as one pathway for the detoxification of endogenous and exogenous substances. Sulfation is exceptionally important for its role in the
excretion of substances such as steroids, bile acids and xenobiotics.
The liver relies upon the sulfation process to
neutralize phenolic (ie
carbonic acid) substances, chemicals found in foods, and both exogenous and
endogenous contaminants. When this system is impaired the resultant is overload
of toxins and can result in liver injury or failure.
Gastrointestinal organ abnormalities
The gastrointestinal system has long been recognized as a source if symptom
triggering abnormalities in AD and ASD individuals (
Much like the liver, the gastrointestinal (GI) tract relies heavily on sulfate
ability for its essential functions. Gastrointestinal mucosa must have sulfate
available in order to conduct neutralization of potentially toxic bacterial
fermentation products (e.g. from proteins), foodborn phenolics, and, as previously mentioned, manmade xenobiotics (Levy, 1986). Again, sulfate impairement has very negative effects and, particularly in
autistics, threatens the stability of the catecholamine (e.g. epinephrine, norepinephrine, and dopamine) transmitter systems, the
integrity of the gut lining, and creates a heightened vulnerability to foodborne or pollutant xenobiotic
overload. Alberti, Pirrone,
Elia et.al. reported impaired sulfation and a
correlation with foods that have relatively high profiles of phenolic amines such as dopamine, tyramine,
and serotonin (1999). These investigators suggested that the impaired sulofation is why these foods – bananas, chocolate, cheese
and other fermented products – “trigger” AD and ASD children. Waring (1997) advanced this finding when he found that the
activity of phenylsulfotransferase (PST), which is
the enzyme that catalyzes the sulfation of
acetaminophen, was abnormally low in AD subjects as measured from blood
platelets. This provides more proof of a systemic incapacity of autistic
subjects to detoxify phenols and amines via sulfation.
Increased Indolyl Acryloyl Glycine and Indolyl Acrylic Acid in Autistic Individuals.
Shattock reports that on numerous occasions they have
found increased Indolyl Acryloyl
Glycine (IAG) and Indolyl
Acrylic Acid (IAcrA) in the urine samples obtained
from subjects diagnosed with AD or ASD (1999). IAG has been found to be rather
planar and rather reactive, thus it has been hypothesized that it is in fact
its precursor, Indolyl Acrylic Acid (IAcrA) that possess the potential for activity and thus
plays a role in autism. IAcrA is claimed to be
involved in the structure of the lipid elements of cell membranes, this would
greatly increase their permeability to other molecules. In AD and ASD the
effects of this would be seen in increased permeability of both the intestinal
walls and the blood brain barrier, thus allowing a translocation of peptides
with biological activity from the intestines to the central nervous system.
One explanation for the increased levels of IAG is the common usage of Organo-Phosphorus (OP) based pesticides. OP compounds were
initially developed as agents of war and insecticides due to their ability to
cause paralysis by inhibiting certain enzyme systems, particularly those
involving anti-cholinesterases (Shattock,
1999). Of particular interest in the consideration of AD and ASD would be the
effects upon enzymes that are involved in the metabolism of tryptophan.
Research has found that Diazinon (an OP pesticide) will seriously interefere with the
metabolism of tryptophan via the kynurenine
pathways. This would force the tryptophan metabolism
towards the IAG route (Sieffert 1992, 1993). Thus,
the increasing levels of OP agents in the environment would, through a
sequencing of stages, create an increasing permeability in the membranes of the
intestines and blood brain barrier. This increased permeability, as previously
mentioned, would create an enhanced passage of peptides, perhaps even larger
poly peptides or even protein material. If these are large enough, and the
present in sufficient qualities then this could lead to production of
antibodies that would generate allergies, hypersensitivities, as well as
developmental delays (Shattock, 1999).
Blood-Brain Barrier
Edelson and Cantor demonstrated a body burden of neurotoxicants in more than 90 percent of autistic children
(2000). This presents evidence for genetic and environmental aspects of a
hypothetical process believed to cause immune system injury secondary to
exposure to the immunotoxins. Edelson
and Cantor posited that “activation” of the immune system is caused by
toxicants leading to the productions of autoantibodies
against haptens, the toxic chemicals attached to
brain proteins. Thus, the subsequent damage may be considered a component in
the etiological process of neurotoxicity in the
autistic spectrum.
Toxic chemicals, such as the aforementioned manmade xenobiotics,
can induce alteration or overexpression of genes involed in regional brain glial fibrillary acidic protein (GFAP) and astroglial
glucose-regulated protein (GRP). The astroglia cytoskeletal element GFAP, neurotypic
and gliotypic proteins are generally accepted as
sensitive indicators of neurotoxic effects in human
brains. Overexpression of the gene results in an
alteration in the structural differentiation of astrocytes
thus effecting autoimmune response to neurofilament
proteins (Qian, Harris, Zheng
& Tiffany-Castiglioni, 2000). Levels of these
antibodies correlate with sensorimotor deficits and
have been known to interfere with neuromuscular function (El-Fawal, Waterman, De Feo, & Shamy, 1999).
Autoantibodies against neurologic
antigens in autism have been studied by three different investigators using
crude antigens: myelin basic protein (Singh, Warren, Odell, Cole & Warren,
1993), brain tissue antigens (Weizman, Weizman, Szekely, Wijsenbeek, & Livni, 1982)
and partially purified preparation of cytoskeletal
intermediate filaments (Singh, Warren, Averett & Ghaziuddin, 1997). The high prevalence of these autoantibodies in neurodegenerative and neuropsychiatric
disorders has led many researchers to believe that these antibodies reflect an
alteration of the blood-brain barrier. This alteration would promote the access
of immunocompetent cells to the central nervous
system (Morse, Plug, Wesseling, Van Der Berg & Brouwer, 1996;
Singh et. al., 1997; Partl, Herbst,
Schaeper, Mohnhaupt & Stoltenburg-Didinger, 1998; Qian
et. al., 2000).
Conclusion
The autistic child may be a casualty of the toxicity of modern society or a
victim of genetic defect. Most researchers point to a combination of the two,
but clearly much more research needs to be conducted on autism. While the
etiology of the disorder still remains a mystery, management techniques
continue to become more plentiful. Trends in research portray a compounding
aspect to autism. Some have suggested that while certain aspects of the disease
are genetic, they only lead to autism if other components are also available,
almost as though they build upon each other to reach the threshold that is
autism. Future research needs to continue to blend these proposed etiological
hypotheses with management techniques to hopefully, some day, find a cure.