According to WHO, the fraction of autistic children in the population is increasing. Today, 1 in 160 children is diagnosed for ASD. The incidence of ASD has increased significantly in the last 10 years. This is believed to be related with environmental pollution which, is a consequence of urbanization and industrialization [38].
Research on the status of trace elements and their relationship to ASD is carried out using various exposure biomarkers: hair mineral analysis, blood, urine and teeth compartments. Autism is also considered as one of the forms of Hg poisoning. Some micronutrients, such as Cu, may contribute to the development of ASD. In turn, Zn plays a protective role against neurodevelopmental problems, as it participates in detoxification and antioxidation, with the participation of e.g. metallothioneins [31].
3.1 Toxic elements and ASD
Due to the increasing number of autism cases, environmental factors (exposure to toxic substances) are believed to contribute to the pathogenesis of ASD (Table 4). Children are more likely to be exposed to environmental toxins as they have a higher absorption rate and a lower detoxification capacity than adults. Hg is believed to contribute in the highest extent to the ASD pathogenesis due to its neurotoxicity. Thiomersal (an organic compound of mercury) present in vaccines as a preservative, e.g. in Measles-Mumps-Rubella, also used as an antiseptic and antifungal agent, has long been thought to have contributed to a large fraction of autism cases. The problems with the metabolism of toxic elements in autistic children are believed to be related to oxidative stress, reduced potential for methylation and trans-sulfuration, as well as mitochondrial dysfunction. In addition, children with autism have higher levels of porphyrins in their urine, which is related to the mercury load in the body [39].
An interesting interpretation is the link between ASD and biomarkers using metallomics (biometal studies) in combination with genomics and proteomics. Meta-analysis study showed a relationship between ASD and Cu, Fe, Zn. The results of studies on patients with ASD showed higher levels of Cu that was related with oxidative damage, Fe deficiency causing anemia, behavioral and emotional problems, lower Zn content, which is associated with autoimmune infection, hyperactivity and mental retardation. Studies have shown that too high Cu administration causes Zn deficiency and is associated with synaptic dysfunction. The optimal Zn/Cu value was suggested at the level of 0.66–0.81 [40].
Scientific literature emphasizes the important role played by glutathione in ASD pathogenesis, as it is significant in maintaining the redox balance within cells. In ASD low levels of reduced glutathione and elevated levels of oxidized glutathione are observed. This results in the malfunction of glutathione-related enzymes in the blood and brain. Exposure to toxic metals is reported to inhibit synthesis and increase glutathione excretion. Low levels of reduced glutathione cause oxidative stress, which is an important factor in inflammation of the nervous system. In turn, the effect of low levels of reduced glutathione causes lower capability to eliminate toxic metals from the body, the consequence of which can be ASD [18].
The etiology of pathophysiology leading to autism is usually difficult to be identified unequivocally. The genetic and environmental factors were indicated. For example, the effects of a low level of iodine and lithium in hair of mother of the child and, consequently, the child were identified. There was a correlation between the severity of autism and the content of toxic elements such as Pb or Hg in hair [41].
The toxic metals contributing to the aetiology of ASD include: mercury (Hg), lead (Pb), aluminum (Al) and the metalloid arsenic (As). The pathogenetic mechanism of ASD is still not fully understood. Nerve inflammation in various areas of the brain, increased cytokine inflammatory profile, abnormal expression of the kappa B factor, are indicated. Due to the increasing level of environmental pollution, the impact of exposure to toxic metals on the appearance of neurodevelopmental disorders is of particular importance [42].
Fiore et al. showed that there is a statistically significant and positive relationship between the content of Pb, Al, As, Cd in hair and the severity of ASD symptoms, including repetitive and restricted behavior, communication deficits. The content of Pb, Mo and Mn in the hair was antagonistic with respect to the cognitive level measured as an IQ. In turn, low zinc content was associated with the severity of ASD symptoms [43].
Table 4
Toxic metals, their chemical forms and the mechanism contributing to ASD
Metal
|
Chemical form
|
Mechanism of ASD contribution
|
Hg
|
|
higher level of antineuronal antibodies; neurological, motor, immune and sensory dysfunctions [44]; Exposure to Hg can also be caused by contamination of fish with methylmercury or a fungicide (the same compound), commonly used as a grain preservative in bread [37]. Children with ASD have higher levels of Hg in the primary teeth and blood. Hg causes metallothionein dysfunction. This is one of the consequences of the Zn deficit [30].
|
|
Mercury ions (Hg2+)
|
are nephrotoxic and damage muscle tissue [5]
|
|
Methylmercury (CH3Hg+)
|
is the most toxic form, capable of crossing the blood-brain barrier. Due to its lipophilic nature, it binds to neurons and is therefore highly neurotoxic. The main source of methylmercury for humans are fish, bacteria and algae, which lead to the biotransformation of elemental Hg to methylmercury [5].
|
As
|
|
alters brain morphology, depression of Mcl-1 in the cerebral cortex; causes degeneration of gliosis, up-regulation of Bax and Bak expression; contributes to impaired neurite growth through suppression of AMPK kinase activation; inhibits Wnt/β-catenin signalling pathway.
|
Pb
|
|
causes neuroinflammation and autoimmunity. Stimulates the synthesis of the anti-ribosomal P antibodies serum. Another theory of the pathogenesis of autism is exposure to Pb derived from leaded gasoline, which was commonly used in the past [37].
|
Al
|
|
interacts with many glycolytic enzymes; inhibits the synthesis of cellular energy; intensifies the neurotoxic effect; Al3+ ion by oxygen-based ligands; activation of microglia that produce IL-6, TNF-α, iNOS, NOS-2, neuroinflammatory PICs and ROS.
|
U
|
|
another toxicant that may contribute to autism is uranium from coal combustion and phosphate fertilizers. There was a higher level of uranium determined in the hair of autistic children (non-radioactive isotope) compared to controls [37].
|
Microelements and ASD
Many studies show unequivocally that nutritional deficiencies may contribute to the pathogenesis of ASD (Table 5). The relationship between ASD and Fe deficiency has been pointed out. ASD and iron deficiency have been found to coexist in patients [45].
In recent years, many studies have been published comparing the content of trace elements in hair (Cu, Zn, Mg, Se). Criteria that were analyzed include age and gender, and the control group of healthy children. In the event of an increased level of toxic elements, it is possible to implement a detoxification program, e.g. with chelators (such as EDTA), to detoxify the organism from toxic metals [41].
There is a theory that excitatory and inhibitory synaptic dysfunction is the cause of ASD, and trace elements are involved [46].
Table 5
Microelements, their chemical forms and the ASD protectory role.
Metal
|
Chemical form
|
Mechanism of ASD contribution
|
Zn
|
|
Zinc is required for scaffolding of ProSAP/Shank proteins, which are associated with excitatory synapses. Too much zinc causes epileptogenesis, and too low doses - depression and ASD. Abnormal zinc levels are indisputably associated with brain malfunctions. Too high doses of copper are antagonistic to zinc and result in dysfunction of the synapses [46]. Zn is located at the active site of 300 enzymes [30].
|
Mg
|
|
Important factor in ASD is also the synthesis of the key neurotransmitter gamma-aminobutyric acid (GABA). The activity of GABA is regulated by magnesium ions [46].
|
Fe
|
|
Iron is a very important element involved in the proper functioning of the brain through gene expression and myelination. Iron homeostasis is impaired in neurodegenerative diseases. Fe deficiency causes depression and anxiety, social and emotional behavior, and thus contributes to ASD [46].
|
Zn/Cu
|
|
It was shown that in children with ASD, the Zn/Cu ratio and Zn content was significantly lower than in healthy children. The ratio of Zn to Cu plays a role in ASD [30].
|
Other elements
|
|
In the case of the content of Cr, I, Se in hair, no association with ASD was demonstrated [30].
|
In a study on 40 autistic and healthy boys, the content of Sb, As, U, Be, Hg, Cd, Al, Be and Pb was found. It has been proven that the hair of children with autism had significantly higher levels of Pb, Hg and U. The ratio between the content of nutritional and toxic elements did not differ between autistic and healthy children [37].
Studies on 52 boys in the group with ASD and 52 in the control group showed that the content of Co, Mg, Mn and V in the hair of ASD patients was significantly lower. Factor analysis showed that ASD was associated with a reduction of the levels of Co, Fe, Mg, Mn and V in the hair. The Zn content was 20% lower. The authors of the study conducted a factor analysis which showed that ASD was associated with a different level in the hair of many elements. On the other hand, regression models showed that the content of Zn and Mg in hair was negatively correlated with the intensity of neurodevelopmental disorders. Moreover, the authors observed a relationship between the content of the same elements in hair in the case of ASD and ADHD. Therefore, it has been hypothesized that supplementation with Mg Mn and Zn in children with ASD and ADHD should be helpful, however it is necessary to conduct clinical trials in the future to confirm it [47].
Skalny et al. performed a study of the elemental composition of hair in 74 children with ASD in relation to 74 children from the control group. These children were divided into groups of the same sex and age (2–4 years and 5–9 years). Children diagnosed with ASD had lower Cr, I and V content in their hair. However, the Se content was higher. Children with ASD had lower levels of Be and Sn, As, B and Be. In this study, no statistically significant differences in the levels of Hg, Zn and Cu in the hair were found. Overall, the authors of this study concluded that children with ASD had a lower content of all elements in their hair, both essential and toxic [32].
The content of elements in the hair of 99 children with ASD was determined. The greatest differences in the levels of elements were found in the younger group of children with ASD than in the group of older ASD patients. This study showed a reduced level of Cu, As, Be, Cd and I and a higher level of Al, Fe and Se as compared with healthy children [31].
In the analysis of hair composition in 52 boys, it was found that in children with ASD, the content of the following elements was significantly lower: Co, Fe, Mg, Mn, and V. The regression method showed that the Zn and Mg content in the hair was negatively related with intensification of neurodevelopmental disorders [48].
Tinkov et al. investigated the relationship between the content of elements in the hair and the concentration in blood serum in boys suffering from ASD with catatonia (N = 30) and without (N = 30). It was found that the content of Ca and Se in hair and blood serum in patients with ASD was lower. On the other hand, the Hg content in the hair was 3 times higher in children with ASD and catatonia, and 2 times higher in children without catatonia. The level of I was the lowest for ASD and catatonia, and Mn was the highest in this group. In turn, the serum levels of Al and Cd were lower, and the concentrations of Cr, Cu and V - higher in patients with ASD than in the control. Multiple regression analysis showed that Hg content in hair and serum Al and Cd were associated with ASD [49].
Yasuda and Tsutsui [50] carried out study on the determination of 26 trace elements on the scalp hair of 1967 children. The epigenetic role of mineral disorders in children in the pathogenesis of autism was investigated. It was found that children with ASD were deficient in Zn and Mg. Increased levels of Al, Cd, Pb, Hg and As have also been demonstrated in children with ASD compared to healthy children. In another study [51], results were presented for the content of other elements. In ASD patients deficiency of Zn, Mg, Ca and increased content of Al, Cd, Pb, Hg, As were found. It has been shown that Zn and Mg deficiency in infants or excessive exposure to toxic elements can cause epigenetic changes in genes that are responsible for the genetic regulation of neurodevelopment in children with ASD. The same authors have shown in another study that zinc deficiency can epigenetically cause the pathogenesis of autism. The role of the nutritional approach in preventing and treating ASD was highlighted [33]. The role of the so-called "infantile window" as critical in the neurological development of ASD was underlined. It has been concluded that metallomic screening in early childhood development can be an important diagnostic and therapeutic tool in the prevention of ASD [50].