Autism and Supplements

Advances in Autism Research
compiled by Teresa Binstock for ARI
April 2008

Environmental factors
Various pollutants are associated with autism

In recent years, a number of studies have described associations between autism spectrum disorders and various environmental pollutants. These findings have important ramifications. For instance, the "must be genetic" model and the notion of "multiple, rare alleles of cognitive genes" needs be tempered by genetic and nutritional aspects of detoxification and immunity. The citations in this section delineate the relationship between toxins and neurodevelopmental problems manifesting as autism-spectrum disorders. One citation documents a weak allele of a glutathione-related gene. Many studies about weak alleles in genes related to detoxification have been published in peer-reviewed scientific literature.

1: Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions.

D'Amelio M et al.
Mol Psychiatry. 2005 Nov;10(11):1006-16.

Organophosphates (OPs) are routinely used as pesticides in agriculture and as insecticides within the household. Our prior work on Reelin and APOE delineated a gene-environment interactive model of autism pathogenesis, whereby genetically vulnerable individuals prenatally exposed to OPs during critical periods in neurodevelopment could undergo altered neuronal migration, resulting in an autistic syndrome. Since household use of OPs is far greater in the USA than in Italy, this model was predicted to hold validity in North America, but not in Europe. Here, we indirectly test this hypothesis by assessing linkage/association between autism and variants of the paraoxonase gene (PON1) encoding paraoxonase, the enzyme responsible for OP detoxification. Three functional single nucleotide polymorphisms, PON1 C-108T, L55M, and Q192R, were assessed in 177 Italian and 107 Caucasian-American complete trios with primary autistic probands. As predicted, Caucasian-American and not Italian families display a significant association between autism and PON1 variants less active in vitro on the OP diazinon (R192), according to case-control contrasts (Q192R: chi2=6.33, 1 df, P<0.025), transmission/disequilibrium tests (Q192R: TDT chi2=5.26, 1 df, P<0.025), family-based association tests (Q192R and L55M: FBAT Z=2.291 and 2.435 respectively, P<0.025), and haplotype-based association tests (L55/R192: HBAT Z=2.430, P<0.025). These results are consistent with our model and provide further support for the hypothesis that concurrent genetic vulnerability and environmental OP exposure may possibly contribute to autism pathogenesis in a sizable subgroup of North American individuals.
PMID: 16027737

2. Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas.Palmer RF et al.
Health Place. 2006 Jun;12(2):203-9.
http://www.generationrescue.org/pdf/seed.pdf

"On average, for each 1,000 lb of environmentally released mercury, there was a 43% increase in the rate of special education services and a 61% increase in the rate of autism."
PMID: 16338635

3. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the san francisco bay area

Windham GC et al.
Environ Health Perspect. 2006 Sep;114(9):1438-44.
http://www.ehponline.org/members/2006/9120/9120.html "The adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated solvents and heavy metals [95% confidence intervals (CIs) , 1.1-2.1], but not for aromatic solvents. Adjusting for these three groups simultaneously led to decreased risks for the solvents and increased risk for metals (AORs for metals: fourth quartile = 1.7 ; 95% CI, 1.0-3.0 ; third quartile = 1.95 ; 95% CI, 1.2-3.1) . The individual compounds that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride."
PMID: 16966102

4. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley

Roberts EM et al.
Environ Health Perspect. 2007 Oct;115(10):1482-9.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2022638&blobtype=pdf

"Multivariate a posteriori models comparing children of mothers living within 500 m of field sites with the highest nonzero quartile of organochlorine poundage to those with mothers not living near field sites suggested an odds ratio for ASD of 6.1 (95% confidence interval, 2.4-15.3). ASD risk increased with the poundage of organochlorine applied and decreased with distance from field sites."
PMID: 17938740

5. Proximity to point sources of environmental mercury release as a predictor of autism prevalence

Palmer RF, Blanchard S, Wood R.
Health Place. 2008 Feb 12 [Epub ahead of print]

The objective of this study was to determine if proximity to sources of mercury pollution in 1998 were related to autism prevalence in 2002. Autism count data from the Texas Educational Agency and environmental mercury release data from the Environmental Protection Agency were used. We found that for every 1000 pounds of industrial release, there was a corresponding 2.6% increase in autism rates (p<.05) and a 3.7% increase associated with power plant emissions (P<.05). Distances to these sources were independent predictors after adjustment for relevant covariates. For every 10 miles from industrial or power plant sources, there was an associated decreased autism Incident Risk of 2.0% and 1.4%, respectively (p<.05). While design limitations preclude interpretation of individual risk, further investigations of environmental risks to child development issues are warranted.
PMID: 18353703

6. Environmental Factors and Limbic Vulnerability in Childhood Autism

Richard Lathe
Am J Biochem Biotech 4(2): 183-197, 2008
http://www.scipub.org/fulltext/ajbb/ajbb42183-197.pdfThe rise in prevalence of autism spectrum disorders (ASD) is suggestive of a new etiology. Diagnostic substitution alone is unlikely to account for the increase, while genetic association with detoxification gene alleles points to an environmental contribution. Subtle structural anomalies in the ASD brain are widespread but limbic damage seems important for the development of behaviors diagnostic of ASD. The limbic brain is especially susceptible to environmental challenge: internal sensing, physiological feedback and neuroinflammatory processes may underlie this sensitivity to insult. Primary damage leading to ASD in later life is likely to take place in utero and/or in the immediate postnatal period. Despite evidence of heavy metal involvement, a causal connection may not yet be concluded because subjects exposed to metals tend to be exposed to other environmental agents. Because maternal minerals and lipids are supplied to the unborn child, historic toxic exposure of the mother may be pivotal. A two-hit combination of genetic susceptibility and environmental challenge is argued to underlie the rise in ASD.

7. Developmental neurotoxicity of industrial chemicals

Grandjean P, Landrigan PJ.
Lancet. 2006 Dec 16;368(9553):2167-78.

Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.
PMID: 17174709

8. Sulfhydryl-reactive metals in autism

Kern JK et al.
J Toxicol Environ Health A. 2007 Apr 15;70(8):715-21.

This study examined the difference between sulfhydryl-reactive metals (mercury, lead, arsenic, and cadmium) in the hair of 45 children with autism (1-6 yr of age) as compared to 45 gender-, age-, and race-matched typical children. Hair samples were measured with inductively coupled mass spectrometry. Some studies, such as Holmes et al. (2003), suggested that children with autism may be poor detoxifiers relative to normally developing children. Metals that are not eliminated sequester in the brain. Our study found that arsenic, cadmium, and lead were significantly lower in the hair of children with autism than in matched controls. Mercury was in the same direction (lower in autism) following the same pattern, but did not achieve statistical significance. The evidence from our study supports the notion that children with autism may have trouble excreting these metals, resulting in a higher body burden that may contribute to symptoms of autism.
PMID: 17365626

9. Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype

Williams TA et al.
Arch Pediatr Adolesc Med. 2007 Apr;161(4):356-61.
http://archpedi.ama-assn.org/cgi/reprint/161/4/356

"Overtransmission of the GSTP1*A haplotype to case mothers suggests that action in the mother during pregnancy likely increases the likelihood of AD in her fetus."
PMID: 17404132

10. How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis

Deth R et al.
Neurotoxicology. 2008 Jan;29(1):190-201.
http://tinyurl.com/2jeerr or http://tinyurl.com/2fwwak

[This paper presents an important summary of relationships among pollutants, oxidative stress, nutritional status, and methylation-related biochemistry and is best read in conjunction with James SJ et al 2004, 2006 and with Kern JK et al 2007]

Recently higher rates of autism diagnosis suggest involvement of environmental factors in causing this developmental disorder, in concert with genetic risk factors. Autistic children exhibit evidence of oxidative stress and impaired methylation, which may reflect effects of toxic exposure on sulfur metabolism. We review the metabolic relationship between oxidative stress and methylation, with particular emphasis on adaptive responses that limit activity of cobalamin and folate-dependent methionine synthase. Methionine synthase activity is required for dopamine-stimulated phospholipid methylation, a unique membrane-delimited signaling process mediated by the D4 dopamine receptor that promotes neuronal synchronization and attention, and synchrony is impaired in autism. Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects. On the basis of these observations, a "redox/methylation hypothesis of autism" is described, in which oxidative stress, initiated by environment factors in genetically vulnerable individuals, leads to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks.
PMID: 18031821

11. Prenatal exposures to persistent and non-persistent organic compounds and effects on immune system development

Hertz-Picciotto I et al.
Basic Clin Pharmacol Toxicol. 2008 Feb;102(2):146-54.
http://www.blackwell-synergy.com/doi/full/10.1111/j.1742-7843.2007.00190.x

Immune system development, particularly in the prenatal period, has far-reaching consequences for health during early childhood, as well as throughout life. Environmental disturbance of the complex balances of Th1 and Th2 response mechanisms can alter that normal development. Dysregulation of this process or an aberrant trajectory or timing of events can result in atopy, asthma, a compromised ability to ward off infection, or other auto-immune disease. A wide range of chemical, physical and biological agents appear to be capable of disrupting immune development. This MiniReview briefly reviews developmental milestones of the immune system in the prenatal period and early life, and then presents examples of environmentally induced alterations in immune markers. The first example involves a birth cohort study linked to an extensive programme of air pollution monitoring; the analysis shows prenatal ambient polycyclic aromatic hydrocarbons (PAH) and fine particle (PM2.5) exposures to be associated with altered lymphocyte immunophenotypic distributions in cord blood and possible changes in cord serum immunoglobulin E levels. The second example is a study of prenatal-polychlorinated biphenyl (PCB) exposures and the foetal development of the thymus, the organ responsible for lymphocyte maturation. Mothers with higher serum concentrations of PCBs gave birth to neonates having smaller indices of thymus size. Finally, this report underscores the tight connection between development of the immune system and that of the central nervous system, and the plausibility that disruption of critical events in immune development may play a role in neurobehavioural disorders.
PMID: 18226068

12. Autism: xenobiotic influences

Edelson SB, Cantor DS.
Toxicol Ind Health. 1998 Jul-Aug;14(4):553-63.

[Early findings reported here called attention to xenobiotic factors.]

The advances in medical technology during the last four decades has provided evidence for an underlying neurological basis for autism. The etiology for the variations of neurofunctional anomalies found in the autistic spectrum behaviors appears inconclusive as of this date but growing evidence supports the proposal that chronic exposure to toxic agents, i.e., xenobiotic agents, to a developing central nervous system may be the best model for defining the physiological and behavioral data found in these populations. A total of 20 subjects (15 males and 5 females) who received a formal diagnosis of autism by a developmental pediatrician, pediatric neurologist, or licensed psychologist were included. The mean age for the sample was 6.35 yrs offnge = 3-12 years). This study employed several measures that collectively would provide evidence of burden levels of xenobiotic agents and abnormal liver detoxication processes. These included: (1) Glucaric Acid Analysis, (2) blood analyses for identification of specific xenobiotic agents, and (3) Comprehensive Liver Detoxification Evaluation. Kolmogorov-Smirnov testing for a chi-square and Normal distribution of the Glucaric Acid finding indicates that each of these distributions is significantly different from expected distributions (p < .01). It is most noteworthy that of the 20 cases examined for this study, 100% of the cases showed liver detoxication profiles outside of normal. An examination of 18 autistic children in blood analyses that were available showed that 16 of these children showed evidence of levels of toxic chemicals exceeding adult maximum tolerance. In the two cases where toxic chemical levels were not found, there was abnormal D-glucaric acid findings suggesting abnormal xenobiotic influences on liver detoxication processes. A proposed mechanism for the interaction of xenobiotic toxins with immune system dysfunction and continuous and/or progressive endogenous toxicity is presented as it relates to the development of behaviors found in the autistic spectrum.
PMID: 9664646

13. Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study

Lonsdale D, Shamberger RJ, Audhya T.
Neuro Endocrinol Lett. 2002 Aug;23(4):303-8.

[An early study decribing benefits from excretion of toxic metals]

OBJECTIVES: In a Pilot Study, the clinical and biochemical effects of thiamine tetrahydrofurfuryl disulfide (TTFD) on autistic spectrum children were investigated. SUBJECTS AND METHODS: Ten children were studied. Diagnosis was confirmed through the use of form E2, a computer assessed symptom score. For practical reasons, TTFD was administered twice daily for two months in the form of rectal suppositories, each containing 50 mg of TTFD. Symptomatic responses were determined through the use of the computer assessed Autism Treatment Evaluation Checklist (ATEC) forms. The erythrocyte transketolase (TKA) and thiamine pyrophosphate effect (TPPE), were measured at outset and on completion of the study to document intracellular thiamine deficiency. Urines from patients were examined at outset, after 30 days and after 60 days of treatment and the concentrations of SH-reactive metals, total protein, sulfate, sulfite, thiosulfate and thiocyanate were determined. The concentrations of metals in hair were also determined. RESULTS: At the beginning of the study thiamine deficiency was observed in 3 out of the 10 patients. Out of 10 patients, 6 had initial urine samples containing arsenic in greater concentration than healthy controls. Traces of mercury were seen in urines from all of these autistic children. Following administration of TTFD an increase in cadmium was seen in 2 children and in lead in one child. Nickel was increased in the urine of one patient during treatment. Sulfur metabolites in urine did not differ from those measured in healthy children. CONCLUSIONS: Thiamine tetrahydrofurfuryl disulfide appears to have a beneficial clinical effect on some autistic children, since 8 of the 10 children improved clinically. We obtained evidence of an association of this increasingly occurring disease with presence of urinary SH-reactive metals, arsenic in particular.
PMID: 12195231

14. Scientific Consensus Statement on Environmental Agents Associated with Neurodevelopmental Disorders

February 2008
http://www.iceh.org/pdfs/LDDI/LDDIStatement.pdf

15: Perinatal exposure to a noncoplanar polychlorinated biphenyl alters tonotopy, receptive fields, and plasticity in rat primary auditory cortex

Kenet T et al.
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7646-51.
http://www.pnas.org/cgi/content/full/104/18/7646

[A murine model offering insights about autism]

Noncoplanar polychlorinated biphenyls (PCBs) are widely dispersed in human environment and tissues.... These findings demonstrate that developmental exposure to this class of environmental contaminant alters cortical development. It is proposed that exposure to noncoplanar PCBs may contribute to common developmental disorders, especially in populations with heritable imbalances in neurotransmitter systems that regulate the ratio of inhibition and excitation in the brain. We conclude that the health implications associated with exposure to noncoplanar PCBs in human populations merit a more careful examination.
PMID: 17460041

16: Developmental neurotoxicity of industrial chemicals

Grandjean P, Landrigan PJ.
Lancet. 2006 Dec 16;368(9553):2167-78.

Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.
PMID: 17174709

17: Mercury and autism: accelerating evidence?

Mutter J et al.
Neuro Endocrinol Lett. 2005 Oct;26(5):439-46.

The causes of autism and neurodevelopmental disorders are unknown. Genetic and environmental risk factors seem to be involved. Because of an observed increase in autism in the last decades, which parallels cumulative mercury exposure, it was proposed that autism may be in part caused by mercury. We review the evidence for this proposal. Several epidemiological studies failed to find a correlation between mercury exposure through thimerosal, a preservative used in vaccines, and the risk of autism. Recently, it was found that autistic children had a higher mercury exposure during pregnancy due to maternal dental amalgam and thimerosal-containing immunoglobulin shots. It was hypothesized that children with autism have a decreased detoxification capacity due to genetic polymorphism. In vitro, mercury and thimerosal in levels found several days after vaccination inhibit methionine synthetase (MS) by 50%. Normal function of MS is crucial in biochemical steps necessary for brain development, attention and production of glutathione, an important antioxidative and detoxifying agent. Repetitive doses of thimerosal leads to neurobehavioral deteriorations in autoimmune susceptible mice, increased oxidative stress and decreased intracellular levels of glutathione in vitro. Subsequently, autistic children have significantly decreased level of reduced glutathione. Promising treatments of autism involve detoxification of mercury, and supplementation of deficient metabolites.
PMID: 16264412
See also:

Pesticide Toxicity and the Developing Brain

Brenda Eskenazi et al.

Basic & Clinical Pharmacology & Toxicology, Volume 102, Issue 2, February 2008, Page 228-236
http://www.blackwell-synergy.com/doi/full/10.1111/j.1742-7843.2007.00171.x

Evidence for a Role of Paternal Exposures in Developmental Toxicity
Sylvaine Cordier
Basic & Clinical Pharmacology & Toxicology, Volume 102, Issue 2, February 2008, Page 176-181
http://www.blackwell-synergy.com/doi/full/10.1111/j.1742-7843.2007.00162.xPrenatal Exposures to Persistent and Non-Persistent Organic

Compounds and Effects on Immune System Development
Irva Hertz-Picciotto et al.
Basic & Clinical Pharmacology & Toxicology Volume 102 Issue 2 Page 146-154, February 2008
http://www.blackwell-synergy.com/doi/abs/10.1111/j.1742-7843.2007.00190.xThe Faroes Statement: Human Health Effects of Developmental

Exposure to Chemicals in Our Environment
Philippe Grandjean et al.
Basic & Clinical Pharmacology & Toxicology, Volume 102, Issue 2, Page 73-75, Feb 2008
http://www.blackwell-synergy.com/doi/full/10.1111/j.1742-7843.2007.00114.x

Developmental Origins of Health and Disease: New Insights
Mark A. Hanson and Peter D. Gluckman
Basic & Clinical Pharmacology & Toxicology, Volume 102, Issue 2, Page 90-93, Feb 2008
http://www.blackwell-synergy.com/doi/full/10.1111/j.1742-7843.2007.00186.x

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