Urinary Tryptophan Metabolites, Trace Element Status, and Autism Spectrum Disorder: An Integrated Metabolomics-Elementomics Study in Children.

Multi-Omic Analysis of Cerebrospinal Fluid Metabolites in Autism Spectrum Disorder: Biomarker Identification, Metabolic Genetics Insights, and Network Toxicology

This study provides suggestive evidence that elevated adenine and proline may be potential risk factors for ASD and suggests possible involvement of the mitochondrial–Hippo–microtubule pathway, and proposes benzo[a]pyrene as a candidate environmental toxicant that may perturb CSF metabolism.

Hair Elemental Homeostasis in Uruguayan Children with Autism Spectrum Disorder: A Multielement Biomonitoring Study.

Joint effects of multi-metal exposure on Autism Spectrum Disorder: Associations, related genes, and biological pathways.

Autism Spectrum Disorder (ASD) is a common, multifactorial neurodevelopmental disorder with complex etiology. Aberrant metal exposure has been linked to ASD pathogenesis, but the independent and joint effects of multi-metal exposure remain unclear. This study investigated the associations between metal exposure and ASD in a case-control study involving 214 children aged 3-8 years, with 112 ASD cases and 102 controls. Plasma concentrations of 15 metals were measured using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Logistic regression and restricted cubic spline models (RCS) were used to assess the associations between metals and ASD. The results indicated that higher plasma concentrations of lead (Pb) were independently associated with ASD, whereas selenium (Se) showed an inverse association. These findings were further supported by sensitivity analyses using Firth logistic regression and bootstrap resampling. Bayesian kernel machine regression (BKMR) and quantile g-computation (Qgcomp) models revealed that the joint effect of Pb and nickel (Ni) on ASD was attenuated when Se was included in the analysis. In addition, analysis of public data identified nine candidate genes potentially related to both metal exposure and ASD. RT-qPCR analysis of local samples confirmed the differential expression of the candidate genes, which were functionally linked to neurodevelopment-related pathways, including thyroid hormone signaling, mTOR/AMPK signaling, and synaptic plasticity. Overall, this study suggests that specific plasma metal profiles may be associated with ASD and highlights the potential relevance of considering multi-metal exposure patterns. Further longitudinal studies and experimental investigations are required to determine the temporal relationship and potential biological mechanisms linking metal exposure to ASD. LAY SUMMARY: Autism Spectrum Disorder is thought to involve both genetic and environmental factors. In this case-control study, we measured multiple metals in children's plasma and found that children with ASD had different metal profiles compared with controls, particularly for lead, nickel, and selenium. When metals were considered together, selenium appeared to influence the observed associations involving lead and nickel. We also identified several genes that may be related to both metal exposure and neurodevelopmental processes. These findings suggest that metal exposure patterns may be relevant to ASD, but larger longitudinal and mechanistic studies are needed to clarify these relationships.

Plasma Metabolic Features Associated with Developmental Regression in Autism Spectrum Disorder: A Pilot Untargeted Metabolomics Study

Developmental regression, the loss of previously acquired language and social skills during the second year of life, affects 20–40% of children with autism spectrum disorder (ASD), yet its metabolic underpinnings remain poorly defined. Existing metabolomics studies have focused on amino acid and acylcarnitine alterations, leaving the eicosanoid, sphingolipid, and glycoconjugate axes largely unexamined. Plasma from 25 children with regressive ASD (REG+), 27 with non-regressive ASD (REG−), and 21 typically developing controls (aged 2–6 years) was profiled using untargeted Q-TOF LC/MS (Agilent 6530, ESI+ mode, 100–1700 m/z). From 6657 detected features, a stepwise curation pipeline combining statistical significance (raw p < 0.05 with Benjamini–Hochberg FDR correction, q < 0.05; FC > 1.5), analytical plausibility, endogenous origin verification, and literature-based directional alignment yielded a prioritized set of 14 annotated metabolic features. Exploratory PLS-DA (Partial Least-Squares Discriminant Analysis) visualization showed separation among the three groups within the present dataset; however, diagnostic or predictive performance was not evaluated. The 14-feature panel clustered along four biochemical axes. A feature putatively annotated as prostaglandin E3 (PGE3) showed a 7.13-fold reduction in REG+ versus controls (1.58-fold in REG−; FC REG+/REG− = 4.52). N-Acetylneuraminosyl-(α2-6)lactosamine and aspartylglycosamine were decreased 4.44-fold and 5.42-fold in REG+, respectively, with regression-specific amplification (FC REG+/REG− > 2.0). Six sphingolipid–myelin metabolites showed coordinated biosynthetic depletion and catabolic elevation in both ASD groups without regression specificity. DHEA-S exhibited the largest subgroup differential (FC REG+/REG− = 8.89), with paradoxically greater depletion in the non-regressive group. This exploratory study identified several plasma metabolic features showing abundance differences among children with REG+, REG−, and typically developing controls. These findings are hypothesis-generating and require confirmation using authenticated standards, targeted quantitative methods, and independently recruited cohorts before any diagnostic, predictive, or therapeutic relevance can be established.

Targeted and Untargeted Urinary Metabolomic Analyses of Organophosphate Pesticides Exposure and Attention-Deficit/Hyperactivity Disorder in Children

Urinary metabolomic analysis suggests that OPs exposure and oxidative stress may be associated with metabolic changes in ADHD, particularly in energy metabolism and amino acid pathways.

Amino acid profiles and clinical phenotypes in young children with autism spectrum disorder

In 394 children with autism spectrum disorder (ASD), we investigated the association between plasma amino acid (AA) concentrations and clinical phenotypes. Multivariable logistic regression models were used to evaluate the associations between 22 AAs and clinical features, reporting odds ratios. The median age at diagnosis was 3.5 years (interquartile range: 2.8–4.6 years) for boys and 3.1 years (interquartile range: 2.3–3.8 years) for girls; 81.5% of the participants were boys. A 25-unit increase in cystine concentration was associated with stereotypies (OR = 2.07), hyperactivity (OR = 1.79), and aggressive behavior (OR = 2.13), suggesting a potential role of oxidative stress in these phenotypes. Similarly, a 25-unit increase in taurine levels was associated with hyperactivity (OR = 1.24) and intellectual disability (OR = 1.38), consistent with oxidative imbalance. Higher arginine levels appeared to have a protective effect against hyperactivity (OR = 0.70), indicating a potential role in ammonia detoxification. Increased glutamine and tyrosine levels were associated with ORs < 1 for stereotypies, supporting potential neuroprotective roles. These findings suggest oxidative stress, urea cycle dysfunction, and altered neurotransmission may contribute to the pathophysiology of ASD and related clinical phenotypes in young children, warranting further investigation to inform the development of personalized clinical and nutritional interventions.