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Autism and environment

Autism is now widely accepted to primarily be a condition resulting from epigenetic changes through environmental and genetic interactions.

Studies have investigated numerous potential environmental toxicants including polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), heavy metals, pesticides, and other known neurotoxins and endocrine disruptors. 

Whether due to increased oxidative stress, an underlying metabolic or mitochondrial dysfunction, or another unknown factor, there is evidence that persons with autism may be more susceptible to adverse effects of toxicants.

While many toxicants have shown some level of correlation, none have emerged as a primary causative agent. Future research should seek to identify sub-cohorts, increased genetic susceptibilities, relative risk, vulnerable periods of development, and align findings with known pathophysiological symptoms found in those with autism.

Selected Studies

The aluminium content of brain tissues from donors with a diagnosis of ASD was extremely high (Table 1). While there was significant inter-tissue, inter-lobe and inter-subject variability the mean aluminium content for each lobe across all 5 individuals was towards the higher end of all previous (historical) measurements of brain aluminium content, including iatrogenic disorders such as dialysis encephalopathy [13,15,16–19]. All 4 male donors had significantly higher concentrations of brain aluminium than the single female donor. We recorded some of the highest values for brain aluminium content ever measured in healthy or diseased tissues in these male ASD donors including values of 17.10, 18.57 and 22.11 μg/g dry wt. (Table 1)...Aluminium was found in both white and grey matter and in both extra- and intracellular locations. The latter were particularly pre-eminent in these ASD tissues. Cells that morphologically appeared non-neuronal and heavily loaded with aluminium were identified associated with the meninges (Fig. 1), the vasculature (Fig. 2) and within grey and white matter (Figs. 3–5). Some of these cells appeared to be glial (probably astrocytic) whilst others had elongated nuclei giving the appearance of microglia [5]. The latter were sometimes seen in the environment of extracellular aluminium deposition. This implies that aluminium somehow had crossed the blood-brain barrier and was taken up by a native cell namely the microglial cell.

M. Mold et. al. "Aluminium in brain tissue in autism" Journal of Trace Elements in Medicine and Biology

Volume 46, March 2018, Pages 76-82

"Evidence of the neurotoxicity of aluminium cations (Al3+) includes: an association between chronic aluminium exposure and the development of AD; the involvement of aluminium adjuvants in the development of ASIA; and epidemiological evidence pointing to an association between the use of aluminium adjuvants and ASD. There is good evidence to suggest that immunisation may accelerate or precipitate the transition between subclinical and overt symptomatic autoimmune conditions within the first 30 days post-immunisation, particularly in those younger than 50 years of age. The immune response to immunisation may be influenced by variations in HLA, TLR and cytokine genes. Moreover, aluminium exposure is associated with the production of pro-inflammatory cytokines and chemokines and with the development of chronic oxidative stress, mitochondrial dysfunction and glial activation or dysfunction; these changes in turn are associated with ASD.

Conclusions and Future Directions

Aluminium has no known beneficial physiological action in the human body and some genetic polymorphisms predispose to a greater susceptibility to its adverse effects. Therefore, a strong case can be made for avoiding unnecessary exposure to environmental sources of aluminium salts, especially on the part of children, pregnant mothers and women of child-bearing age who may become pregnant."

Morris, Gerwyn, Basant K. Puri, and Richard E. Frye. “The Putative Role of Environmental Aluminium in the Development of Chronic Neuropathology in Adults and Children. How Strong Is the Evidence and What Could Be the Mechanisms Involved?” Metabolic Brain Disease 32.5 (2017): 1335–1355. PMC. 

"Rare variants enriched for functions in chromatin regulation and neuronal synapses have been linked to autism. How chromatin and DNA methylation interact with environmental exposures at synaptic genes in autism etiologies is currently unclear. Using whole-genome bisulfite sequencing in brain tissue and a neuronal cell culture model carrying a 15q11.2-q13.3 maternal duplication, we find that significant global DNA hypomethylation is enriched over autism candidate genes and affects gene expression. The cumulative effect of multiple chromosomal duplications and exposure to the pervasive persistent organic pollutant PCB 95 altered methylation of more than 1,000 genes. Hypomethylated genes were enriched for H2A.Z, increased maternal UBE3A in Dup15q corresponded to reduced levels of RING1B, and bivalently modified H2A.Z was altered by PCB 95 and duplication. These results demonstrate the compounding effects of genetic and environmental insults on the neuronal methylome that converge upon dysregulation of chromatin and synaptic genes."

Dunaway, Keith W. et al. “Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes.” Cell reports 17.11 (2016): 3035–3048. PMC. 

"Multi-level negative binomial regression models were used to test associations between ASD prevalence and proximity to industrial facilities in existence from 1991 to 1999 according to the US Environmental Protection Agency Toxics Release Inventory (USEPA-TRI). Data for 2489 census tracts showed that after adjustment for demographic and socio-economic area-based characteristics, ASD prevalence was higher in census tracts located in the closest 10th percentile compared of distance to those in the furthest 50th percentile (adjusted RR = 1.27, 95% CI: (1.00, 1.61), P = 0.049). The findings observed in this study are suggestive of the association between urban residential proximity to industrial facilities emitting air pollutants and higher ASD prevalence."

Dickerson, Aisha S. et al. “Autism Spectrum Disorder Prevalence and Proximity to Industrial Facilities Releasing Arsenic, Lead or Mercury.” The Science of the total environment 536 (2015): 245–251. PMC.

"Disorders of neurobehavioural development affect10–15% of all births,1 and prevalence rates of autism spectrum disorder and attention-deficit hyperactivity disorder seem to be increasing worldwide.2 Subclinical decrements in brain function are even more common than these neurobehavioural developmental disorders. All these disabilities can have severe consequences3—they diminish quality of life, reduce academic achievement, and disturb behaviour, with profound consequences for the welfare and productivity of entire societies.4

The root causes of the present global pandemic of neurodevelopmental disorders are only partly understood. Although genetic factors have a role,5 they cannot explain recent increases in reported prevalence, and none of the genes discovered so far seem to be responsible for more than a small proportion of cases.... Strong evidence exists that industrial chemicals widely disseminated in the environment are important contributors to what we have called the global, silent pandemic of neurodevelopmental toxicity.6,7 The developing human brain is uniquely vulnerable to toxic chemical exposures, and major windows of developmental vulnerability occur in utero and during infancy and early childhood.8 During these sensitive life stages, chemicals can cause permanent brain injury at low levels of exposure that would have little or no adverse effect in an adult."

Grandjean, Philippe et al. "Neurobehavioural effects of developmental toxicity", The Lancet Neurology , Volume 13 , Issue 3 , 330 - 338

"Some studies reported differences that could have a genetic basis in children with ASD compared with controls concerning the ability to metabolize toxicants. For example, two studies suggested that children with ASD appear to metabolize mercury61 and lead104 differently than TD children. One study found ‘altered sensitivity' to 2,2′,4,4′-tetrabrominated biphenyl in children with ASD compared with controls.143 Another study found abnormalities in phase II detoxification in an uncontrolled study of children with ASD, suggesting altered liver detoxification.138 Finally, two studies reported evidence of impaired glucuronidation in children with ASD.138,142 These findings raise the possibility that some children with ASD might not metabolize toxicants as efficiently as TD children and therefore might experience adverse effects of toxicants at lower concentrations compared with TD children...A majority (34/37, 92%) of the studies examining a potential association between ASD and estimated environmental toxicant exposures reported a significant relationship."

Rossignol, D A, S J Genuis, and R E Frye. “Environmental Toxicants and Autism Spectrum Disorders: A Systematic Review.” Translational Psychiatry 4.2 (2014): e360–. PMC.

"Children of mothers who live near agricultural areas, or who are otherwise exposed to organophosphate, pyrethroid, or carbamate pesticides during gestation may be at increased risk for neurodevelopmental disorders. Further research on gene–environment interactions may reveal vulnerable subpopulations."

Shelton, Janie F. et al. “Neurodevelopmental Disorders and Prenatal Residential Proximity to Agricultural Pesticides: The CHARGE Study.” Environmental Health Perspectives 122.10 (2014): 1103–1109. PMC.

"Environmental chemical exposures are increasingly understood to be important in causing autism, with current theories positing that autism is caused by the interplay of multiple genetic and environmental contributions that differ from individual to individual.4,5 While initial studies suggested a strong genetic heritability of autism, recent studies with larger sample sizes have demonstrated a lesser influence, including a study of over 14,000 children with autism in Sweden that demonstrated a heritability of 50%, supporting an equally strong role for environmental risk factors.6 Genetic and environmental factors may combine to disrupt the normal processes of nervous system development, interfering with neuron formation and migration, synapse formation, or neurological connectivity, ultimately causing autism."

Kalkbrenner, Amy E., Rebecca J. Schmidt, and Annie C. Penlesky. “Environmental Chemical Exposures and Autism Spectrum Disorders: A Review of the Epidemiological Evidence.” Current problems in pediatric and adolescent health care 44.10 (2014): 277–318. PMC. 

"Exposure to TRP, NO2, PM2.5, and PM10 during pregnancy and the first year of life was associated with autism. Further epidemiological and toxicological examination of likely biological pathways will help determine whether these associations are causal...Children with autism were three times as likely to have been exposed during the first year of life to higher modeled traffic-related air pollution as compared with typically developing controls. Similarly, exposure to TRP during pregnancy was also associated with autism."

Volk, Heather E. et al. “Traffic Related Air Pollution, Particulate Matter, and Autism.” JAMA psychiatry 70.1 (2013): 71–77. PMC.  

Results: Perinatal exposures to the highest versus lowest quintile of diesel, lead, manganese, mercury, methylene chloride, and an overall measure of metals were significantly associated with ASD, with odds ratios ranging from 1.5 (for overall metals measure) to 2.0 (for diesel and mercury). In addition, linear trends were positive and statistically significant for these exposures (p < .05 for each). For most pollutants, associations were stronger for boys (279 cases) than for girls (46 cases) and significantly different according to sex.

Conclusions: Perinatal exposure to air pollutants may increase risk for ASD. Additionally, future studies should consider sex-specific biological pathways connecting perinatal exposure to pollutants with ASD.

Roberts, Andrea L. et al. “Perinatal Air Pollutant Exposures and Autism Spectrum Disorder in the Children of Nurses’ Health Study II Participants.” Environmental Health Perspectives 121.8 (2013): 978–984. PMC. 

"By comparing hair concentration of autistic vs nonautistic children, elevated hair concentrations were noted for aluminum, arsenic, cadmium, mercury, antimony, nickel, lead, and vanadium. Hair levels of calcium, iron, iodine, magnesium, manganese, molybdenum, zinc, and selenium were considered deficient. There was a significant positive correlation between lead & verbal communication (p = 0.020) and general impression (p = 0.008). In addition, there was a significant negative correlation between zinc & fear and nervousness (p = 0.022).

Conclusion: Our data supports the historic evidence that heavy metals play a role in the development of ASD. In combination with an inadequate nutritional status the toxic effect of metals increase along with the severity of symptoms."

BLAUROCK-BUSCH, Eleonor et al. “Toxic Metals and Essential Elements in Hair and Severity of Symptoms among Children with Autism.” Mædica 7.1 (2012): 38–48. Print.

"Of the 26 genes that correlated with mercury levels in both AU and TD boys, 11 were significantly different between the groups (P(Diagnosis*Mercury) ≤ 0.05). The expression of a large number of genes (n = 316) correlated with mercury levels in TD but not in AU boys (P ≤ 0.05), the most represented biological functions being cell death and cell morphology. Expression of 189 genes correlated with mercury levels in AU but not in TD boys (P ≤ 0.05), the most represented biological functions being cell morphology, amino acid metabolism, and antigen presentation. These data and those in our companion study on correlation of gene expression and lead levels show that AU and TD children display different correlations between transcript levels and low levels of mercury and lead. These findings might suggest different genetic transcriptional programs associated with mercury in AU compared to TD children."

Stamova, Boryana et al. “Correlations Between Gene Expression and Mercury Levels in Blood of Boys With and Without Autism.” Neurotoxicity Research 19.1 (2011): 31–48. PMC.

"First, the prevalence of autism has increased in recent decades at an alarming rate. Second, as with most neurodevelopmental (or immunological) disorders, autism is chronic in nature and the ramifications of the dysfunction are borne across a lifetime. Finally, autism is but one of a disturbingly large cadre of chronic conditions (e.g. asthma, type 1 diabetes, metabolic syndrome, schizophrenia, sleep disorders) that have followed similar paths of increased prevalence...In a scientific consensus statement by the Collaborative on Health and the Environment's Learning and Developmental Disabilities Initiative (50), several environmental agents were identified as strong contributors to learning and developmental disabilities in humans. These included arsenic, lead, manganese, mercury, pesticides, polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and solvents. However, as previously mentioned in the ‘routes to autism’ section, a direct effect on the developing nervous system is not the only route to autism. Environmental agents that affect other systems during development may lead to downstream effects on the developing brain. Limiting research to just those agents that directly impact brain development may exclude a multitude of triggers. In addition, no single agent or specific combination of agents has been identified as a trigger. It is more likely that certain individuals with enhanced susceptibility to environmental chemicals and with certain genetic predispositions are at increased risk for autism after exposure to a variety of environmental triggers including chemicals (51)."

Dietert, Rodney R., Janice M. Dietert, and Jamie C. Dewitt. “Environmental Risk Factors for Autism.” Emerging Health Threats Journal 4 (2011): 10.3402/ehtj.v4i0.7111. PMC

"Among the subset of subjects with available residential history data, measures for distance to the freeway were highly correlated across trimesters, reflecting the limited number of subjects who changed residence during pregnancy (n = 17 between first and second, 13 between second and third, 30 between first and third). In each trimester, living closest to the freeway (< 309 vs. > 1,419 m) was associated with autism, but the OR reached statistical significance only during the third trimester (adjusted OR = 1.96; 95% CI, 1.01–3.93). Effect estimates for the first and second trimesters were slightly lower in magnitude (first trimester: adjusted OR = 1.66; 95% CI, 0.91–3.10; second trimester: adjusted OR = 1.65; 95% CI, 0.85–3.28)."

Volk, Heather E. et al. “Residential Proximity to Freeways and Autism in the CHARGE Study.” Environmental Health Perspectives 119.6 (2011): 873–877. PMC. 

 "Cord blood was analyzed using a FACSort flow cytometer to determine proportions of T lymphocytes (CD3+ cells and their subsets, CD4+ and CD8+), B lymphocytes (CD19+) and natural killer (NK) cells. Ambient air concentrations of 12 polycyclic aromatic hydrocarbons (PAH) and particulate matter < 2.5 micrometer in diameter (PM2.5) were measured using fixed site monitors...PAHs and PM2.5 in ambient air may influence fetal immune development via shifts in cord blood lymphocytes distributions. Associations appear to differ by exposure in early versus late gestation."

Herr, Caroline EW et al. “Air Pollution Exposure during Critical Time Periods in Gestation and Alterations in Cord Blood Lymphocyte Distribution: A Cohort of Livebirths.” Environmental Health 9 (2010): 46. PMC.

"The various correlation analyses found that overall there were multiple positive correlations between the severity of autism and the urinary excretion of some toxic metals (both before and after taking DMSA). Lead (after DMSA) and antimony (at baseline) had the most consistent effect, but other metals were also important. The existence of multiple positive correlations suggested that a regression analysis was appropriate.

The regression analysis found that the body burden of toxic metals (as assessed by urinary excretion before and after DMSA) was significantly related to the variations in the severity of autism, for each of the four scales. The metals of greatest influence were lead (Pb), antimony (Sb), mercury (Hg), tin (Sn), and aluminum (Al)."

J. B. Adams, M. Baral, E. Geis, et al., “The Severity of Autism Is Associated with Toxic Metal Body Burden and Red Blood Cell Glutathione Levels,” Journal of Toxicology, vol. 2009, Article ID 532640, 7 pages, 2009. 

"It is believed that gene by environmental interactions contribute to the pathogenesis of autism spectrum disorders (ASD). We hypothesize that ASD are associated with early and repeated exposures to any of a number of toxicants or mixtures of toxicants. It is the cumulative effects of these repeated exposures acting upon genetically susceptible individuals that lead to the phenotypes of ASD. We report our initial observations of a considerable overlap of identified toxic landfills in the State of New Jersey and the residence of an ASD cohort, and a correlation between the identified toxic Superfund sites on each U.S. state and the total number of diagnosed cases of ASD in those states. The residence of 495 ASD patients in New Jersey by zip code and the toxic landfill sites were plotted on a map of Northern New Jersey. The area of highest ASD cases coincides with the highest density of toxic landfill sites while the area with lowest ASD cases has the lowest density of toxic landfill sites. Furthermore, the number of toxic Superfund sites and autism rate across 49 of the 50 states shows a statistically significant correlation (i.e. the number of identified superfund sites correlates with the rate of autism per 1000 residents in 49 of the states (p = 0.015; excluding the state of Oregon). These significant observations call for further organized studies to elucidate possible role(s) of environmental toxicants contributing to the pathogenesis of ASD."

Ming X, Brimacombe M, Malek JH, Jani N, Wagner GC. Autism Spectrum Disorders and Identified Toxic Land Fills: Co-Occurrence Across States. Environmental Health Insights. 2008;2:55-59.

 Environmental mercury is neurotoxic at doses well below the current reference levels considered to be safe, with evidence of neurotoxicity in children exposed to environmental sources including fish consumption and ethylmercury-containing vaccines. Possible neurotoxic mechanisms of mercury include direct effects on sulfhydryl groups, pericytes and cerebral endothelial cells, accumulation within astrocytes, microglial activation, induction of chronic oxidative stress, activation of immune-inflammatory pathways and impairment of mitochondrial functioning. (Epi-)genetic factors which may increase susceptibility to the toxic effects of mercury in ASD include the following: a greater propensity of males to the long-term neurotoxic effects of postnatal exposure and genetic polymorphisms in glutathione transferases and other glutathione-related genes and in selenoproteins. Furthermore, immune and inflammatory responses to immunisations with mercury-containing adjuvants are strongly influenced by polymorphisms in the human leukocyte antigen (HLA) region and by genes encoding effector proteins such as cytokines and pattern recognition receptors. Some epidemiological studies investigating a possible relationship between high environmental exposure to methylmercury and impaired neurodevelopment have reported a positive dose-dependent effect.

Morris, G., Puri, B.K., Frye, R.E. et al. "The Putative Role of Environmental Mercury in the Pathogenesis and Pathophysiology of Autism Spectrum Disorders and Subtypes" Mol Neurobiol (2017).

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