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.
Abstract
Exposure to organophosphate pesticides (OPs) has been associated with increased oxidative stress and a higher risk of attention-deficit/hyperactivity disorder (ADHD). However, metabolic insights underlying ADHD and the potential pathophysiological role of OPs exposure remain limited. This study characterized urinary metabolomic profiles associated with ADHD and examined their associations with OPs exposure and oxidative stress. Urinary metabolites from 67 children with ADHD and 98 controls were analyzed using nuclear magnetic resonance (NMR) spectroscopy and ultra-perforamnce liquid chromatography quadrupole time-of-flight mass spectrometry analysis (UPLC-QTOF-MS). Dimethyl phosphate (DMP) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) were used as biomarkers of OPs exposure and oxidative stress, respectively. Children were classified into high- and low-exposure/concentration groups based on DMP or HNE-MA levels. Urinary metabolomic profiles differed significantly between children with ADHD and controls. Several metabolites also differed between children with high and low DMP or HNE-MA levels. Metabolites involved in the tricarboxylic acid cycle were significantly higher in ADHD children and positively correlated with both DMP and HNE-MA. Pathway analysis suggested alterations in energy-related and amino acid metabolic pathways. Stepwise logistic regression and receiver operating characteristic curve analysis identified an 11-compound biomarker panel with good discriminatory performance in the discovery (AUC: 0.8450) and validation (AUC: 0.8748) stages. This 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. The identified biomarker panel may help distinguish children with ADHD from controls. Larger studies with multiple exposure assessments are warranted.
Prenatal TBEP exposure was associated with greater behavioral problems in early childhood, and Alter neonatal gut microbiota and related metabolic pathways may partly underlie this association.
Yuhan Zhou, Liyi Zhang, Qiang Li et al.· Environmental Research· 0 citations
The association between childhood exposure to PM2.5-bound organophosphate esters (OPEs) and attention deficit hyperactivity disorder (ADHD) remains poorly understood. In this large population-based study of 131,412 children aged 6-18 years attending schools in the Pearl River Delta, China, we collected ambient fine particulate matter (PM2.5) samples from schools to quantify OPEs levels, and screened for ADHD symptoms using parent-reported ADHD/Diagnostic and Statistical Manual of Mental Disorders (DSM-Ⅳ) Scales. We employed elastic net regression for variable selection, generalized linear mixed models (GLMMs) for association estimates, and weighted quantile sum regression to evaluate mixture effects. Odds ratios (ORs) are expressed as the change in odds of ADHD symptoms per interquartile range (IQR) increase in OPE levels. Elevated PM2.5-bound OPE exposure was associated with higher odds of ADHD symptoms in children, especially for triphenyl phosphate (TPHP) (OR = 1.75, 95% CI: 1.70-1.79), tris(2-ethylhexyl) phosphate (TEHP) (OR = 1.73, 95% CI: 1.69-1.77), tris(1,3-dichloroisopropyl) phosphate (TDCIPP) (OR = 1.71, 95% CI: 1.67-1.75), and tris(3,4-dimethylphenyl) phosphate (T34DMPP) (OR = 1.45, 95% CI: 1.41-1.49). Similar associations were observed across different ADHD subtypes. Stratified analyses indicated heterogeneous associations across age, sex, and breastfeeding subgroups, with no consistent pattern of effect modification across all OPE exposures. These findings suggest that inhalation of OPE mixtures may be associated with adverse neurodevelopmental outcomes in children, highlighting a potential developmental window of susceptibility and raising public health concerns about airborne contaminants.
Chu Chu, Xuan Liu, Yan-xu Chen et al.· Neurotoxicology· 0 citations
BACKGROUND
The association between organochlorine pesticides (OCPs)/synthetic pyrethroids (SPs) and thyroid cancer (TC) remains poorly understood, with metabolic mechanisms unexplored.
METHODS
We conducted a 1:1 age- and sex-matched case-control study (n = 668). Serum levels of 27 target analytes (19 OCPs and 8 SPs) were quantified; subsequent analyses were restricted to 13 compounds (10 OCPs and 3 SPs) with detection frequencies ≥85%. Eight machine learning (ML) algorithms with Shapley Additive Explanations (SHAP) were used to identify key pollutants in the 334 case-control pairs. Untargeted metabolomics was performed in a subset of 50 age- and sex-matched case-control pairs. Mixture effects were assessed by Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) regression. Furthermore, the Latent Unknown Clustering Integrating Multi-Omics Data (LUCID) model was employed to integrate exposure and metabolic data, enabling the identification of TC patient subgroups and the exploration of underlying metabolic mechanisms.
RESULTS
Participants (mean age 45.2 years, 82.3% female) had serum OCPs at 0.007-0.333 ng/mL and SPs at 0.046-0.095 ng/mL. ML algorithms identified fenpropathrin, β-BHC, cyhalothrin, α-BHC, and p,p'-DDD as the top five contributors to TC. Elevated OCPs/SPs exposure was significantly associated with increased TC risk (WQS: adjusted OR = 1.45, 95%CI = 1.34-2.24, P = 0.019; LUCID: OR = 9.33). Fenpropathrin was the primary contributor (BKMR posterior inclusion probability = 1.00; WQS weight = 67.6%). A total of 45 significant differential metabolites (DMs) were identified (VIP ≥1, P < 0.05, and qualitative level 1). LUCID revealed a distinct TC cluster characterized by upregulated S-sulfo-L-cysteine/adenosine and downregulated 2-hydroxycaprylic acid.
CONCLUSION
OCPs/SPs mixtures, driven by fenpropathrin, disrupt amino acid/nucleotide metabolism while suppressing organic acid metabolism, representing a potential TC-associated metabolic signature.
Fei Wang, Chunxiang Li, Linfang Zou et al.· Environment International· 0 citations
Organophosphate flame retardants (OPFRs) are emerging pollutants that pose increasing health risks. The association between urinary metabolites of OPFRs (m-OPFRs) and lipid metabolism remains unclear. This study evaluated lipid metabolism disorders of OPFRs in a population-based observational study and C57BL/6 mice. Urinary m-OPFRs, serum lipid molecules, and biochemical biomarkers in serum were measured. Linear regression and quantile-based g-computation analyses assessed associations between m-OPFRs and lipid markers. Benchmark dose and 95% lower confidence limit (BMDL) for m-OPFRs were determined by Bayesian BMD analysis, and the health risk of internal exposure was further assessed by hazard quotient (HQ). Mediation analysis assessed whether lipid molecules mediated OPFRs-induced hepatotoxicity. Association analyses identified three m-OPFRs, including bis(1-chloro-2-propyl) phosphate (BCIPP), diphenyl phosphate (DPP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), which were significantly associated with the levels of docosahexaenoic acid, 18:0 choline phosphate (LysoPC (18:0)), and 18:0 phosphoethanolamine. The BMDLs of BCIPP, DPP, and BDCIPP were 1.320, 0.100, and 0.030 μg/L, respectively. BDCIPP showed the highest HQ (4.50), followed by BCIPP (2.30) and DPP (0.66), indicating that the non-cancer risk of BDCIPP should be of concern. TDCIPP exposure induced hepatotoxicity in mice. LysoPC (18:0) increased at early exposure and mediated 7.88-30.02% of hepatotoxicity (P < 0.05). In conclusion, TDCIPP may induce hepatic lipid toxicity.
Meiyu Zhou, R. Tian, Jialei Zhu et al.· Environmental Pollution· 0 citations
Background–Aim: Children represent a particularly susceptible population to endocrine-disrupting chemical (EDC) exposure; however, biomonitoring data in this population remain limited. To the best of our knowledge, this is the first study using hair biomonitoring to simultaneously assess the concentrations of phthalate metabolites (PMs), triclosan (TCS) and triclocarban (TCC) in children with obesity (OB), type 1 diabetes mellitus (T1D), and hypothalamic–pituitary-related diseases (HPRD), through hair biomonitoring. Methods: Liquid chromatography–mass spectrometry (LC-MS) was used to measure TCS, TCC and PM levels in head hair samples from 212 children, categorized into control, T1D, HPRD and OB groups. PMs and TCS levels were compared across groups and evaluated in relation to health issues, cosmetics exposure, dietary habits, cardiometabolic, and somatometric parameters. Results: Our hair biomonitoring results showed that the most commonly detected EDCs were MEHP, MBP, MiBP, and TCS, with detection frequencies of samples 95.3%, 84.4%, 79.7%, and 60.8%, respectively. Children with T1D had statistically significantly higher mean MEHP concentrations than the control group. Children with HPRD exhibited higher PM concentrations, primarily driven by elevated mean MEHP and MBP levels compared with the control group. In contrast, mean MiBP levels were lower in the OB group than in the control group. Regarding TCS levels, no statistically significant differences were observed across the disease groups compared with controls. TCS was inversely associated with somatometric parameters in the OB group. Subgroup analyses by age, sex, residence area, and maternal education were conducted to assess statistically significant differences in concentrations of PM and TCS. Conclusions: Overall, our biomonitoring results indicate group-specific concentration patterns of PMs and TCS among children with T1D, HPRD and OB groups compared to the control group. In particular, PM levels were higher in children with T1D and HPRD and lower in those with OB groups compared to the control group. As a result, this is the first study to assess PM and TCS concentrations in children across clinical groups, using hair matrix.
M. Koukakis, Stella Baliou, A. Alegakis et al.· Journal of Xenobiotics· 0 citations
Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with metabolic and environmental factors. We investigated associations between urinary tryptophan-pathway metabolites and essential/toxic trace elements in children with ASD and healthy controls. In a cross-sectional cohort of 216 children (149 ASD, 67 controls), urinary tryptophan metabolites were quantified by LC-MS/MS and normalized to creatinine. Trace elements were assessed by ICP-MS. Matching yielded 1:1 (n = 57/57) and 1:2 (n = 30/60) age- and sex-matched subsets. Correlations (Pearson or Spearman, FDR-adjusted) and group comparisons were performed; autism severity (CARS) was analyzed within ASD. Creatinine-normalized tryptamine, 5-hydroxyindoleacetic acid, and N-acetyltryptophan showed moderate, positive correlations with essential elements (Mg, Zn, Se; r ≈ 0.5-0.7; N-acetyltryptophan and IAA correlated modestly with toxic elements (Tl, Cs; r ≈ 0.3-0.4). Group differences in individual metabolites and elements were modest; however, the composite toxic element index was significantly lower in ASD (P = .002). CARS scores did not show robust, FDR-corrected associations. Essential trace elements are closely linked to tryptophan metabolism, suggesting cofactor-dependent modulation in ASD. N-acetyltryptophan may serve as a sensor for specific toxic elements. Intervention studies are warranted to clarify causality.
Jusko Osredkar, Kristina Kumer, Maja Jekovec Vrhovšek et al.· International Journal of Try...· 0 citations