Introduction

Autism spectrum disorder (ASD) refers to the series of brain developmental pathologies, encompassing varying and lifelong symptoms, revolving around defiant interactive and communicative skills, poor social attitude, and repetitive restricted responses, behaviors, and interests, occurring in children of 3 or less than 3 years of age (Bjørklund et al. 2018; Kelly et al. 2020). ASD portrays typical destruction of social interaction portfolio restricted to the children leading to behavioral symptoms. The difference between the two is based upon repetition, communication, and diagnostic portfolio, where atypical autism accounts for communication and interaction disabilities, with repetitive occurrence along with inability to conform to the diagnostic criteria unlike childhood autism (WHO 1993). Childhood autism has 3 times more prevalence than atypical autism as per a Danish study (Lauritsen et al. 2004). An increase of 30% in ASD progression was reported in the past 20 years (Calabrese et al. 2016). Between 2011 and 2012, the occurrence of ASD in children of 6–17 years of age was 2% and a significant acceleration in ASD cases began from 2007 by 1.16% (Blumberg et al. 2013). The ASD comprises of three functional levels, where the first level is characterized by negligible social interactions and planning capabilities. The second level involved limited interactions revolving around a limited social space and the third level diagnosed verbal and non-verbal interaction problems. Furthermore, ASD patients have been reported to make unusual sensorimotor predictions (Ernst et al. 2019; Kinard et al. 2020). Additionally, ASD patients demonstrating difficulty in generating accuracy in predictions depict greater symptom severity (Greene et al. 2019).

There has been a tremendous increase in ASD prevalence rate, especially in countries like the USA, which are considered to harbor 1 child in 45, diagnosed with ASD (Zablotsky et al. 2015). The children with ASD develop developmental complications, ascending from mild language and speech problems to severe autistic disorders and lifelong disabilities (Green et al. 2020). There are many factors or complications that might play a role in ASD occurrence like obstetrics complications, fetal hypoxia, age of the parents, bleeding of diabetic complications during pregnancy, medicine administration during prenatal period, enhanced glutamine levels, neuroinflammation, oxidative stress, and pollutants occurring in the environment. One of the possible effects of environmental toxins is the genetic mutations caused by the metallic components of the environment, altering the genetic sequence for fetal development. According to the WHO report of 2016, environmental pollution is the major cause of deaths across the globe featuring about 12.6 million people, out of which 1.7 million are the children less than 5 years of age. Maximum environment-related mortality is associated with the Asian countries as per the WHO, because the children residing in the Asian nations are subjected to diverse ethnic, geographical, cultural, socio-developmental, and cultural surroundings that poses a challenge for the researchers to study the associations between environmental toxins and novel emerging threats, to control the health hazards. Many researchers exhibit birth cohort studies to examine the health aspects of the children such as the Japan Environment and Children’s Study (JECS), Korean Children’s Environmental Health Study (KoCHENS), and the China National Birth Cohort (CNBC) (Tsai et al. 2019). In order to prevent the effects of environmental hazards on living beings, which occur as a result of genetic alterations with the geographical and tribal variations, there is a dire need of cooperation among the nations to facilitate cohort studies effectively, promoting development of successful prevention strategies. Such collaborative studies, carried out at a global level, synergistically provide a mechanistic approach to retard the role of environmental pollutants in negatively affecting the health of individuals. Many substances like POPs, polychlorinated biphenyls, mercury, perfluoroalkyl substances, organochlorine pesticides, phthalates, and environmental tobacco smoke are responsible for triggering the release of cytotoxic substances, immune reactions, and neuroinflammation rendering harmful effects of the brain developmental processes of the individuals (Brockmeyer and D’Angiulli 2016). Presence of harmful pollutants in the environment is responsible for one-third premature deaths globally (Mannucci and Franchini 2017), and such pollutants are designated as “new tobacco” by the WHO (Tsai et al. 2019). Heavy metals like cadmium (Cd), mercury (Hg), arsenic (As), and lead (Pb) have exerted neurotoxic effects on children, rendering disturbed psychomotor, learning, cognitive, and intellectual abilities.

Although the exact cause of this disease is still unknown, yet, there has been an evident link between environmental components and ASD prevalence, primarily involving metals like mercury (Hg), lead (Pb), and aluminum (Al) that may penetrate the brain barriers and facilitate oxidative stress-like situations that significantly lead to ASD progression. The neuro-metabolic alterations are significantly associated with ASD patients causing variations in cerebrospinal fluid (CSF). The active blood brain barrier is present, distinguishing blood form CSF, yet the two fluids are intimately related. ASD is associated with multiple risks and pathologies in children, which interfere with the neurodevelopmental progression of the child, initiating conditions like depression, auditory and other sensory disturbances, attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), obsessive compulsive disorder (OCD), anxiety and stress, Tourette’s syndrome, discrepancies in learning, and coordination problems (Skalny et al. 2016). The environmental effects on ASD progression, specifically metals like mercury, lead, and aluminum, are of critical consideration in the present times. All these components are present in the environment, either released by the industries or automobiles, as well as in day to day devices, objects, and equipment that we use, therefore, have become a primary focus in ASD studies. The possible sources of exposure of primary toxic metals are necessary to understand in order to facilitate effective prevention. The primary sources of toxic metallic components include household utensils, wrapping foils, alloys, fuels, paints, ammunitions, batteries, and medicinal substances like antacids, contraceptives, cosmetics, vaccines, astringents, antiseptives, and fungicides. Exposure to metallic components in the environment might cause mutations or imbalance in intracellular metallic concentrations, which might lead to significant degeneration of brain tissue. The human brain is susceptible to all these adverse effects, only during the early developmental and embryonic phases (especially during first 3 months of pregnancy) (Grandjean and Landrigan 2006). Many patients with ASD are diagnosed with genetic alterations as a result of gene interactions with such environmental toxins. Such susceptibilities can either be inherited or induced (Bjørklund et al. 2018).

Role of metallic pollutants in the environment in brain and ASD progression

The metallic impurities present in the environment play a significant role in altering the basic neuronal pathways and degenerating the neural processes. Stimulation of inflammatory mediators and vascular endothelial growth factors, microglial activation, oxidative stress, abnormal astrogliogenesis, glutathione upregulation, cell organelle dysfunction, and autoimmune responses are the primary mechanisms evidently signifying the effect of metallic components on neuronal development (Bjørklund et al. 2018). There are many factors that can possibly generate harmful effects on the brain tissue, such as genetic and environment factors (Fig. 1). Both the factors synergize to exert a harmful effect on the human brain at a young age. In many cases, the environmental factors might activate and aggravate the genetic mutations responsible for the neuronal alterations.

Fig. 1
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Factors contributing towards neurodegeneration

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The mitochondria are the powerhouse of the cell which fulfills the energy requirements of the cell. Mitochondrial dysfunction might cause neuronal damage. Similarly defects in protein aggregation and degradation mechanisms can accelerate the neurodegeneration processes. Free radical production in the body is responsible for maximum diseases and complications due to the induction of oxidative stress. Release of inflammatory mediators and microglial activation can also result in harmful effects on the biotic brain. All these effects can either be due to genetic mutations or alterations in the genetic sequences, or due to environmental pollutants, that exert effects either independently or by induction of genetic mutations. Various studies have been carried out to determine the role of metallic components in ASD and the alterations in the neuronal processes. Some of them have been discussed in Table 1.

Table 1 Studies related to the effects of metals on ASD progression
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Many metals have been associated with ASD; therefore, it is extremely important to study their percentage occurrence in the environment. The primary metals that play a significant role in ASD occurrence are aluminum, lead, and mercury as discussed in this review. Figure 2 below depicts the percentage contribution of metals to total health index, where arsenic and mercury are prime contributors (Gebeyehu and Bayissa 2020).

Fig. 2
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Contribution of metals to total health index

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Aluminum

The Earth’s crust is a home to many metallic components with aluminum as the third most abundant one. From rocks of cryolite, bauxite, and silicates (Tomljenovic et al. 2014), to our households in cooking equipment, cans, boats, foil, airplanes, cars, electrical devices, packaging and building materials, alloys, fuel additives, explosives, additives, antacids, propellants, astringents, and anti-perspirants, it plays an essential role (Bjørklund et al. 2018). Moreover, aluminum is a metal full of superiorities that possesses many distinguishing characteristics. Even, the vaccine adjuvants comprise of hydroxylated aluminum salts (Tomljenovic et al. 2014). But, despite its presence, the metal forms salts, which are slightly soluble and have toxic effects on the biotic beings of the environment, including the microflora, marine life, plants, animals, and humans. Aluminum is the most durable, light metal that has the ability to oxidize very easily (Bjørklund et al. 2018). It is a strong metal, highly resistant to corrosion. It is highly reactive and can form compounds like aluminum lactate and aluminum citrate, which have potent roles in ASD progression. Aluminum lactate is associated with enhanced TNF-α and IL-1-α levels in the brain, causing apoptotic signaling (Lukiw et al. 2005). Aluminum citrate exerts toxic effects on glial cells of hippocampal cultures (Platt et al. 2007).

Numerous studies have depicted the role of aluminum (in elemental or salt form) in ASD prevalence, when taken via oral route or as an adjuvant. Increased brain levels of aluminum were reported in ASD patients (Mold et al. 2018). Aluminum, in combination with fluorine, synergizes to produce critical health effects such as improvement of behavioral and mental conditions in patients with ASD (Sealey et al. 2016). Exposure to vaccine-derived aluminum generated great risks of developing ASD symptom (Shaw and Tomljenovic 2013).

What does aluminum do when it enters our body?

The sarcoplasmic glycolytic enzymes are affected by the presence of aluminum in the body which leads to a halt in the glycolysis process (Bjørklund et al. 2018). Glycolytic enzymes convert glucose-6-phosphate and nicotinamide adenine dinucleotides to pyruvate and NADH by producing two ATP molecules. Upon entry of aluminum in the system, the glycolysis enzyme action is affected, causing glycolysis suppression, thereby causing reduction in energy production mechanisms.

An Egyptian study revealed the presence of aluminum in the hair of the affected children unlike normal children, but the blood aluminum levels were almost similar to the normal subjects (Mohamed et al. 2015). The presence of aluminum was also detected in the hair (Adams et al. 2006). A higher aluminum content was diagnosed in the urine of patients (Adams et al. 2006), unlike their neurotypical siblings, whereas increased levels of aluminum in blood were diagnosed in ASD patients (Rahbar et al. 2016). Therefore, a childhood autism rating scale (CARS) assessed-study deposited a report elaborating the relationship between aluminum content and ASD progression (Metwally et al. 2015). All the studies for aluminum were conducted at different parameters and the positive studies corresponding to the levels of aluminum in different areas are depicted in Table 2.

Table 2 The study parameters of aluminum as reported by various studies for its role in ASD
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Another effect of this toxic metal on neurodevelopmental progress is reactive gliosis induced by aluminum that enhances the GFAP levels and abbreviates the level of anti-oxidant enzymes leading to increased levels of TNF-α and IL-1β, iNOS, and calcium binding adapter molecule 1 (Prakash et al. 2013). Moreover, all these responses induced oxidative stress that led to altered functioning of the powerhouse of the cell, i.e., mitochondria, producing homeostasis imbalance in the brain (Kumar and Gill 2014). Neurogenesis and neurodevelopment might be affected by microglial cells, promoting neuronal proliferation, that might aggravate ASD symptoms (Edmonson et al. 2016). Curcumin and mangiferin had protective actions in such cases (Sood et al. 2012). Not only the elemental form but also the compound form of aluminum (aluminum lactate, aluminum citrate) aggravates the ASD conditions. Moreover, the association of Al3+ ions with oxygen-based ligands or with superoxide anions may be responsible for neurotoxic outcomes (Exley 2012). Cations like Mg 2+ and Ca2+, in association with Al3+, induce neurotoxic and excitotoxic effects (Exley and House 2011).

Mercury

Mercury is a universal environmental pollutant that can be obtained from sea food as well as dental amalgams (Dadar et al. 2014; Bjørklund et al. 2017d). Therefore, not only children but even the adults and the elderly should be cautious against mercury effects. It occupies the position among the top 10 pollutants in the WHO list with a threefold increase in industrial emissions of mercury, and acceleration of atmospheric Hg levels by 1.5% on annual basis (Rice et al. 2014). With every kg of mercury emitted into the environment, an economic loss of 22,937–52,129 Euros is suffered (Nedellec and Rabl 2016). A few studies have indicated the occurrence of ASD in the grandchildren of patients with acrodynia (Shandley and Austin 2011). Therefore, mercuric effects can be long term as an outcome of genetic levels in patients. All the possible effects of mercury can contribute to ASD symptoms. Among several studies carried out between 1999 and 2016, 74% of them revealed an essential link between ASD progression and mercury levels (Kern et al. 2016). Some studies revealed reports of increased mercury levels in teeth of ASD patients and demonstrated that enhanced mercury levels in the body might be due to reduced rate mercury excretion by excessive administration of oral antibiotics (Adams and Romdalvik 2007). An Egyptian study revealed greater mercury levels in the hair and blood samples of ASD patients (Yassa 2014). Another study reported greater mercury levels in blood of pregnant women in late pregnancy and children aged less than 5 years of age, which were found to exhibit autistic symptoms (Ryu et al. 2017). Not only blood and teeth but also endocrine glands and sex hormones, if associated with increased mercury levels, may deteriorate the child developmental procedures, causing ASD-like symptoms (Ryu et al. 2017).

Action of mercury in the brain

Abbreviated levels of glutathione in the body promote mercury retention and deteriorated detoxification processes pave way for mercury toxicity (Jafari et al. 2017). Another pathway of mercury toxicity was revealed by studies depicting exposure of mercury from thimerosal (preservative used in vaccines), leading to atypical autistic symptoms (Geier et al. 2017). Selenium was found to exert protective actions against mercury-induced toxicity (El-Ansary et al. 2017). A study revealed increased concentration of mercury in the urine samples of ASD children unlike normal subjects (Bradstreet et al. 2003). Another risk accounts for mercury placental transfer to the fetus in pregnant mothers with amalgam dental fillings (Bose-O’Reilly et al. 2010). Mercury transfer via breast milk is limited as the fetal digestive system develops metallothioneins to sequester mercury from breast milk (Aschner et al. 2006).

Mercury toxicity indicators, porphyrins, were significantly evaluated in an Egyptian study and enhanced levels of toxic metals like mercury were revealed in ASD patients. Porphyrins like coproporphyrin and precoproporphyrin are relevant biomarkers for mercury toxicity that might be due to excessive exposure to mercury or retarded excretion of the metal from the body, leading to neurological, motor, and sensory differences (Lewis et al. 1992). Neurodevelopmental and cognitive problems were observed in certain studies that highlighted the presence of toxic metals like mercury in amniotic fluid in the fourth and fifth months of pregnancy (Lewis et al. 1992). The study parameters of mercury and the positive results are depicted in Table 3.

Table 3 The study parameters of mercury as reported by various studies for its role in ASD
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Mercury might exert destructive effects on cellular organelles. Hg mediated modulation of cytokine production (IL-6, TNF-α), which may have an adverse impact on ASD patients leading to autoimmune brain response (Curtis 2011), IgG accumulation in brain, and CD4+T cell infiltration (Zhang et al. 2010). Other than this, VEGF activation and IL-6 release from mast cell are also a part of mercury interference protocol which promotes destruction of blood brain barrier (Kempuraj et al. 2010). Another site of mercury toxicity is microglial stimulation-mediated neurotoxicity (Bjørklund et al. 2017d). Mercury toxicity profile resembles that of aluminum in case of oxidative stress induction (Farina et al. 2011). Mercury targets the selenoproteins significantly, on account of their affinity for selenol groups (Farina et al. 2011). Along with glutamate excitotoxicity, oxidative stress primarily leads to cytoskeletal changes as a result of Hg exposure.

Lead

One of the major toxic metals that have adverse effects in nature is lead. The increase in lead levels has been prevalent since 1990s, when lead concentration in soil was increased from 2 to 55 mg/kg (Chen 2016). From 1990 to 2009, lead emissions were approximately 200,000 tons in China (Li et al. 2012). The metal is characterized with many uses in daily life like in ammunitions, car batteries, paints, tin toys, and in automobile and aircraft fuels as anti-knock agents (Bjørklund et al. 2018). Lead obtained from various sources like paints, fuels, batteries, and lead-contaminated water can prove to be disastrous for human consumption (Bellinger 2012). On the Wechsler scale, a loss of 29 million IQ points, on lead exposure, revealed its adverse effects on children (Bellinger 2012). In the USA, lead paints were banned in 1978, and lead present in gasoline and some devices is of critical concern in many areas of globe like Sweden, which is susceptible to periodic surveys in this case (Strömberg et al. 1995). In response to the clean air act, the USA banned the use of leaded gasoline for automobiles in 1996 on account of its role in soil contamination and damage to biotic beings, but as an anti-knock agent, it is still being used (Bjørklund et al. 2018).

Moreover, lead-contaminated water (due to its interaction with lead pipes) alone and when used for processing food and beverages poses a hazardous threat to neurodevelopmental processes in children. Lead synergized with mercury and arsenic lead to neurodevelopmental problems as observed in ASD (Dickerson et al. 2015). The disastrous effect of lead was revealed when a study demonstrated the occurrence of autistic symptoms in children of 8 years of age, even at low concentrations (Kim et al. 2016). Egyptian studies revealed lead levels in blood samples unlike neurotypical children (Khaled et al. 2016). The percentage increase in the levels of blood lead corresponding to different exposure sources is depicted in the Fig. 3 (Lanphear et al. 2002).

Fig. 3
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Percentage increase in blood lead levels with different types of lead contaminations

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Some researchers have depicted a successful study associating the urban emissions of toxic metals and ASD prevalence in such areas, generating a potent evidence for role of lead in ASD progression. Moreover, the blood samples of ASD patients were found to possess increased levels of lead and mercury, with retarded anti-oxidant levels, like glutathione and vitamin E, in some studies (Alabdali et al. 2014). Lead levels were observed in hair and nail samples of ASD patients, as per the data generated in a few studies (Priya and Geetha 2011). An auto-immunity and neuroinflammation stimulatory effect was observed in further studies, due to presence of lead in the system, with certain studies revealing serum anti-ribosomal P antibodies production, as a result of increased lead content (Mostafa et al. 2016b). Different study parameters of lead with the positive results are discussed in Table 4.

Table 4 The study parameters of lead as reported by various studies for its role in ASD
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Many studies conducted in this behalf observed a variation in the level of lead in ASD patients. What could possibly be the reason?

  • Variable geographical exposure to lead

  • Air pollution

  • Socio-demographic differences

  • Lead-contained paints and old houses

  • Lead-contaminated water consumption

  • Leaded gasoline

  • Industrial exposures

Along with being a neuroinflammatory mediator, lead regulates the concentrations of IL-6, IL-18, and TNF-α in specified brain areas, specifically in the cerebral cortex and hippocampus, promoting learning and memory problems. Lead is also associated with upregulation of VEGF, leading to brain toxicity and neuroinflammation (Kasten Jolly et al. 2011). Similar to mercury and aluminum, lead is also associated with microglial activation, which regulates pro-inflammatory cytokine production, causing destruction to the signaling pathways in the brain and promoting autistic behavior (Strużyńska et al. 2006). Astrogliosis was found to be induced by exposure to lead in a study involving young mice (Bjørklund et al. 2018). Oxidative stress is another factor that potentiates neurotoxicity by lead, that is, initiated by SOD (superoxide dismutase) decrease along with retarded actions of glutathione peroxidase and disulfide reductase enzymes, causing damage to the blood brain barrier, thus leaving the brain viable to the destructive effects of toxic metals (Baranowska-Bosiacka et al. 2012). In some studies, the creatine and pyruvate kinase inhibiting effects of lead have been considered to produce neurotoxicity on account of damaged energy homeostasis in the brain (Lepper et al. 2010). Lead-based alterations in lipid profiles of the body were other possible pathways of lead toxicity (Jung et al. 2017). Some studies concluded the role of N-methyl-D-aspartate receptor (target template for lead toxic effects), in promoting BDNF (brain-derived neurotropic factor) inhibition by lead, altering synaptic formation and function, during the developmental stage, leading to neuronal impairment (Neal et al. 2010).

Arsenic

Exposure to arsenic containing compounds poses a significant threat to the biological system in humans (Rosen and Liu 2009). One of the most common sources of arsenic poisoning is the As-contaminated groundwater (Bjørklund et al. 2017e). The excessive presence of As in drinking water, exceeding the limit recommended by the WHO, has exposed about 140 million people to arsenic poisoning. Most people with arsenic poisoning are found in countries like Bangladesh, India, and Argentina (Rahman et al. 2016). However, arsenic is present in the Earth’s crust (in small amounts) and in minerals. It also occurs in the form of salts and organometallic compounds. The industrial production of arsenic is the major source of arsenic poisoning with arsine (H3As) as the most toxic reagent used in the industries. About 4.53 million tons of As was estimated to be produced in 2000 (Han et al. 2003). Furthermore, exposure to As via drinking water is another important consideration in management of As poisoning, with more than 200 million people exposed to As through drinking water across the globe (Kabay et al. 2010). About $3742 is the total cost of 1 kg of As emissions, out of which 20% is related to psychiatric problems and loss of intelligence, therefore, targeting brain as the most affected area of arsenic poisoning (Nedellec and Rabl 2016).

Exposure induces neurodegeneration events and gliosis, deteriorating the morphology of the brain and BBB disruption (Selim et al. 2012). The arsenic compounds are capable of activating JNK and p38 signaling pathway, resulting in apoptosis in the brain (Namgung and Xia 2001), followed by glutathione depression and lipid peroxidation, contributing to the increased oxidative stress in the brain (Yen et al. 2011). The oxidative stress was shown to mediate neurotoxic effects in the brain (Liu et al. 2013). It was reported that As exposure to mice resulted in elevated levels of Bax and Bak, along with retarded Mcl-1 levels in the cerebral cortex of mice. Disabled neurite growth occurs due to As exposure, on account of its ability to suppress activation of AMPK kinase (Wang et al. 2010). Increased level of pro-inflammatory cytokines in astrocytes is produced by exposure to monomethylarsonous acid (Escudero-Lourdes et al. 2016). Arsenic-mediated inflammatory and neuronal damage occurs, due to alterations in arachidonic acid (Anwar-Mohamed et al. 2014). Arsenic exposure in mice led to enhanced expression of glial fibrillation acidic protein, resulting in cognitive defects and impaired learning abilities (Jiang and Sun 2011). It has also been reported that, due to enhanced expression of GRP94, GRP78, and CHOP, As-exposure is capable of mediating endoplasmic stress (Yen et al. 2011). Mitochondria have been observed as the major target of As-mediated toxicity, resulting in apoptotic death in microglial cells (Prakash et al. 2016; Kharroubi et al. 2017). Neurotransmitter metabolism is also altered by As, resulting in neuronal damage due to disruption of release of glutamate-induced glio-transmitter (Wang et al. 2012). Glutamate transport is also affected due to alterations in EAAT1/GLAST activity in glial cells (Castro-Coronel et al. 2011). Moreover, As also mediates neurotoxicity in dopaminergic signaling in the brain (Shavali and Sens 2007). As-mediated cholinergic alterations lead to impaired memory and learning capabilities in rats (Chandravanshi et al. 2014). Epigenetic modification is another mechanism through which As toxicity prevails, which induces his tone modifications in the CNS (Bjørklund et al. 2017e).

Numerous studies have reported the harmful effects of arsenic in children (Lonsdale et al. 2011; Skalny et al. 2017). Obrenovich et al. (2011), in his study conducted on 39 neurotypical children and 26 children with ASD, reported that the As concentration in ASD patients was higher than in neurotypical patients. Similar study was conducted in ASD patients from Saudi, where enhanced levels of As was found in the patients unlike normal ones (Al-Ayadhi 2005). High levels of As were found in hair samples of ASD patients in a study, but there was no significant difference in the concentration of As levels in the urine of ASD and neurotypical children (Blaurock-Busch et al. 2011). Table 5 summarizes the effects and action mechanism of aluminum, lead, mercury, and arsenic, as discussed in the review.

Table 5 Summary of metal, their toxic effects, role and mechanism in ASD progression
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Reducing the metallic toxicity effects

One of the major control parameters of reducing the toxic effects of metals is definitely the reduction of exposure to metallic components and diminishing the possible effects of such exposures. Potentiating the natural detoxification mechanisms might develop appreciable defense against metal toxicity. Use of chelating agents like EDTA, which successfully combines with the metals and promotes their excretion out of the body, can also serve to lower the metal effects (Bjørklund et al. 2017c). Moreover, dietary supplements have proved to be quite beneficial and significant in reducing the effects of metals on the biological systems. Supplements containing zinc and selenium can significantly curb the effects of metallic toxins by promoting GSH upregulation (Rahman et al. 2017). Similarly, vitamin C, methionine, and tocopherol supplementations lower the lead induces oxidative stress in primary areas of the body (Patra et al. 2001).

Conclusion

The alarming increase in incidence of autism spectrum disorder among children has encouraged various researchers to study the possibilities behind the cause of this condition in order to curb the progression of behavioral differences. Most of the times, we focus on physiological, biological, mental, and social causes, but it is very rare that we consider the role of environment in which we breathe, to be responsible. The environment we live in comprises of a number of components, metallic, non-metallic, microbial, and so on that might induce certain biological alterations in the human body and makes it susceptible to various diseases. The metallic toxins like aluminum, cadmium, arsenic, lead, mercury, manganese, and iron are responsible in some or another for such biological alterations. Over the last few years, many studies have revealed the relationship between ASD and toxic metals, due to which is necessary to study the effects and occurrences of such metals. The mechanisms involved in the toxic metals mediated neurotoxicity primarily involve oxidative stress induction, microglial activation, metalloprotein disruption, endoplasmic reticulum stress, autoimmune stimulation, and glycolysis suppression, which curb the neurodevelopmental processes and accelerate the neurodegeneration pathway, aiding neurotoxic and excitotoxic effects, apoptosis, and neuroinflammation. Various studies have evidently depicted the comparison between ASD patients and neurotypical subjects, by using biomarkers, to provide metallic occurrence in urine, erythrocyte, hair, and teeth.

Moreover, parallel to the effect of metallic toxins on biological systems, the treatment strategies form another protocol that needs to be focused upon, involving use of chelating agents, dietary corrections, glutamate antagonists, anti-inflammatory, and antioxidant therapies, enhancing the detoxification ability of the primarily by glutathione enhancement, and ameliorating antibiotics usage during pregnancy, as well as administering protective agents like curcumin, magniferin, selenium, and chelating agents. With the accelerated risks of ASD in the modern world of industrial and technological advancement, it is tremendously necessary to consider the metallic components in the environment critically, and take necessary actions to curb the risks of neurodevelopmental disruptions in the children, in order to promote safe and effective environment for the growing generation of the modern world.

Future perspectives

There is a dire need to understand the effects of environmental pollutants on brain development and their tendency to aggravate ASD symptoms. Currently, there is not enough focus on the environmental metals and their effects on ASD patients. The link between metallic pollutants and brain disorders is faded in the minds of the people globally. Thus, there should be a proper awareness among the people regarding the harm such pollutants can cause in the neuro-developmental processes in children. Such gaps in knowledge should be filled and significant precautionary approaches can be made by developing certain models and undergoing research studies to understand various etiological variations and possible causes of ASD progression, evaluating neurobehavioral responses in different environmental mediums, investigating the effect of environmental pollutants and their exposure in pregnant mothers, lactating mothers, infants, and early childhood and analysis of neurotoxic metals in the environment affecting the brain developmental pathways in children. Other than the three major metals discussed in the review, there are many other metallic components responsible for aggravation of ASD symptoms, especially during early years of life, when the human body is highly susceptible to environmental toxins. Therefore, in order to facilitate proper growth and developmental processes, primary focus is required towards the neurotoxins in the environment, and effective measures should be taken to retard the growing risks of ASD in children due to the harmful pollutants in the environment.