Pregnant blood and urinary metal concentrations in relation to Social Responsiveness Scale—Second Edition total T-scores, SRS-2 subscale T-scores, and ASD diagnosis revealed joint effects of blood metal mixtures on social awareness and cognition.
Abstract
Background: Metal exposures adversely impact prenatal neurodevelopment; however, their associations with child autism spectrum disorder (ASD) remain unclear. Methods: In the Environmental Influences on Child Health Outcomes Cohort, we analyzed prenatal blood (N = 479) and urinary (N = 482) metal concentrations in relation to Social Responsiveness Scale—Second Edition (SRS-2) total T-scores, SRS-2 subscale T-scores, and ASD diagnosis. Associations were examined using linear and logistic regression for individual metals and Bayesian Kernel Machine Regression for mixtures, adjusting for covariates. Results: Interquartile range increases in maternal blood lead and mercury were associated with higher SRS-2 total T-scores (lead: β = 0.11, 95% confidence interval [CI] = 0.03, 0.18; mercury: β = 0.19, 95% CI = 0.01, 0.37), and maternal blood cadmium was associated with higher odds of ASD diagnosis (OR = 2.42, 95% CI = 1.16, 5.03). Bayesian Kernel Machine Regression revealed joint effects of blood metal mixtures (arsenic, cadmium, mercury, and lead) on social awareness and cognition. Blood cadmium correlated with social awareness in females (raw score: β = 0.85, 95% CI = 0.09, 1.61) versus males (p-interaction = 0.02). Urinary barium correlated with social motivation in females (raw score: β = 0.273, 95% CI = 0.067, 0.478) versus males (p-interaction = 0.05). Conclusions: Future research should prioritize metal speciation, larger samples, and mechanistic studies to clarify sex-specific 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.
Lijuan Wei, Wanling Chen, Yingying Lin et al.· Ecotoxicology and Environmen...· 0 citations
Prenatal element exposure has been linked to autism spectrum disorder (ASD) symptoms; however, the mediating role of metabolites remains unclear. Based on the Ma'anshan Birth Cohort, 18 elements were quantified in maternal serum during the first, second, and third trimesters, and averaged concentrations of three trimesters represented the whole pregnancy exposure. Untargeted metabolomics characterized the metabolomic profiles in umbilical cord serum. ASD symptoms at ages 3, 5, and 6 years were evaluated by the Chinese version of the Clancy Autism Behavior Scale and analyzed independently across developmental stages. Analytical strategies encompassed exposure-wide associations, quantile-based g-computation, meet-in-the-middle approach, pathway enrichment, and causal mediation model. At age 3, each log10-unit increase in cadmium and magnesium concentrations was associated with 1.29-point (95%CI: 0.09, 2.50) and 4.59-point (95%CI: 0.97, 8.22) increases in ASD symptom scores, respectively, whereas selenium was associated with a 3.41-point decrease (95%CI: -6.00, -0.83). Vanadium and copper were inversely associated with ASD symptom scores at age 5; cadmium was positively associated at age 6; and mercury was inversely associated at ages 3 and 6. Overlapping exposure- and outcome-associated metabolites were identified only at age 5. Alpha-Furyl Methyl Diketone mediated an inverse indirect association between cobalt exposure and ASD symptom scores (indirect effect = -0.24, 95%CI: -0.46, -0.08), whereas 3-Methoxypropylamine showed a positive indirect association between barium exposure and ASD symptom scores (indirect effect = 0.13, 95%CI: 0.03, 0.28). Neither cobalt nor barium exhibited a significant total association; thus, these indirect associations were considered exploratory. These findings indicate element- and age-specific patterns rather than a uniform direction of association, while the indirect associations involving cord serum metabolites require confirmation in independent studies.
Ying-Ying Zuo, C. Geng, Chun-Mei Liang et al.· Environmental Pollution· 0 citations
Inconsistent evidence exists on the association between maternal essential metals exposure and birth outcomes. We aim to investigate these associations and explore potential effect modification by maternal thyroid hormones (THs). We collected data from the Ma'anshan birth cohort, including 953 mother-infant pairs. Metals and THs were measured in early pregnancy. Multiple regression and restricted cubic spline (RCS) models were used to evaluate associations between individual metals and outcomes. Bayesian Kernel Machine Regression (BKMR) was applied to assess mixture effects. Stratified analyses with interaction tests were performed to evaluate effect modification by THs. Multiple regression models showed that higher manganese (Mn) and zinc (Zn) concentrations were associated with higher birth weight z-score (BWZ) (Mn: β = 0.44, 95% CI: 0.17, 0.72; Zn: β = 0.38, 95% CI: 0.09, 0.68) and increased large for gestational age (LGA) risk (Mn: OR = 2.82, 95% CI: 1.28, 6.21; Zn: OR = 2.50, 95% CI: 1.08, 5.80). Copper (Cu) was inversely associated with small for gestational age (SGA) risk (OR = 0.27, 95% CI: 0.08, 0.97). RCS analyses revealed significant non-linear associations with LGA for both Se and Zn, with a more clearly inverted U-shaped pattern for Se. BKMR showed a monotonic increasing association of the metal mixture with both BWZ and LGA, with the trend significant at lower-to-moderate concentrations. Mn was the primary contributor for both outcomes, whereas no significant associations were observed for SGA. Interaction and stratified analyses showed that Cu was positively associated with BWZ and LGA in the overall population, with stronger effects in the high FT4 subgroup (BWZ: β = 0.35, 95% CI: 0.05, 0.80; LGA: OR = 2.14, 95% CI: 1.01, 8.20), whereas no associations were found in the low FT4 subgroup, indicating a potential modifying role of FT4. Other stratified findings lacked interaction evidence and were considered exploratory.
Xiao-yu Zhao, Zhen-Hua Li, Kai Huang et al.· Environmental Pollution· 0 citations
The prenatal period is a critical window for neurodevelopment, during which maternal metabolic processes are increasingly recognized to shape later behavioral and autism-related traits. We examined associations between targeted maternal urinary metabolomic profiles across pregnancy and preschool emotional, behavioral, and autism-related outcomes in the New York University Children's Health and Environment Study (NYU CHES), a large prospective birth cohort. Targeted metabolomics was conducted on maternal urine samples collected in early, mid, and late pregnancy. Child outcomes were assessed at a mean age of 2.3 years using the Child Behavior Checklist (CBCL) total and DSM-5-oriented autism spectrum disorder (ASD) subscale scores. We applied two-stage mixed-effects models to assess overall pregnancy metabolite levels and timepoint-specific negative binomial models to evaluate trimester-specific associations, with covariate adjustment, sex-stratification, and false discovery rate (FDR) correction. Few associations were observed two-stage models. In timepoint-specific analyses, a robust sex- and timing-specific association emerged: among males, higher third-trimester urinary lysoPC a C26:1 was associated with lower CBCL total and ASD subscale scores, surviving stringent FDR correction and remaining robust after adjustment for maternal diet quality. Additional associations involving taurine, inflammatory markers, and acylcarnitines were observed primarily in sex-stratified or diet-adjusted models but were less robust to multiple testing correction. These findings suggest that prenatal metabolic profiles, particularly lipid- and mitochondrial energy-related pathways in late gestation, may contribute to early behavioral and autism-related traits in a sex-specific manner, underscoring the importance of exposure timing and maternal metabolism in the etiology of neurodevelopmental outcomes.
Haleigh Cavalier, Heather E. Volk, Yelena Afanasyeva et al.· Molecular Psychiatry· 0 citations
BACKGROUND
Lead is a well-recognized neurotoxic metal with demonstrated consistent detrimental effects on children's intelligence quotient (IQ) in the postnatal period. However, there is no such consensus about the effects of prenatal exposures.
AIM
We aimed to examine the effect of prenatal lead exposure on children's intelligence quotient.
METHODOLOGY
We conducted a systematic review with meta-analysis based on three databases: PubMed (MEDLINE), Web of Science, and Lilacs (Latin American and Caribbean Health Sciences Literature). We included studies where exposure involved biomarkers of lead exposure (e.g., blood, urine, etc.) during the prenatal period, and global IQ assessments were conducted in children aged 5 years or older. We standardized the estimates to linear point estimates. The Risk of Bias (RoB) in Non-randomized Studies of Exposures (ROBINS-E) tool was used to evaluate potential systematic errors. We analyzed the pooled estimates using random effects models, also considering fixed effects models. Pooled effects were examined separately by sex. To assess heterogeneity across studies, we employed the I2 statistic and Cochran's Q test.
RESULTS
Only 7 studies were included in analyses. In those studies evaluating blood lead levels, we found a modest negative association between prenatal Pb and standardized IQ scores, although the confidence interval included the null value (β: -0.06; 95%CI: -0.17, 0.05; I2: 24.1%).
CONCLUSION
Results from our study suggest that prenatal lead exposure may be associated with modestly lower intelligence quotient scores in children 5 years and older. However, research is sparse and more studies are needed to investigate confounding factors and whether the effect varies by sex.
V. Flórez-García, Edwin Guevara-Romero, J. Rod et al.· Ecotoxicology and Environmen...· 0 citations
INTRODUCTION
Few studies have examined prenatal co-exposure to organophosphate esters (OPEs) and phthalic acid esters (PAEs) in relation to childhood autism spectrum disorder (ASD) symptoms, and whether vitamin D modifies these associations.
METHODS
Included 2400 mother-child dyads from the Ma'anshan Birth Cohort and examined levels of maternal OPEs, PAEs, and vitamin D across the three trimesters. Used the Clancy Autism Behavior Scale to assess preschoolers' ASD symptoms at ages 3, 5, and 6, then used group-based trajectory modeling to fit ASD symptom trajectories.
RESULTS
ASD symptom scores fit 3 trajectories: low, moderate, and high. Average-MEOHP, average-ΣHMWP, first-trimester-ΣHMWP, third-trimester-DPHP, and third-trimester-BCIPP were associated with increased risk in the moderate group (p < 0.05). Average-MMP, average-ΣHMWP, second-trimester-BEHP, and third-trimester-ΣHMWP were associated with increased risk in the high-score group (p < 0.05). By contrast, first-trimester-BCIPP was negatively correlated with the moderate group. DPHP, DBP, and Σdi-OPEs showed sex-specific effects (psex-int < 0.05). Maternal vitamin D levels modified these associations, with women with vitamin D deficiency showing significantly higher risks. OPEs and PAEs showed mixed effects.
CONCLUSION
Prenatal exposure to OPEs/PAEs exhibited heterogeneous associations with preschoolers' ASD symptom trajectories, and maternal vitamin D deficiency exacerbates the effects of OPEs/PAEs individual exposure on symptom trajectories.
Xing Wang, J. Tong, Ling Luo et al.· Environment International· 0 citations
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