APPENDIX II-AT: Truitt, The Role of Genetic and Xenobiotic Factors in the Etiology of Autism , Loyola Marymount University [Blood Brain Barrier – Autism].


This appendix is copied from:


Saturday, October 08, 2005

Environmental Toxins

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.

The Role of Genetic and Xenobiotic
Factors in the Etiology of

Kate Truitt

Loyola Marymount University

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.


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 California jumped 273 percent (1999).

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 America , between 1950-2000. Both have posited that these environmental factors play a large role in the increased incidence of AD and ASD (Baker, 2002; Kunin, 2002). Some of the factors considered are: increased antibiotic use; mercury exposure by injection in infancy; increase in combined love viral vaccines and numbers of these vaccinations; increased soil depletion leading to vitamin/mineral deficits; decreased omega-3 and –6 essential fatty acids in diet; and great exposure to xenobiotic toxins.

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 ( Torrente , Ashwood & Day, 2002; Furlano, Anthony & Day, 2001). Common symptoms include diarrhea and/or constipation, gas, bloating, abdominal pain, burping and gastro-esophageal reflux. Horvath, Papadimitriou, Rabsztyn (1999) found reflux esophagitis in 69 percent of an AD sample, duodenal inflammation in 67 percent, abnormal pancreatic response to secrein in 75 percent and low carbohydrate digesting enzymes (lactase) in 58 percent.

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 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).


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.