metallothionein and Autistic-Disorder

Topics: Adult; Animals; Autistic Disorder; Brain; Child; Child, Preschool; Developmental Disabilities; Female; Fishes; Food Contamination; Humans; Infant; Mercury; Mercury Poisoning; Metallothionein; Organomercury Compounds; Pilot Projects; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Water Pollutants, Chemical

Gene expression profiles in the amygdala of juvenile rats were compared between the two autistic rat models for mechanistic insights into impaired social behavior and enhanced anxiety in autism. The rats exposed to VPA by intraperitoneal administration to their dams at embryonic day (E) 12 were used as a model for autism (E2IP), and those by subcutaneous administration at postnatal day (P) 14 (P14SC) were used as a model for regressive autism; both of the models show impaired social behavior and enhanced anxiety as symptoms. Gene expression profiles in the amygdala of the rats (E12IP and P14SC) were analyzed by microarray and compared to each other. Only two genes, Neu2 and Mt2a, showed significant changes in the same direction in both of the rat models, and there were little similarities in the overall gene expression profiles between them. It was considered that gene expression changes per se in the amygdala might be an important cause for impaired social behavior and enhanced anxiety, rather than expression changes of particular genes.

Topics: Amygdala; Animals; Animals, Newborn; Anxiety; Autistic Disorder; Behavior, Animal; Disease Models, Animal; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Maternal Exposure; Maternal-Fetal Exchange; Metallothionein; Neuraminidase; Pregnancy; Rats; Rats, Wistar; Social Behavior; Transcriptome; Valproic Acid

Topics: Autistic Disorder; Child, Preschool; Drug Implants; Gold; Humans; Metallothionein; Oxidative Stress

Autism is a common neurodevelopmental disorder with genetic and environmental components. Though unproven, genetic susceptibility to high mercury (Hg) body burden has been suggested as an autism risk factor in a subset of children. We hypothesized that exposure to "safe" Hg levels could be implicated in the etiology of autism if genetic susceptibility altered Hg's metabolism or intracellular compartmentalization. Genetic sequences of four genes implicated in the transport and response to Hg were screened for variation and association with autism. LAT1 and DMT1 function in Hg transport, and Hg exposure induces MTF1 and MT1a. We identified and characterized 74 variants in MT1a, DMT1, LAT1 and MTF1. Polymorphisms identified through screening 48 unrelated individuals from the general and autistic populations were evaluated for differences in allele frequencies using Fisher's exact test. Three variants with suggestive p-values <0.1 and four variants with significant p-values <0.05 were followed-up with TaqMan genotyping in a larger cohort of 204 patients and 323 control samples. The pedigree disequilibrium test was used to examine linkage and association. Analysis failed to show association with autism for any variant evaluated in both the initial screening set and the expanded cohort, suggesting that variations in the ability of the four genes studied to process and transport Hg may not play a significant role in the etiology of autism.

Topics: Adolescent; Autistic Disorder; Case-Control Studies; Cation Transport Proteins; Child; Child, Preschool; DNA-Binding Proteins; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Large Neutral Amino Acid-Transporter 1; Linkage Disequilibrium; Male; Mercury; Metallothionein; Phenotype; Polymorphism, Genetic; Risk Assessment; Risk Factors; Tennessee; Transcription Factor MTF-1; Transcription Factors; Young Adult

Metallothioneins (MTs) are a family of small proteins containing 61-68 amino acids with an unusually high concentration of cysteine. MT-1, the most functional and active MT in humans, has the ability to react with and enhance the detoxification of a number of metals including zinc, mercury, copper and cadmium. MT dysfunction may result, then, in many of the aetiological syndromes observed in autistic children, such as the leaky gut. It has been proposed that allergic autoimmune reactions occurring after exposure to heavy metals, may contribute to some symptoms associated with autism. Therefore abnormalities in MT concentration and/or structure, as well as the presence of anti-MT antibodies, may be associated with autism. We used direct ELISAs to quantitate the concentration of serum anti-metallothionein IgG in 66 individuals (parents and children) from 14 families with autistic children, as well as 11 controls from families with no history of autism. We measured the concentration of serum metallothionein in 39 of the above family members from 8 families. Our results indicate that a significantly high number (23 of 66) of autistic family members had high levels of anti-metallothionein IgG, when compared to controls (1 ) and the production of these antibodies correlated with levels of metallothionein, suggesting that the production of these antibodies is inherited. However, the presence of these antibodies does not correlate with autism, types of autism, including regression, or demographics such as allergies, respiratory problems or GI disease. This suggests that the presence of anti-metallothionein antibodies is not causative to autism and may be the result of other immunological pathology seen in many autistics.

Topics: Autistic Disorder; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Family; Humans; Immunoglobulin G; Metallothionein

Topics: Autistic Disorder; Autoantibodies; Ethylmercury Compounds; Humans; Metallothionein; Preservatives, Pharmaceutical; Thimerosal; Vaccines

Allergic autoimmune reaction after exposure to heavy metals such as mercury may play a causal role in autism, a developmental disorder of the central nervous system. As metallothionein (MT) is the primary metal-detoxifying protein in the body, we conducted a study of the MT protein and antibodies to metallothionein (anti-MT) in normal and autistic children whose exposure to mercury was only from thimerosal-containing vaccines. Laboratory analysis by immunoassays revealed that the serum level of MT did not significantly differ between normal and autistic children. Furthermore, autistic children harboured normal levels of anti-MT, including antibodies to isoform MT-I (anti-MT-I) and MT-II (anti-MT-II), without any significant difference between normal and autistic children. Our findings indicate that because autistic children have a normal profile of MT and anti-MT, the mercury-induced autoimmunity to MT may not be implicated in the pathogenesis of autism.

Topics: Autistic Disorder; Autoantibodies; Biomarkers; Child; Enzyme-Linked Immunosorbent Assay; Humans; Metallothionein; Preservatives, Pharmaceutical; Protein Isoforms; Reference Values; Thimerosal; Vaccines