Review articleToxic metal(loid)-based pollutants and their possible role in autism spectrum disorder
Introduction
Autism spectrum disorder (ASD) is currently defined as a spectrum of lifelong heterogeneous neuro-developmental disorders, characterized by deficits in social interaction and communication, and restricted, repetitive interests and behaviors, onset usually occurs before the age of three years (APA, 2013; Yenkoyan et al., 2017). During the past two decades, the increased worldwide ASD prevalence rate has led to great concern because a worrisome 30% increase in incidence and prevalence in children was reported (Calabrese et al., 2016). It has been shown that the prevalence of children with ASD aged 6–17 was 2% in 2011–2012, while a marked increase from the past 1.16% was reported since 2007 (Blumberg et al., 2013). In the US, the increase in the prevalence of ASD has been even more dramatic over a shorter period (Boyle et al., 2011, Christensen et al., 2016, Baio et al., 2018). In the years 2006–2008, approximately one in six American children had a developmental disability, classified from mild (like language and speech impairments) to severe (like cerebral palsy, ASD, and intellectual disabilities) (Boyle et al., 2011). According to the Centers for Disease Control and Prevention (CDC), about one in 59 (16.8 per 1000) US school-aged children has an ASD diagnosis (Baio et al., 2018).
To date, there is no consensus on the pathogenesis of this disorder. Research has suggested that there are multiple risk factors related to the pathogenesis of ASD. Some suggested idiopathic risk factors are: obstetric complications, fetal hypoxia, maternal or paternal age, bleeding during pregnancy, gestational diabetes, diet and medication used during the prenatal period (Kolevson et al., 2007, Meguid et al., 2017). Maternal or paternal age at the time of birth may be associated with ASD due to its link with an increase in the risk of chromosomal abnormalities (Kolevson et al., 2007, Goddard et al., 2016, Martinelli and Staiano, 2017) or mutations in genes involved in fetal neuro-development (Ezra et al., 1995, Rosenthal and Paterson-Brown, 1998, Kourtian et al., 2017, Stessman et al., 2017). These mutations may be spontaneous or caused by environmental factors including exposures to metal-derived toxicants; but collectively mutations have been estimated to be causal in about 7% of those subjects diagnosed with ASD (Kazmaura and Lie, 2002, Tang et al., 2006, Geier et al., 2009a, Geier et al., 2009b, Geier et al., 2016, Shen et al., 2010, Pietropaolo et al., 2017). Furthermore, in a recent study, glutamine was reported as a predictive prognostic marker in ASD patients, and it was reported that an anomaly in the balance between GABAergic and glutamatergic neurotransmission was prevalent in ASD cases (Al-Otaish et al., 2018). Oxidative stress and neuroinflammation also play a significant role in ASD (Rossignol and Frye, 2012).
However, it is also known that environmental factors such as exposure to some toxic chemicals present in the environment and the dysregulation of intracellular trace metals can lead to human brain injury (National Academy of Sciences, 1993, Stork and Li, 2016). This vulnerability is greatest during embryonic and fetal development and maybe especially significant in the first trimester of pregnancy (Grandjean and Landrigan, 2006, Caserta et al., 2013, Costa et al., 2017). The neonate is considered exceptionally vulnerable to toxic metal exposure and reduced uptake of essential elements like zinc (Zn) and manganese (Mn) (Oskarsson et al., 1998, Arora et al., 2017). During these periods, the central nervous system (CNS) is experiencing a rapid growth rate and is highly vulnerable to the effects of both toxins and toxicants (Oskarsson et al., 1998, Ethier et al., 2012, Miyazaki et al., 2016).
Prenatal, neonatal and/or early childhood exposure to environmental factors may contribute or be a relevant factor in the child's development of the symptoms used to place children within the autism spectrum (Bailey et al., 1995, Monaco and Bailey, 2001, Hultman et al., 2002, Daniels, 2006, Sutcliffe, 2008). Interactions of gene and environmental factors, such as exposure to toxic metal pollutants, are associated with several nervous system disorders (Bjørklund, 2013, Pietropaolo et al., 2017). Exposure to environmental toxins and toxicants may also be causal factors for gene mutations or genetic variations, which has been suggested to lead to ASD diagnosis; but given the observed neurodevelopmental differences in twins having ASD diagnoses, these factors are still to be fully elucidated as causing ASD (Santangelo and Tsatsanis, 2005, Daniels, 2006, Wender and Veenstra-VanderWeele, 2017). Environmental factors could act in conjunction either with inherited susceptibilities or by inducing epigenetic changes (Mehler, 2008, Homs et al., 2016, Bjørklund et al., 2017a, Zhubi et al., 2017). For example, epigenetic effects on the regulation of the reelin gene (RELN) and glutamate decarboxylase 67 (GAD1) have been reported in the frontal cortex of the brains of individuals diagnosed with ASD (Wasser and Herz, 2017, Zhubi et al., 2017).
Exposure to environmental toxicants such as: a) lead (Pb); b) all forms of mercury (Hg) including elemental Hg, inorganic Hg compounds (e.g., calomel [Hg2Cl2] and mercuric chloride [HgCl2]) and organic Hg compounds (e.g. methylmercury (MeHg) chloride [MeHgCl], MeHg cysteine [MeHgCys] and the sodium salt of ethylmercury (EtHg) thiosalicylate [Na+ EtHg Thiosalicylate–]); c) toxic aluminum (Al) compounds (e.g., the sparingly soluble hydroxy Al salts and, for those with certain kidney diseases, the highly soluble Al (III) salts like aluminum sulfate [(Al3+)2(SO4–)3]; and d) arsenic (As), have been found to be associated with disorders ranging from overt toxicity at high levels of exposure down to subclinical dysfunction when exposure is at minimal levels (Gibson, 1904, Landrigan et al., 1975, Harada, 1995, Canfield et al., 2003, Tomljenovic et al., 2014, Strunecka et al., 2016, Kalkbrenner et al., 2018, Wu et al., 2018). Evidence indicates that the interplay between these factors, i.e., Pb, Hg, Al, As, and the presence of certain genetic predispositions or epigenetic effects can lead to the symptoms characteristic of ASD (Hodgson et al., 2014, Tomljenovic et al., 2014; Yassa et al., 2014; Felice et al., 2015; Macedoni-Lukšič et al., 2015). Moreover, a very recent study reported synergistic neurotoxic effects of Al and Hg in primary human neuronal-glial (HNG) cells by a substantial increase of pro-inflammatory signaling pathways through significant induction of NF-kB (p50/p65) in response to Al and Hg alone or in a combination of both (Alexandrov et al., 2018).
A recent study reported that there is a close relationship between the level of industrial pollutants of As, Pb and/or Hg species and the prevalence of children having ASD diagnosis (Dickerson et al., 2015). This study corroborated a previous study by Roberts et al. (2013) that found that perinatal exposures to the highest versus lowest quintile of diesel, Pb, Mn, Hg, methylene chloride, and an overall measure of metals were significantly associated with ASD. Also, a study in Riyadh area, Saudi Arabia reported significantly higher levels of toxic metals (i.e., Hg, Pb, As and cadmium [Cd] species) in children having ASD diagnosis as compared to the levels of these metal species in neurotypical children (Al-Ayadhi, 2005). Again, in Saudi Arabia, researchers found elevated levels of Hg and Pb together with a significant decrease in the selenium (Se) levels in red blood cells (RBCs) of patients with ASD when compared to neurotypical children (El-Ansary et al., 2017a, El-Ansary et al., 2017b). On the other hand, glutathione (GSH) as the predominant cellular free radical scavenger in the brain is the primary defense against many toxic metals, and low GSH has been reported in ASD patients. Therefore, although high exposure to heavy metals is a problem, low GSH seems to be the primary reason for elevated toxic metals in ASD (Nair et al., 2015, Endres et al., 2017). Also, a decreased ratio of reduced GSH to oxidized GSH (GSH/GSSG) and elevated oxidative stress in the brain of ASD patients may result in increased mitochondrial superoxide production, oxidative protein and DNA damage, and chronic inflammatory response (Rose et al., 2012; Chauhan and Chauhan, 2015).
A recent systematic review and meta-analysis of 48 studies by meta-regression analyses reported a link between ASD and toxic metals in different specimens such as whole blood, red blood cells, serum, plasma, urine and hair of ASD patients. Specifically, they found higher blood and erythrocyte levels for Hg and Pb and reported the role of toxic metals as environmental factors in the ASD etiology (Saghazadeh and Rezaei, 2017). Also, Gump et al. (2017) assessed blood Pb and Hg levels in a biracial cohort of 9–11-year-old children (N = 203) using neurodevelopmental and psychological functioning assessments. Increased Pb levels in these children were associated with deviant behaviors, unstable emotionality, and difficulties in communication. Increased Hg levels were associated with various autism spectrum behaviors for children with sustained vagal tone during acute stress. A large Mothers and Children's Environmental Health (MOCEH) study of 458 mother-child pairs found associations between prenatal and early childhood Hg exposure and autistic behaviors at five years of age using the Social Responsiveness Scale (Ryu et al., 2017). The variations of the level of toxic metals in ASD subjects are presented in Table 1.
A small number of studies, however, have demonstrated a significant decrease in levels of heavy metals in the hair of children who have ASD (Holmes et al., 2003, Kern et al., 2007, Skalny et al., 2017a, Skalny et al., 2017b, Skalny et al., 2017c). Kern et al. (2007) have proposed that this observation may be indicative of altered mechanisms of heavy metal excretion and their subsequent sequestration in the organism.
Exposure to some environmental toxic metals can lead to an initial stimulation of the immune cells. This may lead to an increase in the serum neurokinin A level with a subsequent enhancement in the release of this tachykinin from these cells that have been found in children with ASD (Mostafa et al., 2016a). A recent study of 47 ASD patients with 46 neurotypical individuals reported a positive association between PGE2, COX-2, and mPGES-1 and ascertains the potential role of PGE2 pathway and neuroinflammation in the etiology of ASD, and the possibility of using PGE2, COX-2 and mPGES-1 as biomarkers of autism severity (Qasem et al., 2018). The combination of corticotrophin-releasing hormone (CRH), neurotensin (NT) and environmental pollutants could hyperstimulate the already activated mammalian target of rapamycin (mTOR) as well as stimulate mast cell and microglia activation and proliferation and, thereby, increase the affected child's risk for ASD onset (Mostafa et al., 2008, Angelidou et al., 2010, Theoharides et al., 2013). In conclusion, the vast majority of the research suggests that children with ASD have increased levels of Pb, Hg, and Al and that there are mixed results for As (Table 1).
Section snippets
Lead and the environment
Lead (Pb) is a non-essential toxic metal, which is widely distributed in the environment because of its use in many different applications, particularly as: a) the yellow pigments in paints, b) a constituent in tin toys, c) the projectile in small caliber ammunition, and d) an anti-knock agent in automobile and aircraft fuels. Lead exposure levels have been a matter of public health concern in many countries for decades (Fuentes-Albero et al., 2015, Tan et al., 2016, Laidlaw et al., 2017). For
Mercury as a pollutant in the environment
Mercury (Hg) is a universal environmental contaminant that bio-accumulates as MeHg species in the food chain (Cardenas et al., 2017). The main sources of Hg exposure are currently seafood (Dadar et al., 2014, Dadar et al., 2016) and dental amalgams (Bjørklund et al., 2017d). Hg salts have immunomodulatory and allergenic properties (Stejskal et al., 1996), stimulate autoimmunity in genetically susceptible animals (Pelletier et al., 1988) and can also induce or promote the development of
Aluminum and the environment
Aluminum is the third most abundant metal in the Earth's crust and is one of the most durable, light, strong and corrosion resistant elements in the periodic table. It is naturally found in silicates, cryolite, and bauxite-containing rock (Krewski et al., 2007). Its slightly soluble salts are neurotoxic compounds with known adverse health effects in a variety of living organisms, including microbes, plants, fish, and mammals (Rahbar et al., 2016). Aluminum has a constant presence in our daily
Arsenic and the environment
Arsenic is released into the environment via both geochemical and anthropogenic processes. As-based compounds are considered to pose one of the most significant potential threats to human health as judged by their frequent occurrence, toxicity, and by the number of humans exposed (Rosen and Liu, 2009). Worldwide, As poisoning through As-contaminated groundwater is one of the most threatening public health problems (Tyler and Allan, 2014, Bjørklund et al., 2017e). Recent studies reported that
Overview of intervention for metal-(loids) toxicity
Toxic metal exposure exerts certain stresses on body's immune system (disrupting antioxidant defense) and can be viewed as a potential candidate for the environmental factor of ASD etiology (Table 1). Research has shown that immune dysregulation and inflammation can be crucial factors for ASD development and are key components of the diagnosis and treatment of ASD (Bjørklund et al., 2016). However, current toxic metal detoxifying procedures are still unable to provide complete remission from
Conclusion
The dramatic rise in the number of children diagnosed with ASD in the past two decades has actualized the need for safe and effective preventive measures. Over the last three decades, numerous studies have reported a possible relationship between ASD and Hg exposure. However, there are also some investigations that conclude that heavy metal exposure is not a risk factor for ASD. Therefore, an accurate evaluation of the relationship between ASD and heavy metals urgently needs more research.
Acknowledgments
The publication was prepared with the support of the RUDN University Program 5-100.
References (338)
- et al.
Mercury induces proliferation and reduces cell size in vascular smooth muscle cells through MAPK, oxidative stress and cyclooxygenase-2 pathways
Toxicol. Appl. Pharmacol.
(2013) - et al.
Novel cellular and molecular mechanisms of induction of immune responses by aluminum adjuvants
Trends Pharmacol. Sci.
(2009) - et al.
Interplay of glia activation and oxidative stress formation in fluoride and aluminium exposure
Pathophysiology
(2015) - et al.
Redox-active complexes formed during the interaction between glutathione and mercury and/or copper ions
J. Inorg. Biochem.
(2010) - et al.
Toxic effects of perinatal lead exposure on the brain of rats: involvement of oxidative stress and the beneficial role of antioxidants
Food Chem. Toxicol.
(2008) - et al.
Disrupted pro-and antioxidative balance as a mechanism of neurotoxicity induced by perinatal exposure to lead
Brain Res.
(2012) - et al.
Neurotoxicity of lead. Hypothetical molecular mechanisms of synaptic function disorders
Neurol. Neurochir. Pol.
(2012) - et al.
Aluminum and copper in drinking water enhance inflammatory or oxidative events specifically in the brain
J. Neuroimmunol.
(2006) Comparing the population neurodevelopmental burdens associated with children's exposures to environmental chemicals and other risk factors
Neurotoxicology
(2012)- et al.
Autism: a novel form of mercury poisoning
Med. Hypotheses
(2001)
Health impact assessment and monetary valuation of IQ loss in pre-school children due to lead exposure through locally produced food
Sci. Total. Environ.
Concerns about environmental mercury toxicity: do we forget something else?
Environ. Res.
Molecular interaction between mercury and selenium in neurotoxicity
Coord. Chem. Rev.
The toxicology of mercury: current research and emerging trends
Environ. Res.
Mercury exposure and children's health
Curr. Probl. Pediatr. Adolesc. Health Care
Mercury and selenium interaction in vivo: effects on thioredoxin reductase and glutathione peroxidase
Free Radic. Biol. Med.
Early life arsenic exposure and brain dopaminergic alterations in rats
Int. J. Dev. Neurosci.
Reversibility of changes in brain cholinergic receptors and acetylcholinesterase activity in rats following early life arsenic exposure
Int. J. Dev. Neurosci.
Methylmercury causes glial IL-6 release
Neurosci. Lett.
A century long sedimentary record of anthropogenic lead (Pb), Pb isotopes and other trace metals in Singapore
Environ. Pollut.
Arsenic trioxide mediates HAPI microglia inflammatory response and the secretion of inflammatory cytokine IL-6 via Akt/NF-κB signaling pathway
Regul. Toxicol. Pharmacol.
Chelation treatment for autism spectrum disorders: a systematic review
Res. Autism Spectr. Disord.
Autism spectrum disorder prevalence and proximity to industrial facilities releasing arsenic, lead or mercury
Sci. Total Environ.
The association between a genetic polymorphism of coproporphyrinogen oxidase, dental mercury exposure and neurobehavioral response in humans
Neurotoxicol. Teratol.
Hair mercury measurement in Egyptian autistic children
Egypt J. Med. Hum. Genet.
Effects of environmental contaminant exposure on visual brain development: a prospective electrophysiological study in school-aged children
Neurotoxicology
The pro-oxidant activity of aluminum
Free Radic. Biol. Med.
The coordination chemistry of aluminium in neurodegenerative disease
Coord. Chem. Rev.
High delivery intervention rates in nulliparous women over age 35
Eur. J. Obstet. Gynecol. Reprod. Biol.
Oxidative stress in MeHg-induced neurotoxicity
Toxicol. Appl. Pharmacol.
Metals, oxidative stress and neurodegeneration: a focus on iron, manganese and mercury
Neurochem. Int.
Mercury, lead, and zinc in baby teeth of children with autism versus controls
J. Toxicol. Environ. Health A
Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers
Biol. Trace Elem. Res.
Mercury in first-cut baby hair of children with autism versus typically-developing children
Toxicol. Environ. Chem.
Toxicological status of children with autism vs. neurotypical children and the association with autism severity
Biol. Trace Elem. Res.
A key role for an impaired detoxification mechanism in the etiology and severity of autism spectrum disorders
Behav. Brain Funct.
Heavy metals and trace elements in hair samples of autistic children in central Saudi Arabia
Neurosciences
Normal concentrations of heavy metals in autistic spectrum disorders
Minerva Pediatr.
Synergism in aluminum and mercury neurotoxicity
Integr. Food Nutr. Metab.
Levels of heavy metals and essential minerals in hair samples of children with autism in Oman: a case-control study
Biol. Trace Elem. Res.
Relationship between absolute and relative ratios of glutamate, glutamine and GABA and severity of autism spectrum disorder
Metab. Brain Dis.
Neurotensin is increased in serum of young children with autistic disorder
J. Neuroinflamm.
Acute arsenic treatment alters arachidonic acid and its associated metabolite levels in the brain of C57Bl/6 mice
Can. J. Physiol. Pharmacol.
Diagnostic and Statistical Manual of Mental Disorders
Management of lead encephalopathy with DMSA after exposure to lead-contaminated moonshine
J. Med. Toxicol.
Fetal and postnatal metal dysregulation in autism
Nat. Commun.
Metallothioneins: mercury species-specific induction and their potential role in attenuating neurotoxicity
Exp. Biol. Med. (Maywood)
Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity
Braz. J. Med. Biol. Res.
Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study
Pediatrics
Autism as a strongly genetic disorder: evidence from a British twin study
Psychol. Med.
Cited by (68)
Proteome signatures of joint toxicity to arsenic (As) and lead (Pb) in human brain organoids with optic vesicles
2024, Environmental ResearchMitophagy alleviates AIF-mediated spleen apoptosis induced by AlCl<inf>3</inf> through Parkin stabilization in mice
2023, Food and Chemical ToxicologyThe role of MAPK/NF-κB-associated microglial activation in T-2 toxin-induced mouse learning and memory impairment
2023, Food and Chemical ToxicologyA systematic literature review on the association between exposures to toxic elements and an autism spectrum disorder
2023, Science of the Total EnvironmentAdverse Prenatal Exposures and Fetal Brain Development: Insights From Advanced Fetal Magnetic Resonance Imaging
2022, Biological Psychiatry: Cognitive Neuroscience and NeuroimagingCitation Excerpt :Lead-related neuroinflammatory changes were most pronounced in the hippocampus (61). Similar immune-mediated neurotoxic effects have been suggested for mercury and arsenic (61). Prenatal exposure to heavy metals such as lead has been shown to alter fetal functional connectivity in regions that support higher-order cognitive functions and behavior regulation (62).