The diagnostic prevalence of autism spectrum disorders (ASD) shows boys to be more affected than girls. Due to this reason, there is a lack of research including and observing ASD girls. Present study was aimed to detect hormones of steroidogenesis pathway in prepubertal girls (n = 16) diagnosed with ASD and sex and age matched neurotypical controls (CTRL, n = 16). Collected plasma served for detection of conjugated and unconjugated steroids using gas chromatography tandem-mass spectrometry. We observed higher levels of steroids modulating ionotropic receptors, especially, GABAergic steroids and pregnenolone sulfate in ASD group. Concentration of many steroids throughout the pathway tend to be higher in ASD girls compared to CTRL. Pregnenolone and its isomers together with polar progestins and androstanes, i.e. sulfated steroids, were found to be higher in ASD group in comparison with CTRL group. Based on steroid product to precursor ratios, ASD group showed higher levels of sulfated/conjugated steroids suggesting higher sulfotransferase or lower steroid sulfatase activity and we also obtained data indicating lower activity of steroid 11β-hydroxylase compared to CTRL group despite higher corticosterone level observed in ASD. These findings need to be generalized in future studies to examine both genders and other age groups.
- MeSH
- dítě MeSH
- lidé MeSH
- plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
- poruchy autistického spektra * metabolismus MeSH
- předškolní dítě MeSH
- pregnenolon * metabolismus krev MeSH
- steroidy metabolismus krev MeSH
- studie případů a kontrol MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Autism spectrum disorder is a heterogeneous neurodevelopmental disease. Currently, no biomarker of this disease is known. Diagnosis is performed through observation, standardized behavioral scales, and interviews with parents. In practice, diagnosis is often delayed to the average age of four years or even more which adversely affects a child's perspective. A laboratory method allowing to detect the disorder at earlier stages is of a great need, as this could help the patients to start with treatment at a younger age, even prior to the clinical diagnosis. Recent evidence indicates that metabolomic markers should be considered as diagnostic markers, also serving for further differentiation and characterization of different subgroups of the autism spectrum. In this study, we developed an ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry method for the simultaneous determination of six metabolites in human urine. These metabolites, namely methylguanidine, N-acetyl arginine, inosine, indole-3-acetic acid, indoxyl sulfate and xanthurenic acid were selected as potential biomarkers according to prior metabolomic studies. The analysis was carried out by means of reversed-phase liquid chromatography with gradient elution. Separation of the metabolites was performed on a Phenomenex Luna® Omega Polar C18 (100 × 1.0 mm, 1.6 µm) column at a flow rate of 0.15 mL/min with acetonitrile/water 0.1% formic acid aqueous as the mobile phase. The analysis was performed on a group of children with autism spectrum disorder and age-matched controls. In school children, we have detected disturbances in the levels of oxidative stress markers connected to arginine and purine metabolism, namely methylguanidine and N-acetylargine. Also, products of gut bacteria metabolism, namely indoxyl sulfate and indole-3-acetic acid, were found to be elevated in the patients' group. We can conclude that this newly developed method is fast, sensitive, reliable, and well suited for the quantification of proposed markers.
- Publikační typ
- časopisecké články MeSH
The etiology of autism spectrum disorders (ASD) remains unknown, but associations between prenatal hormonal changes and ASD risk were found. The consequences of these changes on the steroidogenesis during a postnatal development are not yet well known. The aim of this study was to analyze the steroid metabolic pathway in prepubertal ASD and neurotypical boys. Plasma samples were collected from 62 prepubertal ASD boys and 24 age and sex-matched controls (CTRL). Eighty-two biomarkers of steroidogenesis were detected using gas-chromatography tandem-mass spectrometry. We observed changes across the whole alternative backdoor pathway of androgens synthesis toward lower level in ASD group. Our data indicate suppressed production of pregnenolone sulfate at augmented activities of CYP17A1 and SULT2A1 and reduced HSD3B2 activity in ASD group which is partly consistent with the results reported in older children, in whom the adrenal zona reticularis significantly influences the steroid levels. Furthermore, we detected the suppressed activity of CYP7B1 enzyme readily metabolizing the precursors of sex hormones on one hand but increased anti-glucocorticoid effect of 7α-hydroxy-DHEA via competition with cortisone for HSD11B1 on the other. The multivariate model found significant correlations between behavioral indices and circulating steroids. From dependent variables, the best correlation was found for the social interaction (28.5%). Observed changes give a space for their utilization as biomarkers while reveal the etiopathogenesis of ASD. The aforementioned data indicate a direction of the future research with a focus on the expression and functioning of genes associated with important steroidogenic enzymes in ASD patients from early childhood to adrenarche.
- MeSH
- biologické markery MeSH
- dítě MeSH
- lidé MeSH
- poruchy autistického spektra * MeSH
- předškolní dítě MeSH
- steroidy MeSH
- studie případů a kontrol MeSH
- těhotenství MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Research increasingly suggests that nitric oxide (NO) plays a role in the pathogenesis of schizophrenia. One important line of evidence comes from genetic studies, which have repeatedly detected an association between the neuronal isoform of nitric oxide synthase (nNOS or NOS1) and schizophrenia. However, the pathogenetic pathways linking nNOS, NO, and the disorder remain poorly understood. A deficit in sensorimotor gating is considered to importantly contribute to core schizophrenia symptoms such as psychotic disorganization and thought disturbance. We selected three candidate nNOS polymorphisms (Ex1f-VNTR, rs6490121 and rs41279104), associated with schizophrenia and cognition in previous studies, and tested their association with the efficiency of sensorimotor gating in healthy human adults. We found that risk variants of Ex1f-VNTR and rs6490121 (but not rs41279104) were associated with a weaker prepulse inhibition (PPI) of the acoustic startle reflex, a standard measure of sensorimotor gating. Furthermore, the effect of presence of risk variants in Ex1f-VNTR and rs6490121 was additive: PPI linearly decreased with increasing number of risk alleles, being highest in participants with no risk allele, while lowest in individuals who carry three risk alleles. Our findings indicate that NO is involved in the regulation of sensorimotor gating, and highlight one possible pathogenetic mechanism for NO playing a role in the development of schizophrenia psychosis.
- MeSH
- dospělí MeSH
- exony MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé MeSH
- minisatelitní repetice MeSH
- oxid dusnatý fyziologie MeSH
- prepulsní inhibice genetika MeSH
- schizofrenie genetika MeSH
- senzorický gating genetika MeSH
- synthasa oxidu dusnatého, typ I genetika MeSH
- úleková reakce genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by impaired social interaction and communication, as well as repetitive behavior and restricted interests. There is convincing evidence that the intestinal inflammation is involved in etiology of ASD. Increased levels of inflammatory markers were shown to be associated with more aberrant behaviors and communication of subjects with ASD. Calprotectin in the feces is produced by activated neutrophils and epithelial cells of the gut mucosa, and its levels reflect local inflammation of the gastrointestinal tract. Concentration of fecal calprotectin was determined by ELISA method in 87 individuals with ASD and 51 controls, of that 29 siblings of children with ASD and 22 non-related controls. In non-relatives significantly lower values of fecal calprotectin were observed than in both subjects with ASD and their siblings. In the group with ASD significant correlations of fecal calprotectin with all domains of the ADI-R diagnostic tool were found: qualitative abnormalities in reciprocal social interaction and communication, restrictive and repetitive patterns of behavior. Results suggest that low grade intestinal inflammation may be one of factors implicated in the pathophysiology of ASD.
- MeSH
- dítě MeSH
- ELISA metody MeSH
- feces * chemie MeSH
- interpersonální vztahy * MeSH
- leukocytární L1-antigenní komplex analýza metabolismus MeSH
- lidé MeSH
- mladiství MeSH
- neuropsychologické testy * MeSH
- poruchy autistického spektra diagnóza epidemiologie metabolismus MeSH
- předškolní dítě MeSH
- průřezové studie MeSH
- zánět diagnóza epidemiologie metabolismus MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Slovenská republika epidemiologie MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
