Environmental Research

Ambient particulate matter (PM2.5) is a major environmental carcinogen linked to lung cancer, yet its molecular insights on asymptomatic non-smokers remains unclear. This study examined the effect of seasonal fluctuations of PM2.5 on oxidative stress and pro-oncogenic signaling in rural (RU) and urban (UR) cohorts from West Bengal, India. Environmental monitoring revealed higher PM2.5 and associated benzo[]pyrene in UR, during winter, induced oxidative stress (elevated ROS, 8-OHdG), reduced antioxidants (SOD, catalase, GPx), and promoted airway inflammation. Transcriptomic and bioinformatic analyses identified activation of IL-6/EGFR-driven JAK2/STAT3 signaling and its crosstalk with Ras/Raf/MAPK, leading to increased expression of downstream effectors (BCL-2, MCL-1, c-MYC, cyclin D1) and repression of tumor suppressors (BAX, p21). Notably, downregulation of JAK/STAT inhibitors PIAS2 and SOCS2 suggested persistent activation of oncogenic signaling. Linear mixed-effects models linked winter PM2.5 surges to oxidative stress, inflammation, and altered JAK2/STAT3 signaling, while regression models showed stronger responses in UR. Risk modeling predicted significantly higher lung cancer mortality in UR, underscoring the role of seasonal PM2.5 surges in JAK2/STAT3-driven carcinogenic susceptibility and the urgent need for targeted interventions.

Long-term exposure to air pollution has been associated with changes in levels of several metabolites measured in the peripheral blood. However, most work has been conducted in ethnically homogenous populations. We studied the relationship between the plasma metabolome and long-term exposure to three air pollutants: particulate matter (PM) less than 2.5 {micro}m in aero diameter (PM2.5), PM less than 10 {micro}m in aero diameter (PM10) and nitrogen dioxide (NO2) among 107 participants of the Washington Heights and Inwood Community Aging Project (WHICAP) in New York City. Plasma metabolomic profiles were generated using untargeted liquid chromatography coupled with high-resolution mass spectrometry. We estimated the association between each metabolic feature and predicted annual mean exposure to the air pollutants using three approaches: 1. A metabolome wide association study (MWAS) framework; 2. Feature selection using elastic net regression; and 3. A multivariate approach using partial least squares discriminant analysis. Additionally, we identified the pathways enriched by metabolic features associated with exposure through pathway analysis. The samples were collected from 1995 - 2015 and included non-Hispanic white, Caribbean Hispanic, and non-Hispanic Black older adults. Through the MWAS, we found 79 features associated with exposure to PM2.5 (false discovery rate at 5%) but none associated with PM10 or NO2. Pathway analysis revealed that PM2.5 exposure was associated with altered amino acid metabolism, energy production, and oxidative stress response. Six features were found to be associated with PM2.5 exposure through all three approaches, annotated as: cysteinylglycine disulfide, a diglyceride, and a dicarboxylic acid. Additionally, we found that the relationship between several features and PM2.5 exposure was modified by diet and metabolic diseases. These signals, identified in a neighborhood-representative older population, could help understand the mechanisms through which PM2.5 exposure can lead to altered metabolic outcomes in an older population. HIGHLIGHTSO_LILong-term exposure to PM2.5 is associated with altered plasma metabolic features in an aging population C_LIO_LIThese associations are modified by a dementia diagnosis, history of diabetes, APOE-{varepsilon}4 allele, and diet C_LIO_LIPathways related to energy production, amino acid metabolism, and redox homeostasis are associated with exposure to PM2.5 C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/22284045v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1c77e99org.highwire.dtl.DTLVardef@4872ccorg.highwire.dtl.DTLVardef@68ccf8org.highwire.dtl.DTLVardef@68e45c_HPS_FORMAT_FIGEXP M_FIG C_FIG

AbstractO_ST_ABSBackgroundC_ST_ABSOrganophosphate and pyrethroid insecticides can affect childrens neurodevelopment and increase inflammation. Limited evidence exists among adolescents and on whether inflammation may mediate pesticide-neurobehavior associations. We examined the associations between insecticide metabolite concentrations and neurobehavior among adolescents in Ecuadorian agricultural communities. MethodsWe included 520 participants aged 11-17 years. We measured urinary insecticide metabolites (mass spectrometry) and neurobehavior (NEPSY-II). Associations were adjusted for socio-demographic and anthropometric characteristics. The associations of insecticide mixtures with neurobehavior were evaluated using PLS regression, and mediation by inflammatory biomarkers (TNF-, IL-6, CRP, SAA, sICAM-1, sVCAM-1 and sCD-14) was conducted. ResultsAmong organophosphates, para-nitrophenol (PNP) and 3,5,6-Trichloro-2-pyridinol (TCPy) were inversely associated with Social Perception (score difference per 50% increase [{beta}50%] = -0.26 [95%CI: - 1.07, -0.20] and -0.10 [-0.22, 0.01], respectively). PNP and TCPy also had significant inverse associations with Attention/Inhibitory Control at concentrations >60th percentile ({beta}50%= -0.26 [95%CI: -0.51, -0.01] and {beta}50%= -0.22 [95%CI: -0.43, -0.00], respectively). The pyrethroid, 3-phenoxybenzoic acid (3-PBA), was inversely associated with Language ({beta}50% = -0.13 [95%CI: -0.19, -0.01]) and had a negative quadratic association with Attention/Inhibitory Control. The neonicotinoid 5-Hydroxy imidacloprid (OHIM) was positively associated with Memory/Learning ({beta}50% = 0.20 [95%CI: 0.04, 0.37]). Mixtures of all insecticides were significantly negatively related to all domains, except for Memory/Learning, which was positively associated. No mediation by inflammatory markers on these associations was observed. ConclusionsConcurrent organophosphate, pyrethroid, and the mixtures of all metabolites were associated with lower performance in all domains except for Memory/Learning. Neonicotinoids were positively associated with Memory/Learning and Social Perception scores.

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

Organophosphate and pyrethroid pesticides are widely used, but their combined effects on brain health remain unclear. This study analyzed observational research from 2014 to 2024 on their simultaneous exposure and its association with neurobehavioral, neurodegenerative, and neurological disorders through a systematic review following PRISMA guidelines in PubMed and Web of Science. Studies assessing co-exposure with validated methods and reporting brain health outcomes were included, while reviews, animal studies, and those without simultaneous exposure data were excluded. Risk of bias in cohort studies was evaluated using ROBINS-E. Of the 34 studies included, nine were cohort studies, four with low risk of bias and four with concerns related to sample size or exposure assessment. Three linked co-exposure to attention deficits and cognitive decline in children. Evidence on neurodegenerative diseases and autism spectrum disorder was inconsistent due to conflicting results. Cross-sectional and case-control studies associated co-exposure with depression and anxiety but lacked follow-up data. Variability in exposure assessment reduced comparability. Research remains limited, indicating possible neurodevelopmental effects and the need for standardized methodologies to refine risk assessment.

Prenatal pesticide exposure may adversely affect child neurodevelopment which may partly arise from impairing the placentas vital role in fetal development. In a cohort of pregnant farmworkers from Thailand (N=248), we examined the links between urinary metabolites of pyrethroid pesticides during pregnancy, placental gene expression networks derived from transcriptome sequencing, and newborn neurobehavior assessed using the NICU Network Neurobehavioral Scales (NNNS) at 5 weeks of age. Focusing on the 21 gene network modules in the placenta identified by Weighted Gene Co-expression Network Analysis (WGCNA), our analysis revealed significant associations between metabolites and nine distinct modules, and between thirteen modules and NNNS, with eight modules showing overlap. Notably, stress was negatively associated with the interferon alpha response and Myc target modules, and the interferon alpha response module was correlated positively with attention, and negatively with arousal, and quality of movement. The analysis also highlighted the early and late trimesters as critical periods for the influence of exposures on placental function, with pyrethroid metabolites measured early in pregnancy significantly negatively associated with the protein secretion module, and those measured later in pregnancy negatively associated with modules related to oxidative phosphorylation (OXPHOS) and DNA repair. Additionally, the cumulative sum of 3-phenoxybenzoic acid across pregnancy was significantly negatively associated with the OXPHOS module. These findings suggest that prenatal exposure to pyrethroid pesticides may influence neonatal neurobehavior through specific placental mechanisms that impact gene expression of metabolic pathway, and these effects may be pregnancy period specific. These results offer valuable insights for future risk assessment and intervention strategies.

BackgroundAmbient air pollution exposures increase risk for Alzheimers disease (AD) and related dementias, possibly due to structural changes in the medial temporal lobe (MTL). However, existing MRI studies examining exposure effects on the MTL were cross-sectional and focused on the hippocampus, yielding mixed results. MethodTo determine whether air pollution exposures were associated with MTL atrophy over time, we conducted a longitudinal study including 653 cognitively unimpaired community-dwelling older women from the Womens Health Initiative Memory Study with two MRI brain scans (MRI-1: 2005-6; MRI-2: 2009-10; Mage at MRI-1=77.3{+/-}3.5years). Using regionalized universal kriging models, exposures at residential locations were estimated as 3-year annual averages of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) prior to MRI-1. Bilateral gray matter volumes of the hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex (ERC) were summed to operationalize the MTL. We used linear regressions to estimate exposure effects on 5-year volume changes in the MTL and its subregions, adjusting for intracranial volume, sociodemographic, lifestyle, and clinical characteristics. ResultsOn average, MTL volume decreased by 0.53{+/-}1.00cm3 over 5 years. For each interquartile increase of PM2.5 (3.26{micro}g/m3) and NO2 (6.77ppb), adjusted MTL volume had greater shrinkage by 0.32cm3 (95%CI=[-0.43,-0.21]) and 0.12cm3 (95%CI=[-0.22,-0.01]), respectively. The exposure effects did not differ by APOE {varepsilon}4 genotype, sociodemographic, and cardiovascular risk factors, and remained among women with low-level PM2.5 exposure. Greater PHG atrophy was associated with higher PM2.5 (b=-0.24, 95%CI=[-0.29,-0.19]) and NO2 exposures (b=-0.09, 95%CI=[-0.14,-0.04]). Higher exposure to PM2.5 but not NO2 was also associated with greater ERC atrophy. Exposures were not associated with amygdala or hippocampal atrophy. ConclusionIn summary, higher late-life PM2.5 and NO2 exposures were associated with greater MTL atrophy over time in cognitively unimpaired older women. The PHG and ERC - the MTL cortical subregions where AD neuropathologies likely begin, may be preferentially vulnerable to air pollution neurotoxicity. HighlightsO_LIFirst longitudinal study on air pollution and medial temporal lobe (MTL) volume. C_LIO_LILate-life PM2.5 and NO2 associated with MTL atrophy over time in older women. C_LIO_LIHeterogeneous adverse effects were observed across different subregions of the MTL. C_LIO_LIResults not differ by APOE genotype, age, education, or cardiovascular risk factors. C_LIO_LIAdverse effects remained at low-level exposure compliant with regulatory standards. C_LI

BackgroundShort-term exposure to ambient temperature is linked to various health outcomes, raising public health concern in the context of climate change. We aimed to investigate longitudinal associations of temperature exposure with inflammation-related proteins among Swedish young adults. MethodsWe conducted three repeated measurements (2020-2022) by collecting self-sampled volumetric dry blood spots (DBS) from 807 participants from the Swedish BAMSE cohort (mean age 25.9 years). We estimated individual-address level daily temperature using a high-resolution spatiotemporal model. Inflammation-related proteins were measured using the Olinks Explore Inflammation panel. Temperature-related proteins were identified using mixed-effect model adjusting for potential covariates, with potential effect modification by sex, smoking, asthma and air pollution explored. We further linked the temperature-related proteins to lung function, blood pressure and HbA1c. In addition, we built an inflammation-proteomic aging clock using a machine-learning approach and estimated the association between temperature exposure and proteomic age acceleration. Findingswe found that 58 (16%) of the 365 studied inflammation-related proteins were significantly associated with short-term exposure to ambient temperatures (P<0.05 after correcting for multiple comparison). The impact of temperature exposure was modified by sex, smoking, asthma, and concurrent exposure to air pollution. A total of five, three and three temperature-related proteins were found to be associated with lung function, blood pressure, and HbA1c, respectively and validated in the UK Biobank. Peak temperature exposure (both cold and heat) was associated with significantly increased proteomic age acceleration. InterpretationOur findings suggest that ambient temperature exposure may cause adverse health effects through perturbating inflammation-related proteins. SynopsisThis study reports significant effects of ambient temperature exposure on inflammation-related proteins, highlighting potential health impacts from ambient temperature exposure. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/25331135v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@16e3eb3org.highwire.dtl.DTLVardef@d67d61org.highwire.dtl.DTLVardef@1c190a2org.highwire.dtl.DTLVardef@feba21_HPS_FORMAT_FIGEXP M_FIG C_FIG

The majority of people worldwide live in cities, yet how urban living affects brain and mental illness is scarcely understood. Urban lives are exposed to a a wide array of environmental factors that may combine and interact to influence mental health. While individual factors of the urban environment have been investigated in isolation, to date no attempt has been made to model how the complex, real life exposure to living in the city relates to brain and mental illness, and how it is moderated by genetic factors. Using data of over 150,000 participants of the UK Biobank, we carried out sparse canonical correlation analyses (sCCA) to investigate the relation of urban living environment with symptoms of mental illness. We found three mental health symptom groups, consisting of affective, anxiety and emotional instability symptoms, respectively. These groups were correlated with distinct profiles of urban environments defined by risk factors related to social deprivation, air pollution and urban density, and protective factors involving green spaces and generous land use. The relations between environment and symptoms of mental illness were mediated by the volume of brain regions involved in reward processing, emotional processing and executive control, and moderated by genes regulating stress response, neurotransmission, neural development and differentiation, as well as epigenetic modifications. Together, these findings indicate distinct biological pathways by which different environmental profiles of urban living may influence mental illness. Our results also provide a quantitative measure of the contribution of each environmental factor to brain volume and symptom group. They will aid in targeting and prioritizing important decisions for planning and public health interventions.

Testicular cancer is an increasing burden in modern societies and the most common malignancy among young adult males. Environment contaminants, especially endocrine disrupting compounds (EDC), may play a significant role in the development of these cancers through epigenetic alterations occurring during fetal and neonatal development. As long-term studies in humans and suitable experimental models with the potential to develop testicular cancer are lacking, no causal link can be established between endocrine disruptor exposure and testicular cancer incidence. Therefore, we developed an experimental model that recapitulates the differentiation of germ cells from primordial germ cells (pluripotency) into spermatocytes (meiosis) by using xenografted human fetal testis combined with germ cell transplantation into adult testis compartments. Using this model, we demonstrate that long-term fetal exposure (until 12 weeks) to a mixture of Di-2-ethylhexylphthalate (DEHP) and Bisphenol A (BPA), two most prevalent plasticizers, could interfere with fetal germ cell differentiation, leading to carcinogenesis and seminomas. Transcriptome, methylome, and histological analyses reveal that BPA/DEHP exposure induced some significant hallmarks of germ cell tumors to occur: persistent pluripotent and proliferative germ cells, global hypomethylation of CpGs in germ cells, abnormal expression of meiotic markers and fibrotic signatures in fetal testis. Additionally, we found that EDC-exposed fetal germ cells were more likely to develop seminoma in a context that allows spermatogenesis to begin. This study proposes the first experimental evidence that EDC exposure can cause long-term, irreversible lesions in fetal germ cells, which then lead to testicular tumorigenesis in adults.

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

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.

Per- and polyfluoroalkyl substances (PFASs) and pesticides are ubiquitous environmental exposures with increasingly recognized adverse health outcomes; however, their impact on lung function, particularly in combination, remains poorly understood. We included 381 adolescent participants from a prospective cohort study in Ecuador who underwent measurements of serum PFAS (perfluorooctanoic acid [PFOA], perfluorooctanesulfonic acid [PFOS] and perfluorononanoic acid [PFNA]) and urinary herbicides (glyphosate, 2,4D) and fungicides (ethylene thiourea) and had spirometric measurements in either 2016 or 2022. We characterized the association between each PFAS or pesticide and each lung function measure in log-log models estimated via ordinary least squares regression. We used quantile g-computation to assess the association of the mixture of PFAS and pesticides with lung function outcomes. After accounting for multiple hypothesis testing, and in models adjusting for household income, parental education, and exposure to tobacco, we found that, individually, PFOA, glyphosate, and ETU were associated with slight increases in FEV1/FVC between 2016 and 2022. No other individual associations were significant. In mixtures analyses, a one quartile increase in all PFASs and pesticides simultaneously was also not associated with statistically significant changes in lung function outcomes after accounting for multiple hypothesis testing. In large part, we do not provide evidence for associations of PFAS and herbicide and fungicide pesticides with lung function among adolescents in moderate-to-high-altitude agricultural communities in Ecuador.

IntroductionGrowing evidence suggests pesticide exposure can affect emotional well-being; limited research exists across adolescence and young adulthood. We examined cross-sectional and longitudinal associations of pesticide biomarkers with anxiety and depression scores. MethodsWe analyzed 646 participants from Ecuadorian agricultural communities: 510 in 2016 (ages 11-17y) and 485 in 2022 (17-24y). Twelve urinary insecticide metabolites were measured. Validated questionnaires assessed depression and anxiety. Generalized estimating equations (GEE) estimated associations for continuous scores and logit GEE calculated odds ratios (OR) of elevated symptoms, adjusting for demographic and anthropometric variables. ResultsIn 2016, an interquartile range higher overall pesticides summed ({beta}=1.01 95%CI:[0.48, 1.53]), organophosphates summed ({beta}=0.99 [0.47, 1.51]), 3,5,6-trichloro-2-pyridinol (TCPy; {beta}=0.97 [0.49, 1.45]), pyrethroids summed ({beta}=0.69 [0.11, 1.27]) and 3-phenoxybenzoic acid ({beta}=0.31 [0.01, 0.61]) were positively associated with depression. Detectable 5-hydroxy imidacloprid (OHIM) doubled elevated depression odds. In 2022, higher sulfoxaflor isomers were protective, but higher clothianidin increased elevated depression odds. Longitudinally, depression was positively associated with overall pesticides summed ({beta}=0.06 [0.02, 0.11]), organophosphates summed ({beta}=0.05 [0.001, 0.10]), TCPy ({beta}=0.06 [0.02, 0.10]), pyrethroids summed and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (trans-DCCA; {beta}=0.01 [0.003, 0.02]). For anxiety, in 2016 detectable trans-DCCA (OR=2.52 [1.52, 4.16]) was associated with elevated symptoms. In 2022, higher clothianidin increased elevated anxiety odds (OR=1.44 [1.07, 1.93]). Longitudinally, trans-DCCA (OR=1.39 [1.03, 1.87]) and OHIM (OR=1.44 [1.02, 2.04]) increased elevated anxiety odds. ConclusionsOrganophosphates, pyrethroids, and neonicotinoids were generally linked to higher depression and anxiety, while sulfoximines and one organophosphate appeared protective. OHIM and trans-DCCA showed consistent adverse associations across years.

INTRODUCTIONEnvironmental organic pollutants impact brain function and cognitive aging, but the effects of real-world complex mixtures of these pollutants is unexplored. METHODSUsing data collected at two time points from 170 cognitively normal adults, we used hierarchical Bayesian kernel machine regression to examine the association between joint exposure to 49 organic pollutants and latent variables, derived from neuropsychological tests, that capture key aspects of cognitive aging. RESULTSWe observed a non-linear, inverted U-shaped relationship between the pollutant mixture and the global cognitive score. Polychlorinated biphenyls (PCBs) were the most important pollutant group in the mixture followed by industrial-use pollutants. DISCUSSIONExposure to a mixture of organic pollutants was associated with poor cognitive aging. Even though many of these pollutants, like PCBs, have been banned for decades, they persist in our environment. Strategies to reduce exposure to these organic pollutants are needed to minimize their impact on cognitive aging.

IntroductionThe association between air pollution and poor respiratory health outcomes is well established, however less is known about the biological mechanisms, especially in early life. Children are particularly at risk from air pollution, especially during the prenatal period as their organs and systems are still undergoing crucial development. Therefore, our study aims to investigate if maternal exposure to air pollution during pregnancy is associated with oxidative stress (OS) and inflammation in pregnancy or infant lung function at 4 weeks of age, and the extent to which the association is modified by an infants genetic risk of OS. MethodsThe Barwon Infant Study (BIS) is a longitudinal study of Australian children from the region of Geelong, Victoria. A total of 314 infants had available lung function and maternal OS markers. Exposure to annual air pollutants (NO2 and PM2.5) were estimated using validated, satellite-based, land-use regression models. Infant lung function was measured by multiple-breath washout, and the ratio of peak tidal expiratory flow over expiratory time was calculated at 4 weeks of age. An inflammation biomarker, glycoprotein acetyls (GlycA), was measured in maternal (36 weeks) and cord blood, and oxidative stress (OS) biomarkers, 8-hydroxyguanine (8-OHGua) and 8-hydroxy-2-deoxyguanosine (8-OHdG) were measured in maternal urine at 28 weeks. A genetic pathway score for OS (gPFSox) was calculated for each infant participant in the BIS cohort, and high risk defined as score >8. Linear regression was used to explore the association of maternal air pollution exposure with infant lung function, and potential modification by OS genotype was tested through use of interaction terms and other methods. ResultsThere was no evidence of a relationship between maternal exposure to air pollution and infant lung function in the whole population. We did not find an association between air pollution and GlycA or OS during pregnancy. We found evidence of an association between NO2 and lower in functional residual capacity (FRC) for children with a high genetic risk of OS ({beta}=-5.3 mls, 95% CI (-9.3, -1.3), p=0.01). We also found that when NO2 was considered in tertiles, the highest tertile of NO2 was associated with increase in lung clearance index (LCI) ({beta}=0.46 turnovers, (95% CI 0.10, 0.82), p=0.01) in children with a genetic propensity to OS. ConclusionOur study found that high prenatal levels of exposure to ambient NO2 levels is associated with lower FRC and higher LCI in infants with a genetic propensity to oxidative stress. There was no relationship between maternal exposure to air pollution with maternal and cord blood inflammation or OS biomarkers.

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.

BackgroundThe impact of chemical exposures on breast cancer progression is poorly characterized and may influence the development of more severe and aggressive subtypes. ObjectivesThere is a suite of toxicants, including metals, pesticides, and personal care product compounds, which are commonly detected at high levels in US Center for Disease Controls National Health and Nutrition Examination Survey (NHANES) chemical biomarker screens. To characterize the impact of these toxicants on breast cancer pathways, we performed high throughput dose-response transcriptomic analysis of toxicant exposed breast cells. MethodsWe treated non-tumorigenic mammary epithelial cells, MCF10A, with 21 chemicals at four doses (25nM, 250nM, 2.5{micro}M, 25{micro}M) for 48 hours. We conducted RNA-sequencing for these 408 samples, adapting the PlexWell plate-based RNA-sequencing method to analyze changes in gene expression resulting from these exposures. For each chemical, we calculated gene and biological pathway specific benchmark doses using BMDExpress2, identifying differentially expressed genes and generating the best fit benchmark dose models for each gene. We employed enrichment testing to test whether each chemicals upregulated or downregulated genes were over-represented in a biological process or pathway. We contextualized benchmark doses relative to human population biomarker concentrations in NHANES. ResultsOverall, significant changes in gene expression varied across doses of each chemical and benchmark dose modeling revealed dose-responsive alterations of thousands of different genes. Comparison of benchmark data to NHANES chemical biomarker concentrations indicated an overlap between actual exposure levels and levels sufficient to cause a gene expression response. Enrichment and cell deconvolution analyses showed benchmark dose responses correlated with changes in cancer and breast cancer related pathways, including induction of basal-like characteristics for some chemicals, including p,p-DDE, lead, copper, and methyl paraben. DiscussionThese analyses revealed that these 21 chemicals induce significant changes in pathways involved in breast cancer initiation and progression at human exposure relevant doses.

Several recent studies have found troubling links between air pollution and both incidence and mortality of COVID-19, the pandemic disease caused by the virus SARS-CoV-2. Here, we investigate whether such a link can be found also in Sweden, a country with low population density and a relatively good air quality in general, with low background levels of important pollutants such as PM2.5 and NO2. The investigation is carried out by relating normalized emission levels of several air pollutants to normalized COVID-19 deaths at the municipality level, after applying a sieve function using an empirically determined threshold value to filter out noise. We find a fairly strong correlation for PM2.5, PM10 and SO2, and a moderate one for NOx. We find no correlation neither for CO, nor (as expected) for CO2. Our results are statistically significant and the calculations are simple and easily verifiable. Since the study considers only emission levels of air pollutants and not measurements of air quality, climatic and meteorological factors (such as average wind speeds) can trivially be ruled out as confounders. Finally, we also show that although there are small positive correlations between population density and COVID-19 deaths in the studied municipalities (which are for the most part rural and non densely populated) they are either weak or not statistically significant.

Air pollution is increasingly discussed as a risk factor for dementia, but the biological mechanisms are not yet fully understood. Cellular integrity markers like telomere length are relevant to investigate in relation to air pollution exposure in this context, as they are associated with aging and dementia. Previous studies on air pollution and telomere length have somewhat mixed results, which may partly be due to differences in air pollution modelling, composition, and concentrations. The study aimed to investigate the relationship between source-specific air pollution exposure and telomere length in a low-level air pollution area. Data were obtained from the Betula project, a longitudinal study in Northern Sweden dedicated to studying aging, memory and dementia. A total of 519 participants who were recruited between 1988 and 1995 were included, whose relative telomere length was measured, and who were followed-up with respect to dementia for more than 20 years. To estimate annual mean air pollution concentrations, a dispersion model linked to each participants residential address was employed. We conducted linear regression to explore the associations between annual mean air pollution concentrations at participants residences and relative leukocyte telomere length. In the whole sample, there was no support for air pollution to affect telomere length, with regression slope estimates close to zero and p-values >0.10. There were tendencies for a positive association of longer telomere length and higher exposure to air pollution among individuals who were later diagnosed with dementia (N = 74), but these findings were not conclusive (p-values >0.10). The findings raise questions about susceptibility to air pollution and the state of the inflammatory response in individuals who later will develop dementia. Given the imprecise nature of these estimates, caution is advised in their interpretation however, and validation in other studies is essential.