According to the United States Centers for Disease Control and Prevention (CDC), as of July 11, 2016, the reported average incidence of children diagnosed with an autism spectrum disorder (ASD) was 1 in 68 (1.46%) among 8-year-old children born in 2004 and living within the 11 monitoring sites' surveillance areas in the United States of America (USA) in 2012. ASD is a multifaceted neurodevelopmental disorder that is also considered a hidden disability, as, for the most part; there are no apparent morphological differences between children with ASD and typically developing children. ASD is diagnosed based upon a triad of features including impairment in socialization, impairment in language, and repetitive and stereotypic behaviors. The increasing incidence of ASD in the pediatric population and the lack of successful curative therapies make ASD one of the most challenging disorders for medicine. ASD neurobiology is thought to be associated with oxidative stress, as shown by increased levels of reactive oxygen species and increased lipid peroxidation, as well as an increase in other indicators of oxidative stress. Children with ASD diagnosis are considered more vulnerable to oxidative stress because of their imbalance in intracellular and extracellular glutathione levels and decreased glutathione reserve capacity. Several studies have suggested that the redox imbalance and oxidative stress are integral parts of ASD pathophysiology. As such, early assessment and treatment of antioxidant status may result in a better prognosis as it could decrease the oxidative stress in the brain before it can induce more irreversible brain damage. In this review, many aspects of the role of oxidative stress in ASD are discussed, taking into account that the process of oxidative stress may be a target for therapeutic interventions.

Oxidative Stress in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder with a complex pathogenesis. Many studies over the last four decades have recognized altered immune responses among individuals diagnosed with ASD. The purpose of this critical and comprehensive review is to examine the hypothesis that immune dysfunction is present more frequently, and it is related to ASD in humans. It was found that that often individuals diagnosed with ASD have alterations in immune cells such as T cells, B cells, monocytes, natural killer cells, and dendritic cells. Also, many individuals diagnosed with ASD have alterations in immunoglobulins and increased autoantibodies. Finally, an important portion of individuals diagnosed with ASD has elevated peripheral cytokines and chemokines and associated neuroinflammation. In conclusion, immune dysregulation and inflammation are important components of ASD diagnosis and are key components of the diagnosis and treatment of ASD.

Immune dysfunction and neuroinflammation in autism spectrum disorder.

The relationship between mercury and autism: A comprehensive review and discussion.

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products.

Background Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that affects cognitive and higher cognitive functions. Increasing prevalence of ASD and high rates of related comorbidities has caused serious health loss and placed an onerous burden on the supporting families, caregivers, and health care services. Heavy metals are among environmental factors that may contribute to ASD. However, due to inconsistencies across studies, it is still hard to explain the association between ASD and toxic metals. Therefore the objective of this study was to investigate the difference in heavy metal measures between patients with ASD and control subjects. Methods We included observational studies that measured levels of toxic metals (antimony, arsenic, cadmium, lead, manganese, mercury, nickel, silver, and thallium) in different specimens (whole blood, plasma, serum, red cells, hair and urine) for patients with ASD and for controls. The main electronic medical database (PubMed and Scopus) were searched from inception through October 2016. Results 52 studies were eligible to be included in the present systematic review, of which 48 studies were included in the meta-analyses. The hair concentrations of antimony (standardized mean difference (SMD) = 0.24; 95% confidence interval (CI): 0.03 to 0.45) and lead (SMD = 0.60; 95% confidence interval (CI): 0.17 to 1.03) in ASD patients were significantly higher than those of control subjects. ASD patients had higher erythrocyte levels of lead (SMD = 1.55, CI: 0.2 to 2.89) and mercury (SMD = 1.56, CI: 0.42 to 2.70). There were significantly higher blood lead levels in ASD patients (SMD = 0.43, CI: 0.02 to 0.85). Sensitivity analyses showed that ASD patients in developed but not in developing countries have lower hair concentrations of cadmium (SMD = − 0.29, CI: − 0.46 to − 0.12). Also, such analyses indicated that ASD patients in developing but not in developed lands have higher hair concentrations of lead (SMD = 1.58, CI: 0.80 to 2.36) and mercury (SMD = 0.77, CI: 0.31 to 1.23). These findings were confirmed by meta-regression analyses indicating that development status of countries significantly influences the overall effect size of mean difference for hair arsenic, cadmium, lead, and mercury between patients with ASD and controls. Conclusion The findings help highlighting the role of toxic metals as environmental factors in the etiology of ASD, especially in developing lands. While there are environmental factors other than toxic metals that greatly contribute to the etiology of ASD in developed lands. It would be, thus, expected that classification of ASD includes etiological entities of ASD on the basis of implication of industrial pollutants (developed vs. developing ASD).

Systematic review and meta-analysis links autism and toxic metals and highlights the impact of country development status: Higher blood and erythrocyte levels for mercury and lead, and higher hair antimony, cadmium, lead, and mercury.

The aim of the present study was to determine the levels of metals in blood (zinc (Zn), copper (Cu), aluminium (Al), lead (Pb) and mercury (Hg)), as well as the specific porphyrin levels in the urine of patients with autism spectrum disorder (ASD) compared with patients with other neurological disorders. The study was performed in a group of children with ASD (N = 52, average age = 6.2 years) and a control group of children with other neurological disorders (N = 22, average age = 6.6 years), matched in terms of intellectual abilities (Mann-Whitney U = 565.0, p = 0.595). Measurement of metals in blood was performed by atomic absorption spectrometry, while the HPLC method via a fluorescence detector was used to test urinary porphyrin levels. Results were compared across groups using a multivariate analysis of covariance (MANCOVA). In addition, a generalized linear model was used to establish the impact of group membership on the blood Cu/Zn ratio. In terms of blood levels of metals, no significant difference between the groups was found. However, compared to the control group, ASD group had significantly elevated blood Cu/Zn ratio (Wald χ
 2 = 6.6, df = 1, p = 0.010). Additionally, no significant difference between the groups was found in terms of uroporphyrin I, heptacarboxyporphyrin I, hexacarboxyporphyrin and pentacarboxyporphyrin I. However, the levels of coproporphyrin I and coproporphyrin III were lower in the ASD group compared to the controls. Due to observed higher Cu/Zn ratio, it is suggested to test blood levels of Zn and Cu in all autistic children and give them a Zn supplement if needed.

Levels of Metals in the Blood and Specific Porphyrins in the Urine in Children with Autism Spectrum Disorders

Arsenic metabolites; selenium; and AS3MT, MTHFR, AQP4, AQP9, SELENOP, INMT, and MT2A polymorphisms in Croatian-Slovenian population from PHIME-CROME study.

Background : The aim of our study was to determine the levels of heavy metals in blood (zinc, copper, aluminium, lead, mercury), as well as the specific porphyrin levels in the urine of patients with ASD compared with patients with other neurological disorders. Methods : The study was performed in a group of children with ASD (N = 52, average age = 6.2y) and control group of children with other neurological disorders (N = 22, average age = 6.6y), matched in terms of intellectual abilities (Mann-Whitney U = 565.0, p = .595). Measurement of heavy metals in blood was performed by atomic absorption spectrometry, while the HPLC method by means of a fluorescence detector was used to test urinary porphyrin levels. Results were compared across groups using a multivariate analysis of covariance (MANCOVA). In addition, a generalized linear model was used to establish the impact of group membership on the blood Cu/Zn ratio. Results : In terms of heavy metal blood levels, no significant difference between the groups was found. However, compared to the control group, ASD group had significantly elevated blood Cu/Zn ratio (Wald χ2 = 6.6, df = 1, p = .010). Additionaly, no significant difference between the groups was found in terms of Uroporphyrin I, Heptacarboxyporphyrin I, Hexacarboxyporphyrin and Pentacarboxyporphyrin I. However, the levels of Coproporphyrin I and Coproporphyrin III were lower in the ASD group compared to the controls. Conclusions : Due to the observed higher Cu/Zn ratio we’d suggest that blood levels of zinc and cupper should be tested in all children with ASD and a Zn supplement should be given as needed.

Heavy metals and specific porphyrine levels in children with autism.

The impacts of single-nucleotide polymorphisms (SNPs) in ALAD and VDR genes on Pb health effects and/or kinetics are inconclusive at low exposure levels, while studies including APOE SNPs are rare. In this study, we examined the associations of ALAD, VDR and APOE SNPs with exposure biomarkers of Pb and other trace elements (TEs) in Italian pregnant women (N = 873, aged 18-44 years) and their newborns (N = 619) with low-level mixed-element exposure through diet, the environment or endogenously. DNA from maternal peripheral venous blood (mB), sampled during the second and third trimesters, was genotyped for ALAD (rs1800435, rs1805313, rs1139488, rs818708), VDR (rs2228570, rs1544410, rs7975232, rs731236) and APOE (rs429358, rs7421) using TaqMan SNP assays. Personal and lifestyle data and TE levels (mB, maternal plasma, hair and mixed umbilical cord blood [CB]) from the PHIME project were used. Multiple linear regression models, controlling for confounding variables, were performed to test the associations between SNPs and TEs. The geometric means of mB-Pb, mB-Hg, mB-As and mB-Cd (11.0 ng/g, 2.16 ng/g, 1.38 ng/g and 0.31 ng/g, respectively) indicated low exposure levels, whereas maternal plasma Zn and Se (0.72 μg/mL and 78.6 ng/g, respectively) indicated adequate micronutritional status. Variant alleles of ALAD rs1800435 and rs1805313 were negatively associated with mB-Pb levels, whereas a positive association was observed for rs1139488. None of the VDR SNPs or their haplotypes had any association with Pb levels. Regarding APOE, the ϵ4 allele was associated with lower mB-Hg and CB-Hg, while a positive association was found with the ϵ2 allele and CB-Pb when the model included only newborn girls. The observed associations indicate possible modification effects of ALAD and APOE SNPs on Pb or Hg kinetics in women and their newborns with low exposure to non-essential TEs, as well as an adequate nutritional status of Zn and Se. 

ALAD and APOE polymorphisms are associated with lead and mercury levels in Italian pregnant women and their newborns with adequate nutritional status of zinc and selenium.

Alenka France-Štiglic

Papers

Levels of Metals in the Blood and Specific Porphyrins in the Urine in Children with Autism Spectrum Disorders

Arsenic metabolites; selenium; and AS3MT, MTHFR, AQP4, AQP9, SELENOP, INMT, and MT2A polymorphisms in Croatian-Slovenian population from PHIME-CROME study.

Heavy metals and specific porphyrine levels in children with autism.

ALAD and APOE polymorphisms are associated with lead and mercury levels in Italian pregnant women and their newborns with adequate nutritional status of zinc and selenium.