Environmental Research

PurposePregnancy loss affects 10-15% of clinically recognized pregnancies and is driven by genetic and environmental factors. Interactions between genes and chemicals critically shape developmental outcomes, yet existing resources do not organize chemical-gene evidence by gestational timing, maternal-fetal compartment, or lethality context. MethodsTo minimize this gap, we merged Intolerome genes and the Comparative Toxicogenomics Database databases to create a filtered network of 928 lethality-associated genes and [~]4,000 chemicals. We developed the Chemical-Gene Atlas (CGA) application, which analyzes chemical-gene interactions using four filters supporting hypothesis generation and clinical translation. ResultsUsing recurrent pregnancy loss (RPL) as a case study, CGA identified five clinically important genes (F5, F2, AURKB, PADI6, and FOXD1) demonstrating different exposomic patterns with Bisphenol A (BPA) and Benzo[a]pyrene (B[a]P). These exposures affect gene expression, methylation, and coagulation pathways and placental function. Our findings demonstrate that genes with loss-of-function intolerance, especially those expressed in metabolic and cardiovascular systems, are susceptible to environmental disruption during critical windows of development, including implantation, placental development, and early organogenesis. ConclusionThe CGA platform provides a scalable model to investigate chemical-gene interactions leading to developmental lethality. CGA is available at https://cgatlas.org/.

BackgroundPesticides, commonly employed in both agricultural and domestic environments, have been associated with disturbing the balance of the immune system during prenatal and early childhood phases of development. This disturbance has the potential to result in various outcomes such as autoimmunity, immunosuppression, inflammation, hypersensitivity, tissue damage, and overall alterations in immune modulation. The escalating concern regarding the immunotoxic effects of pesticides necessitates a systematic review and potential meta-analysis to consolidate empirical evidence and address the knowledge gaps. This systematic review aims to comprehensively assess the immunotoxic impact of pesticide exposure on children, considering alterations in immune system function induced by specific types of pesticides. MethodsThrough a meticulous search of the literature and synthesis of findings, the review will scrutinize prevalence, effect size, mechanisms, vulnerable periods, and the role of pre-existing conditions. The submitted protocol to PROSPERO aligns with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement, ensuring methodological rigor. A preliminary exploration involved a systematic search in electronic databases based on a pre-defined Population, Exposure, Comparator, and Outcome (PECO) statement. Data extraction sheets and risk of bias assessment tools were piloted on eight eligible articles to ensure reliability and efficiency. Subsequently, a rerun of the search will be executed, and two independent reviewers will employ the systematic review tool Covidence for article screening and data extraction, and Excel for risk of bias assessment. The results will be synthetized narratively in summary tables, and, if findings allow, meta-analysis including subgroup and sensitivity analysis will be conducted. DiscussionBy elucidating the intricate relationship between pesticide exposure and immunotoxicity during prenatal and early childhood, this review will provide insights into immune response that can contribute to public health awareness and guide interventions. PROSPERO Registration number[CRD42024510916]. Impact StatementThis study will establish a high level of evidence to highlight the critical immunotoxic risks of prenatal and early childhood pesticide exposure, offering essential insights for public health policies and interventions to safeguard the infants during this vulnerable developmental periods.

BackgroundMetal exposures are associated with gut microbiome (GM) composition and function, and exposures early in development may be particularly important. Considering the role of the GM in association with many adverse health outcomes, understanding the relationship between prenatal metal exposures and the GM is critically important. However, there is sparse knowledge of the association between prenatal metal exposure and GM later in childhood. ObjectivesThis analysis aims to identify associations between prenatal lead (Pb) exposure and GM composition and function in children 9-11 years old. MethodsData come from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort based in Mexico City, Mexico. Prenatal metal concentrations were measured in maternal whole blood drawn during the second and third trimesters of pregnancy. Stool samples collected at 9-11 years old underwent metagenomic sequencing to assess the GM. This analysis uses multiple statistical modeling approaches, including linear regression, permutational analysis of variance, weighted quantile sum regression (WQS), and individual taxa regressions, to estimate the association between maternal blood Pb during pregnancy and multiple aspects of the child GM at 9-11 years old, adjusting for relevant confounders. ResultsOf the 123 child participants in this pilot data analysis, 74 were male and 49 were female. Mean prenatal maternal blood Pb was 33.6(SE=2.1) ug/L and 34.9(SE=2.1) ug/L at second and third trimesters, respectively. Analysis suggests a consistent negative relationship between prenatal maternal blood Pb and the GM at age 9-11, including measures of alpha and beta diversity, microbiome mixture analysis, and individual taxa. The WQS analysis showed a negative association between prenatal Pb exposure and the gut microbiome, for both second and third trimester exposures (2T{beta}=-0.17,95%CI=[-0.46,0.11]; 3T{beta}=-0.17,95%CI=[-0.44,0.10]). Ruminococcus gnavus, Bifidobacterium longum, Alistipes indistinctus, Bacteroides caccae, and Bifidobacterium bifidum all had weights above the importance threshold from 80% or more of the WQS repeated holdouts in association with both second and third trimester Pb exposure. DiscussionPilot data analysis suggests a negative association between prenatal Pb exposure and the gut microbiome later in childhood; however, additional investigation is needed.

BackgroundEvidence suggests that early-life exposure to certain environmental chemicals increases the risk of allergic diseases, while gut microbiota diversity and microbiota-derived short-chain fatty acid (SCFA) metabolites may be protective. ObjectivesWe assessed associations between persistent organic pollutants (POPs), microbial markers, and subsequent risk of asthma and lower respiratory tract infection (LRTI). MethodsWe studied a Norwegian birth cohort (HUMIS). Twenty-six POPs [polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), perfluoroalkyl substances (PFASs), and organochlorine pesticides (OCPs)] were quantified in maternal breastmilk (n=993). Shannon diversity and SCFAs were assessed at multiple time points before 2 years of age in a subset of children. We evaluated registry-based diagnosis of asthma when children were a median age of 10 years, along with maternal-reported asthma and LRTI by 2 years of age. Results{sum}14PCBs was associated with decreased odds and {sum}4OCPs with increased odds of asthma; associations between {beta}-HCH (OR=2.99 per 2-SD increase; 95% CI: 1.66, 5.43) and PCB-138 (OR=0.43; 95% CI: 0.20, 0.91) and asthma by age 10 years were most robust. PBDEs and PFASs were not consistently associated with asthma and no POPs were associated with LRTI. There were both inverse and positive associations between diversity and respiratory outcomes, and generally imprecise associations for SCFAs. There was limited evidence that POP exposures perturbed diversity or production of SCFAs, except for an association between {sum}14PCBs and reduced diversity at 2 years, and there was no clear evidence of mediation effects. ConclusionsThis study provides support for associations between some POPs and risk of childhood asthma, and indications of a potential independent role of gut microbiota.

Prenatal exposure to environmental contaminants is a significant health concern because it has the potential to interfere with host metabolism, leading to adverse health effects in early childhood and later in life. Growing evidence suggests that genetic and environmental factors, as well as their interactions, play a significant role in the development of autoimmune diseases. In this study, we hypothesized that prenatal exposure to environmental contaminants impacts cord serum metabolome and contributes to the development of autoimmune diseases. We selected cord serum samples from All Babies in Southeast Sweden (ABIS) general population cohort, from infants who later developed one or more autoimmune-mediated and inflammatory diseases: celiac disease (CD), Crohns disease (IBD), hypothyroidism (HT), juvenile idiopathic arthritis (JIA), and type 1 diabetes (T1D) (all cases, N = 62), along with matched controls (N = 268). Using integrated exposomics and metabolomics mass spectrometry (MS) based platforms, we determined the levels of contaminants and metabolites. Differences in exposure levels were found between the controls and those who later developed various diseases. High contaminant exposure levels were associated with changes in metabolome, including amino acids and free fatty acids. Specifically, we identified marked associations between metabolite levels and exposure levels of deoxynivalenol (DON), bisphenol S (BPS), and specific per- and polyfluorinated substances (PFAS). Our study suggests that prenatal exposure to specific environmental contaminants alters the cord serum metabolomes, which, in turn, might increase the risk of various immune-mediated disease later in life.

BackgroundMany analytical methods used in gut microbiome research focus on either single bacterial taxa or the whole microbiome, ignoring multi-bacteria relationships (microbial cliques). We present a novel analytical approach to identify multiple bacterial taxa within the gut microbiome of children at 9-11 years associated with prenatal Pb exposure. MethodsData came from a subset of participants (n=123) in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort. Pb concentrations were measured in maternal whole blood from the second and third trimesters of pregnancy. Stool samples collected at 9-11 years old underwent metagenomic sequencing to assess the gut microbiome. Using a novel analytical approach, Microbial Co-occurrence Analysis (MiCA), we paired a machine-learning algorithm with randomization-based inference to first identify microbial cliques that were predictive of prenatal Pb exposure and then estimate the association between prenatal Pb exposure and microbial clique abundance. ResultsWith second-trimester Pb exposure, we identified a 2-taxa microbial clique that included Bifidobacterium adolescentis and Ruminococcus callidus, and a 3-taxa clique that added Prevotella clara. Increasing second-trimester Pb exposure was associated with significantly increased odds of having the 2-taxa microbial clique below the 50th percentile relative abundance (OR=1.03,95%CI[1.01-1.05]). In an analysis of Pb concentration at or above vs. below the United States and Mexico guidelines for child Pb exposure, odds of the 2-taxa clique in low abundance were 3.36(95%CI[1.32-8.51]) and 6.11(95%CI[1.87-19.93]), respectively. Trends were similar with the 3-taxa clique but not statistically significant. DiscussionUsing a novel combination of machine-learning and causal-inference, MiCA identified a significant association between second-trimester Pb exposure and reduced abundance of a probiotic microbial clique within the gut microbiome in late childhood. Pb exposure levels at the guidelines for child Pb poisoning in the United States, and Mexico are not sufficient to protect against the potential loss of probiotic benefits. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/23290127v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@175d914org.highwire.dtl.DTLVardef@1fef16corg.highwire.dtl.DTLVardef@9bf2aeorg.highwire.dtl.DTLVardef@59bb5e_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundEnvironmental exposures to chemical toxicants during gestation and infancy can dysregulate multiple developmental processes, causing lifelong effects. There is compelling evidence of PFAS-associated immunotoxicity in adults and children. However, the effect of developmental PFAS exposure on infant T-cell immunity is unreported, and, if present, could be implicated in immune-related health outcomes. ObjectivesWe seek to model longitudinal changes in CD4+ T-cell subpopulations from birth through 12 months and their association with in-utero PFAS exposure and postnatal CD4+ T-cell frequencies and functions. MethodsMaternal-infant dyads were recruited as part of the UPSIDE-ECHO cohort during the first trimester between 2015 and 2019 in Rochester, New York; dyads were followed through the infants first birthday. Maternal PFAS concentrations (PFOS, PFOA, PFNA, and PFHXS) were quantified in serum during the second trimester using high-performance liquid chromatography and tandem mass spectrometry. Infant lymphocyte frequencies were assessed at birth, 6- and 12-months using mass cytometry and high-dimensional clustering methods. Linear mixed-effects models were employed to analyze the relationship between maternal PFAS concentrations and CD4+ T-cell subpopulations (n=200). All models included a PFAS and age interaction and were adjusted for parity, infant sex, and pre-pregnancy body mass index. ResultsIn-utero PFAS exposure correlated with multiple CD4+ T-cell subpopulations in infants. The greatest effect sizes were seen in T-follicular helper (Tfh) and T-helper 2 (Th2) cells at 12 months. A log2-unit increase in PFOS was associated with lower Tfh [0.17% (95%CI: -0.30, -0.40)] and greater Th2 [0.27% (95%CI: 0.18, 0.35)] cell percentages at 12 months. Similar trends were observed for PFOA, PFNA, and PFHXS. DiscussionMaternal PFAS exposures correlate with cell-specific changes in the infant T-cell compartment, including key CD4+ T-cell subpopulations that play central roles in coordinating well-regulated, protective immunity. Future studies into the role of PFAS-associated T-cell distribution and risk of adverse immune-related health outcomes in children are warranted.

Ambient particulate matter (PM) is a well-established environmental risk factor for non-communicable diseases, yet its influence on mitochondrial function remains poorly defined. Mitochondrial DNA copy number (mtDNA-CN) serves as a biomarker of mitochondrial biogenesis, making it a candidate exposure biomarker. We conducted the study per PRISMA guidelines (PROSPERO-CRD420261320957) and examined the association between ambient PM exposure and mtDNA-CN. Risk of bias was assessed using Joanna Briggs Institute tools, and relative and absolute changes in mtDNA-CN were pooled using random-effects models, with subgroup analyses by pollutant type and descriptive synthesis of mechanistic evidence. Of 1,224 records identified, 24 studies met inclusion criteria for quantitative analysis, with 12 reporting percentage change and 12 reporting absolute values, covering 13,092 participants. PM exposure was significantly associated with decreased percentage mtDNA-CN (ES: -4.90; 95% CI: -7.97 to -1.82; p = 0.002), while absolute mtDNA-CN levels increased significantly (ES = 0.55; 95% CI: 0.05 to 1.04; p = 0.030). Mechanistic pathways contributing included mtDNA hypermethylation, impaired mitochondrial biogenesis and dynamics. Our findings show ambient PM exposure alters mtDNA-CN, though directionality differs by metric, pointing to the need for larger prospective studies to validate mtDNA-CN as a reliable biomarker of airborne PM and nanoparticulate exposure.

A growing body of literature suggests that higher developmental exposure to individual or mixtures of environmental chemicals (ECs) is associated with autism spectrum disorder (ASD). However, the effect of interactions among these ECs is challenging to study. We introduced a composition of the classical exposure-mixture Weighted Quantile Sum (WQS) regression, and a machine-learning method called signed iterative random forest (SiRF) to discover synergistic interactions between ECs that are (1) associated with higher odds of ASD diagnosis, (2) mimic toxicological interactions, and (3) are present only in a subset of the sample whose chemical concentrations are higher than certain thresholds. In the case-control Childhood Autism Risks from Genetics and Environment study, we evaluated multi-ordered synergistic interactions among 62 ECs measured in the urine samples of 479 children in association with increased odds for ASD diagnosis (yes vs. no). WQS-SiRF discovered two synergistic two-ordered interactions between (1) trace-element cadmium(Cd) and alkyl-phosphate pesticide - diethyl-phosphate(DEP); and (2) 2,4,6-trichlorophenol(TCP-246) and DEP metabolites. Both interactions were suggestively associated with increased odds of ASD diagnosis in a subset of children with urinary concentrations of Cd, DEP, and TCP-246 above the 75th percentile. This study demonstrates a novel method that combines the inferential power of WQS and the predictive accuracy of machine-learning algorithms to discover interpretable EC interactions associated with ASD. SynopsisThe effect of interactions among environmental chemicals on autism spectrum disorder (ASD) diagnosis is challenging to study. We used a combination of Weighted Quantile Sum regression and machine-learning tools to study multi-ordered synergistic interactions between environmental chemicals associated with higher odds of ASD diagnosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/23285222v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@cf1aborg.highwire.dtl.DTLVardef@1ce3fbdorg.highwire.dtl.DTLVardef@1ba954borg.highwire.dtl.DTLVardef@9fab4f_HPS_FORMAT_FIGEXP M_FIG C_FIG

The association between air pollution and adverse health outcomes has been extensively studied, and while oxidative stress in likely to be involved, the underlying mechanism(s) remain unclear. Recent studies propose environmentally persistent free radicals (EPFRs) as the missing connection between air pollution and detrimental health impacts. However, the indoor environment is rarely considered in EPFR research. We measured EPFRs in household dust from two locations in Australia and investigated household characteristics associated with EPFRs. Random forest models were built to identify important household characteristics through variable importance plots and the associations were analysed using Spearmans rho test. We found that age of house, type of garage, house outer wall material, heating method used in home, frequency of extractor fan use when cooking, traffic related air pollution, frequency of cleaning and major house renovation were important household characteristics associated with EPFRs in Australian homes. The direction of association between household characteristics and EPFRs differ between the locations. Hence, further research is warranted to determine the generalisability of our results.

This symmetric bidirectional case-crossover study examined the association between short-term ambient air pollution exposure during weeks 3-8 of pregnancy and certain common congenital anomalies in Ulaanbaatar, Mongolia, between 2014 and 2018. Using predictions from a Random Forest regression model, authors assigned daily ambient air pollution exposure of particulate matter <2.5 um aerodynamic diameter, sulphur dioxide, nitrogen dioxide, and carbon monoxide for each subject based on their administrative area of residence. We used conditional logistic regression with adjustment for corresponding apparent temperature to estimate relative odds of select congenital anomalies per IQR increase in mean concentrations and quartiles of air pollutants. The adjusted relative odds of cardiovascular defects (ICD-10 subchapter: Q20-Q28) was 2.64 (95% confidence interval: 1.02-6.87) per interquartile range increase in mean concentrations of particulate matter <2.5 um aerodynamic diameter for gestational week 7. This association was further strengthened for cardiac septal defects (ICD-10 code: Q21, odds ratio: 7.28, 95% confidence interval: 1.6-33.09) and isolated ventricular septal defects (ICD-10 code: Q21.0, odds ratio: 9.87, 95% confidence interval: 1.6-60.93). We also observed an increasing dose-response trend when comparing the lowest quartile of air pollution exposure with higher quartiles on weeks 6 and 7 for Q20-Q28 and Q21 and week 4 for Q21.0. Other notable associations include increased relative odds of cleft lip and cleft palate subchapter (Q35-Q37) and PM2.5 (OR: 2.25, 95% CI: 0.62-8.1), SO2 (OR: 2.6, 95% CI: 0.61-11.12), and CO (OR: 2.83, 95% CI: 0.92-8.72) in week 4. Our findings contribute to the limited body of evidence regarding the acute effect of ambient air pollution exposure on common adverse birth outcomes.

Ulaanbaatar city (UB), the capital and the home to half of Mongolias total population, has experienced extreme seasonal air pollution in the past two decades with levels of fine particulate matter with an aerodynamic diameter less than 2.5 micrometers (PM2.5) exceeding 500 g/m3 during winter. Based on monitoring data, (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and carbon monoxide (CO) exposures were estimated for residential areas across UB using Random Forest models. We collected individual-level data on 1093 stillbirths from UB hospital records (2010-2013) and a surveillance database (2014-2018). Using a time-stratified case-crossover design, we investigated whether short-term increases in daily ambient air pollutants with different exposure lags (2 to 6 days) before delivery were associated with stillbirth. We estimated associations using conditional logistic regression and examined individual-level characteristics for effect modification. During the cold season (Oct-Mar) we observed significantly elevated relative odds of stillbirth per interquartile range increase in mean concentrations of PM2.5 (odds ratio [OR]=1.35, 95% confidence interval [CI]=1.07-1.71), SO2 (OR=1.71, 95% CI=1.06-2.77), NO2 (OR=1.30, 95% CI=0.99-1.72), and CO (OR=1.44, 95% CI=1.17-1.77) 6 days before delivery after adjusting for apparent temperature with a natural cubic spline. The associations of pollutant concentrations with stillbirth were significantly stronger among those younger than 25, nulliparous, and without comorbidities or pregnancy complications during stratified analyses. There was a clear pattern of increased risk for women living in areas of lower socioeconomic status. We conclude that acute exposure to ambient air pollution before delivery may trigger stillbirth, and this risk is higher for certain subsets of women.

Amyotrophic lateral sclerosis (ALS) is an always fatal neurodegenerative disease characterised by a gradual death of motor neurons in the spinal cord and brain. The cause of ALS is unknown. There appears to be both a genetic and an environmental aspect of ALS disease causation. Multiple occupations are associated with an elevated ALS risk. Interestingly, many of these occupations involve exposure to lead, indicating a possible connection between ALS and lead exposure. Examples include mechanical workers, military service occupations, leather workers and tanners. Gasoline station forecourt attendants, also known as petrol station assistants, show a severely increased ALS risk, and our measurements on forecourt attendants in South Africa show that they display significantly elevated blood lead concentrations. Thus, forecourt attendants can be added to the list of occupations with overlapping risks for lead exposure and ALS incidence. These occupational risks for forecourt attendants are expected to decrease in the future, as leaded gasoline is being phased out worldwide. Nonetheless, the overlapping risks for ALS incidence and lead exposure among forecourt attendants and several other occupations strengthen the hypothesis that lead exposure contributes to ALS.

Ambient air pollution is associated with adverse pregnancy outcomes such as stillbirth, miscarriage, and preterm birth. However, its effects on the viability, implantation, and survival of conceptuses--largely unobserved before the clinical detection of pregnancy-- remain poorly understood. Shifts in the sex ratio at birth (SRB) provide a sensitive, population-level indicator of sex-biased conception and pregnancy loss. This systematic review examined whether maternal exposure to ambient air pollution before conception and during pregnancy is associated with deviations in the SRB. We searched MEDLINE, Embase, and Global Health from inception to 12 February 2025 for observational studies assessing both ambient air pollution exposure and SRB. Eleven studies met the inclusion criteria, representing data from eight countries spanning 1970-2023. PM10 was the most frequently investigated pollutant, followed by PM2.5. Six studies reported no significant association, while four observed increased feminisation with higher exposure levels. Air pollution may plausibly influence SRB through effects on gamete quality, conceptus viability, and placental development. The SRB therefore provides a valuable proxy for detecting early biological vulnerability, revealing effects of air pollution that are otherwise hidden due to the selective observation of clinically recognised pregnancies. However, current evidence remains limited, heterogeneous, and inconclusive. As ambient air quality continues to deteriorate, more standardised research is needed to improve comparability and quantify the impact of air pollution on reproductive outcomes.

BackgroundParkinsons disease (PD), multiple sclerosis (MS) and motor neurone disease (MND) are progressive and debilitating diseases that are increasing in prevalence globally. Some primary studies show an increased risk from long-term outdoor air pollution exposure, while others contradict this association. MethodsAs per Khreis et al.1 protocol, a systematic review and meta-analysis was undertaken to assess the associations of long-term (>1 year) outdoor air pollution exposure with PD, MS and MND incidence. We searched eight databases for publications up to October 2023. Primary case-control, cohort, cross-sectional or ecological studies investigating the association of long-term air pollution and adult (>18 years old) PD, MS, or MND incidence were included. Meta-analyses were carried out using random-effects models with assessment of heterogeneity and meta-bias. PROSPERO (CRD42023417961). ResultsOf 31 papers included, 22 and 3 were meta-analysed for PD and MS outcomes, respectively. Most studies were from North America (14) followed by Europe (8), and Asia (6). For every 5 g/m3 increase of Particulate Matter 2.5 (PM2.5) concentration, there was a higher PD risk (1.06; 95%CI: 1.00-1.12), but this was not true for all study settings (Prediction Interval: 0.95-1.19). This risk was largest in Asia (1.16, 95%CI:0.96-1.41). There was no evidence that PM2.5 or nitrogen dioxide (NO2) were associated with increased risk of MS. ConclusionThis systematic review reports an increased risk of PD from long-term PM2.5 exposure. The neurodegenerative diseases investigated here are rare and therefore alternatives to insufficiently powered cohort studies are needed to strengthen the evidence on risk.

BackgroundEvidence suggests maternal exposure to ambient air pollution increases the risk of stillbirth, but few studies conducted in the United States have evaluated temporally varying exposures or susceptibility across gestational windows. Moreover, the generalizability of existing findings is often limited by restricted geographic coverage or reliance on selected study populations. MethodsUsing Georgia vital records from 2005 to 2014, we conducted a matched case-control study including 8,384 stillbirths and 33,459 live birth controls matched on maternal county of residence and conception month. We used stratified Cox proportional hazards models with time-varying covariates to estimate hazard ratios (HRs) for ten air pollutants across five exposure windows (first month, weekly, and first, second, and third trimester). Our primary analysis included all stillbirths combined, with subgroup analyses separating second and third trimester losses. ResultsStillbirths had a median gestational age of 27 weeks (IQR: 6.67) compared with 38 weeks for live births (IQR: 2.13). Particulate matter showed strong associations in the second trimester exposure window for all stillbirths (PM10: HR = 1.07; 95% CI: 1.04, 1.11; PM2.5: HR = 1.05; 95% CI: 1.01, 1.09). This pattern was consistent for NO2 and NH4, which also exhibited positive associations across early and entire pregnancy exposure windows (first month, first trimester, weekly), with the strongest associations for the second trimester exposures. Associations were larger for second trimester stillbirths, whereas estimates for third trimester stillbirths were largely null or negative. ConclusionsIn this population-based study in Georgia, time-varying ambient air pollution exposures during pregnancy were associated with increased risk of stillbirth, particularly for second trimester exposures and for stillbirths occurring earlier in pregnancy. These findings highlight the importance of considering gestational timing when evaluating environmental risk factors for stillbirth. What this study addsThis study is the first to evaluate maternal ambient air pollution exposure and stillbirth using time-varying exposures on vital records in the state of Georgia. By examining ten air pollutants across multiple gestational windows and subset analyses by timing of stillbirth, we identified second trimester susceptibility to NO2, PM10, PM2.5, and NH4. These findings highlight periods of vulnerability to ambient air pollution during pregnancy.

Environmental exposures rarely occur in isolation, yet biomarkers capturing early brain responses to complex metal mixtures remain limited. Neuron-derived miRNAs detectable in peripheral blood may provide minimally invasive indicators of brain-related molecular processes. We profiled miRNAs from neuron-derived extracellular vesicles in 66 adults and identified 50 dysregulated miRNAs. Among these, miR-16-5p, miR-93-5p, and miR-486-5p were reduced in individuals with higher exposure levels. Metal mixture models identified Pb as the metal most consistently associated with these miRNAs. To explore the translational relevance of these findings, we integrated brain MRI measures and observed that mediation analyses suggested miR-16-5p may represent a potential pathway linking Pb exposure to iron-sensitive MRI signals (R2*, a marker of brain iron) in the red nucleus. Together, these results suggest circulating neuron-derived miRNAs may capture molecular signatures linking complex metal mixtures, with Pb as a key component, to neuronal regulatory pathways and early brain-related perturbation to real-world exposures.

Prenatal phthalate exposure has previously been linked to the development of autism spectrum disorder (ASD). However, the underlying biological mechanisms remain unclear. We investigated whether maternal and child central carbon metabolism is involved as part of the Barwon Infant Study, a population-based birth cohort of 1074 Australian children. We estimated phthalate daily intakes using third-trimester urinary phthalate metabolite concentrations and other relevant indices. The metabolome of maternal serum in the third trimester, cord blood at birth and child plasma at 1 year were measured by nuclear magnetic resonance. We used the Small Molecule Pathway Database and principal component analysis to construct composite metabolite scores reflecting metabolic pathways. ASD symptoms at 2 and 4 years were measured by subscales of the Child Behavior Checklist and the Strengths and Difficulties Questionnaire, respectively. Multivariable linear regression analyses demonstrated (i) associations between higher prenatal di(2-ethylhexyl) phthalate (DEHP) levels and increased activity in maternal non-oxidative energy metabolism pathways, specifically non-oxidative pyruvate metabolism and the Warburg Effect, and (ii) associations between increased activity in these pathways and increased offspring ASD symptomology at 2 and 4 years of age. Mediation analyses suggested that part of the mechanism by which higher prenatal DEHP exposure influences the development of ASD symptoms in early childhood is through a maternal metabolic shift in pregnancy towards non-oxidative energy pathways, which are inefficient compared to oxidative metabolism. Interventions targeting maternal metabolic activity in pregnancy may be beneficial in reducing the potential risk to the developing fetus.

ObjectiveTo investigate associations between long-term environmental exposures, both external (ambient air pollution and built environment) and internal (circulating anthropogenic chemicals), and the human plasma metabolome, with the aim of generating biologically plausible hypotheses about affected metabolic pathways. MethodsWe analyzed plasma from 989 Estonian Biobank participants using untargeted LC-HRMS (Metabolon HD4). External exposures (PM2.5, PM10, NO2, ozone and built-environment metrics) were assigned using spatiotemporally resolved models developed in the EXPANSE project. Internal exposures were defined as ubiquitous anthropogenic compounds detected in the same metabolomics dataset. Associations between exposures and individual metabolites were quantified using left-censored regression models and then mapped to metabolite classes (Metabolon) and KEGG pathways. For enrichment analyses, one-sided Kolmogorov-Smirnov tests were applied to external exposures and Fishers exact tests to internal exposures. False discovery rate was controlled at 1% per exposure and database. ResultsExternal air pollutants exhibited distinct metabolic patterns: Higher NO2 exposure was associated with enrichment of metabolites involved in tyrosine metabolism; higher ozone with monohydroxy and dicarboxylate fatty acids (consistent with lipid peroxidation); and higher PM2.5 with acyl-carnitine subclasses and carbohydrate metabolism (glycolysis / gluconeogenesis / pyruvate). Built-environment associations were heterogeneous across metabolites and pathways. Internal anthropogenic chemicals showed broader metabolic associations than external exposures, involving a larger number of metabolites and metabolic classes. PFAS (PFOA, PFOS) were associated with long-chain polyunsaturated fatty acids (n3/n6) and lysophospho-lipids. Associations with 4-hydroxychlorothalonil, a fungicide, pointed to androgenic steroid metabolites and alpha-linolenic acid metabolism. The phenolic 2,4-di-tert-butylphenol, a plastic associated chemical, showed widespread associations with lipid classes, suggesting disruption of membrane remodeling and fatty acid handling. ConclusionLong-term environmental exposures, both external and internal, are measurably reflected in the human plasma metabolome. Across exposure domains, recurrent signals involved lipid metabolism, membrane composition, and oxidative stress-related pathways, highlighting these as common biological targets of environmental exposures. The findings generate testable hypotheses, including nitrosative stress-related alterations for NO2, lipid peroxidation for ozone, energy-metabolism perturbations for PM2.5, potential endocrine activity for chlorothalonil metabolites, and possible obesogenic effects of 2,4-di-tert-butylphenol.

BackgroundA growing body of research links environmental factors with neurodegeneration and premature mortality. However, the biological mechanisms through which pollutants affect early Alzheimers disease (AD) pathology in asymptomatic stages are largely unknown. We aimed to assess the association between air pollution and changes in cerebrospinal fluid (CSF) biomarkers of AD and neuroinflammatory processes in cognitively unimpaired (CU) individuals at risk of AD dementia. MethodWe included 225 middle-aged CU participants from the ALFA+ study, many within the Alzheimers continuum, with baseline and one follow-up measurement of CSF biomarkers of primary pathology of AD (e.g. A{beta}42/40 ratio, phosphorylated tau181 and total tau). Markers of neurodegeneration (e.g NfL), astrocytic (e.g. GFAP, YKL40), and microglial (e.g. sTREM 2) reactivity, and general inflammation (e.g. IL-6) were also included. Land use regression models were used to estimate individual levels of air pollution, including nitrogen oxide (NO2), particulate matter (PM2.5, PM10), and PM2.5 absorbance, at the participants residential address. We conducted sex-specific analyses using general linear models adjusted for age and time between measurements, with an interaction term for sex and environmental exposure. The influence of AD-related factors, like genetic predisposition and baseline amyloid pathology, on the relationship between air pollution and CSF biomarkers was also assessed. Moreover, we performed mediation analysis to investigate the pathways through which air pollution affected a 3-year rate of change in cognition and biological brain age via significant biomarkers. ResultsResults indicated sex-specific responses to air pollution. Women showed increases in IL-6 and GFAP, markers linked to neuroinflammation and astroglial activity, while men experienced impacts at baseline GFAP levels. The findings were consistent regardless of genetic predisposition to AD and amyloid pathology. Mediation analysis showed significant effects of GFAP on the relationship between air pollution and rate of change of attention and executive functions in women, highlighting primary influence pathways dependent on GFAP mediation. No significant mediation, neither direct effect was found for brain age. ConclusionsOur findings highlight air pollutions significant role in contributing to sex-specific neuroinflammatory and astrocytic response to air pollutants and its involvement in cognitive performance, underscoring the need for further research to elucidate these mechanisms. Highlights[bullet] The study evaluates the 3-year rate of change in CSF biomarkers and incorporates an assessment of vulnerability based on genetic factors related to Alzheimers disease and amyloid pathology, enriching the understanding of individual differences in response to air pollution. [bullet]The study establishes significant associations between air pollution and changes in CSF biomarkers related to neuroinflammatory processes in cognitively unimpaired individuals at risk of AD dementia. [bullet]We identified distinct impacts of air pollution on men and women, with women showing more long term detrimental effects. [bullet]CSF GFAP levels mediated the relationship between air pollution and rate of change of attention and executive functions in women. [bullet]Mediation analysis showed that pathways through which air pollution affected a 3-year rate of change in cognition are significantly influenced by astrocytic reactivity.