NeuroToxicology

Neurodevelopmental disorders, including autism spectrum disorder (ASD), are influenced by both genetic abnormalities and environmental toxicants. Among environmental risk factors, endocrine-disrupting chemicals such as bisphenol A (BPA) and pharmaceutical drugs such as valproic acid (VPA) have been associated with an increased risk of autism. In this study, human induced pluripotent stem cell (iPSC)-derived forebrain organoids were used to model early neurodevelopmental disruptions induced by BPA and VPA exposure. On day 62 of differentiation, forebrain organoids were treated with physiologically relevant concentrations of BPA or VPA for 28 days. Following treatment, morphological, molecular, and electrophysiological changes were assessed across experimental conditions. Both compounds produced distinct alterations in organoid morphology, neurodevelopmental gene expression, and network electrical activity, with VPA inducing markedly stronger effects. Overall, these data suggest forebrain organoids as a robust, physiologically relevant in vitro model system for studying neurodevelopment. This platform enables systematic investigation of environmental and pharmacological risk factors implicated in the pathogenesis of neurodevelopmental disorders.

Background/ObjectivesOccupational exposure to neurotoxicants such as pesticides, metals, and solvents has long been implicated in Parkinsons disease (PD) and Parkinsonism, yet the cumulative impact of multiple occupational exposure families over the working life remains insufficiently characterized. This study evaluated whether long-term cumulative occupational exposures, derived from the ALOHA+ Job-Exposure Matrix (ALOHA+-JEM), were associated with PD and Parkinsonism. MethodsA hospital-based matched case-control study was conducted in the province of Brescia, Italy, including 668 participants (334 PD/Parkinsonism cases and 334 matched controls). Cases and controls were 1:1 matched based on sex, age, and lifetime occupational duration. Lifetime occupational histories were coded using ISCO-08 and harmonized to ISCO-88 for linkage with ALOHA+-JEM. Conditional logistic regression estimated associations between cumulative exposures (none/low/high) and disease status, adjusting for smoking, parental history of PD/tremor, and SNCA rs356219 genotype. Multi-agent occupational exposure burden indexes were evaluated using positively constrained repeated-holdout Weighted Quantile Sum (WQS) regression (100 bootstraps, 100 holdouts) ResultsIn conditional logistic regression, parental history of PD or tremor (OR = 4.55, 95% CI: 2.44-8.48; q < 0.001) and the SNCA rs356219 CC genotype (OR = 2.17, 95% CI: 1.33-3.52; q = 0.013) were significantly associated with disease. High cumulative all pesticide exposure showed positive associations with combined PD + Parkinsonism (OR = 2.98, 95% CI: 1.23-7.25) and PD alone (OR = 3.56, 95% CI: 1.25-10.15). In WQS analyses, the composite occupational exposure burden index was positively associated with disease (combined PD + Parkinsonism: OR = 1.15, 95% CI: 1.00-1.30). All pesticides received the highest mean weight in all models (w = 0.434 for combined PD + Parkinsonism), followed by metals (w = 0.210), identifying them as contributing most strongly to the composite exposure index. ConclusionsLong-term cumulative occupational exposures were associated with increased odds of PD and Parkinsonism. All pesticides and metals were most strongly associated with PD and Parkinsonism, consistent with established neurotoxic mechanisms attributable to occupational environments. These findings underscore the importance of occupational exposure prevention and risk-reduction strategies in occupational settings and highlight workplace exposures as preventable contributors to Parkinsonian disorders.

Air pollution has been increasingly linked to adverse neurodevelopmental and neurodegenerative outcomes. While experimental and preclinical studies suggest that exposure to particulate matter (PM), particularly during gestation, may disrupt cognitive development, the impact of short-term PM exposure on cognitive and behavioral functioning in healthy young populations remains insufficiently explored in Spain. Moreover, few studies have incorporated individualized dosimetry models to estimate exposure more accurately. This study included 186 healthy young adults (mean age = 20.4 years) recruited from three Spanish cities (Teruel, Almeria, and Talavera) characterized by different pollution levels. Ambient fine and coarse PM concentrations were recorded 8, 15, and 30 days prior to psychological assessment. Instead of relying solely on raw in situ environmental measurements, individualized PM deposition was estimated using the Multiple-Path Particle Dosimetry Model (MPPD), allowing a more biologically meaningful exposure approximation. Psychological outcomes were assessed using validated questionnaires: DASS-21 (depression, anxiety, stress), BIS-11 (impulsivity), UCLA Loneliness Scale, and SWLS (life satisfaction). Behavioral performance was evaluated using computerized versions of the Attentional Network Task (ANT) and the Stroop Task. Blood NRF2 concentrations were analyzed as a biomarker potentially related to oxidative stress mechanisms. In situ data indicated that Talavera presented the highest pollution levels, followed by Almeria and Teruel. Linear regression analyses showed that coarse PM exposure across 8-, 15-, and 30-day windows significantly predicted poorer Executive Control Index performance in the ANT. Additionally, 15-day coarse PM and 30-day fine PM exposure were associated with greater cognitive interference. Oxidative stress markers were significantly associated with PM exposure levels. These findings support emerging evidence that short-term PM exposure may negatively affect executive and attentional processes even in healthy young adults. Further longitudinal research incorporating individualized exposure modeling is warranted to clarify causal pathways and underlying biological mechanisms. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/713644v1_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@1a0ac13org.highwire.dtl.DTLVardef@1812accorg.highwire.dtl.DTLVardef@120bf07org.highwire.dtl.DTLVardef@dd9a7c_HPS_FORMAT_FIGEXP M_FIG C_FIG

Widespread exposure to multiple pesticides might potentially represent a genotoxic risk to humans. However the effects of these mixtures are largely unknown. Genotoxicity is a key characteristic of carcinogens, and its assessment represents an important component of the overall safety assessment of pesticides. In the present study, in vitro micronucleus test on intestinal Caco-2 human cells was performed according to OECD TG 487 in order to ascertain the genotoxicity of ten commonly used pesticides (dose range 0-100 mg L-1), tested as individual pesticides or mixtures. Significant dose-related increases in micronuclei were observed for exposures to lambda-cyhalothrin, tebuconazole, glyphosate, deltamethrin, fluopyram and the synergist piperonyl butoxide. Significant increases of micronuclei were also observed at different doses for cypermethrin, acetamiprid and cyprodinil, however these increases were not dose-dependent. Imazalil genotoxicity could not be analyzed due to confounding of high cytotoxicity even at low doses. Results show that the co-formulant piperonyl butoxide was genotoxic to human cell lines at all tested doses. Moreover, glyphosate, acetamiprid and fluopyram showed genotoxic effects at concentrations of 0.01-1.0 mg L-1. Although previously reported to be not genotoxic cyprodinil and deltamethrin were observed to be genotoxic to Caco-2 cells. A combination of 3 prioritzided pesticides (acetamiprid, glyphosate, tebuconazole) showed genotoxic effects even at the lowest dose. A combination of 8 prioritized pesticides showed genotoxicity at the highest dose. No synergistic interactions in micronuclei formation were evident in either the mixture of 3 or 8 prioritized pesticides. This study provides important information on the genotoxicity of different widely used pesticides and confirms the validity of a component-based approach in genotoxicity assessment of pesticide mixtures. This study was performed as part of the EU SPRINT (Sustainable Plant Protection Transition: A Global Health Approach) project.

Ethylene oxide (EtO) is primarily used as an intermediate in the manufacture of chemicals, with a minor use as a sterilant for medical equipment and food products. It is a direct-acting alkylating agent that reacts with cellular macromolecules, including proteins and DNA. EtO has been shown to induce tumors in rodents and humans. DNA reactivity has been the postulated mode of action (MOA) for its carcinogenicity. The current study has investigated the dose response for EtO-induced genetic damage to inform the biological plausibility of a dose-response model for cancer risk assessment. Male and female B6C3F1 mice were exposed to 0, 0.05, 0.1, 0.5, 1, 50, 100, or 200 ppm EtO by whole-body inhalation (6 hours/day for 28 days, 7 days/week). Mutagenicity was assessed by determining the frequency of mutant Pig-a phenotype in reticulocytes (RET) and mature red blood cells (RBC) on Day 28. Cytogenetic damage was evaluated by the erythrocyte micronucleus (MN) test in blood samples collected on Days 5 and 28. EtO is a relatively weak genotoxicant with treatment-related increases in Pig-a and MN frequencies being seen primarily at 200 ppm. The hockey-stick shaped dose response for genetic damage may be conservatively interpreted as being no more than a linear response with a single slope. Thus, a cancer risk assessment dose-response model consisting of a single linear slope throughout the exposure range is biologically plausible and consistent if EtO were acting through a mutagenic MoA for its carcinogenicity.

Mosquito-borne diseases such as dengue, chikungunya, and malaria remain major public health challenges in South Asia, particularly in Bangladesh, where mosquito repellents are widely used as primary preventive tools. This study presents a comparative evaluation of commonly used repellent products, including mosquito coils, liquid vaporizers and aerosols, DEET-based creams, and natural formulations, focusing on their efficacy, protection duration, and potential health risks. Efficacy was assessed using controlled laboratory methods, including chamber-based exposure and arm-in-cage tests against Aedes aegypti (Barnard & Xue, n.d.). Safety was evaluated through in vivo toxicological analysis in a rat model, incorporating clinical observations, hematological and biochemical profiling, and histopathological examination. The results indicated an overall mean effectiveness of 85%, with DEET-based creams demonstrating the highest efficacy (95%), while natural repellents showed the lowest (70%). Mosquito coils provided the longest protection duration ([~]10 hours) but were associated with the highest health risk due to combustion-related emissions. Vaporizers and aerosols offered moderate efficacy with moderate health risk. Toxicological findings revealed that coil exposure induced significant respiratory stress, elevated liver enzymes (ALT, AST), increased leukocyte count, and notable lung tissue damage. Vaporizer and aerosol exposure resulted in mild physiological changes, whereas DEET-based and natural repellents showed minimal systemic toxicity. Overall, the study highlights a clear trade-off between efficacy and safety across repellent types. These findings emphasize the need for informed product selection, stronger regulatory control, and the development of safer, cost-effective, and sustainable mosquito repellent technologies for effective vector control in endemic regions.

Of the cytochrome P450 enzymes, CYP3A4 is the most abundant isoform in the human liver, and this enzyme plays a dominant role in the metabolism of a wide range of clinical drugs and xenobiotics. Previous studies have demonstrated that CYP3A4 participates in the oxidative metabolism of several organophosphorus (OP) pesticides involving both thion (P=S) and oxon (P=O) forms. In the present study, we evaluated the capacity of CYP3A4 to metabolize a structurally diverse set of OP compounds using LC-MS/MS methods and assessed their potential to inhibit CYP3A4 activity using previously developed pFlour50 fluorogenic assay. Our results demonstrate that CYP3A4 preferentially metabolizes thions, as compared to oxons, and several OP compounds were also found to inhibit CYP3A4 activity in a time-dependent manner. To gain further mechanistic structural insight into the CYP3A4-OP interactions, molecular docking studies were performed using a crystal structure of CYP3A4 (PDB ID: 3NXU). Linear correlation analysis between in silico parameters like molecular weight or binding energy correlated with experimental data including inhibition data for 10 or 30 minutes or the LC-MS/MS data showing the degradation at 1 or 2 hours showed moderate but significant correlation. Soman surrogate PiMP, and cyclosarin surrogate CMP, were both effectively metabolized by CYP3A4, while docking of these surrogates and authentic agents with CYP3A4 receptor revealed very similar binding poses and interactions. Collectively, these findings highlight the important role of CYP3A4 in OP metabolism and support the potential of integrating experimental and in silico data to predict CYP3A4-mediated metabolism of existing and emerging OP compounds, including those of toxicological and chemical warfare relevance.

Neonatal meconium provides a non-invasive matrix for assessing prenatal or near-birth exposure to environmental contaminants. Although microplastics and metals have each been reported in human biological samples, integrated assessments of concurrent particle and metal exposure in meconium remain scarce, particularly in South Asia. In this cross-sectional biomonitoring study, meconium from 30 Cesarean-delivered neonates born in Dhaka, Bangladesh, was analyzed for microplastic occurrence, morphology, and polymer composition using stereomicroscopy, scanning electron microscopy, and Raman spectroscopy, and for fifteen metals using inductively coupled plasma mass spectrometry. Maternal breast milk from a subset of lactating mothers was analyzed as a complementary maternal exposure context. Microplastics were detected in all analyzable meconium samples (n=28), with a median burden of 149 particles/g wet weight, dominated by polyethylene terephthalate fragments and nylon fibers. All fifteen measured metals were also detected in all analyzable meconium samples, with median Pb and Cr concentrations of 1.18 and 3.92 ug/g dry weight, respectively. No microplastic-metal associations remained significant after multiple-testing correction, suggesting partly distinct exposure or accumulation pathways. Here, we show that neonatal meconium captures concurrent microplastic and metal exposure in an urban South Asian birth cohort. This study provides one of the first integrated meconium-based assessments of concurrent microplastic and metal exposure from the region and highlights meconium as a practical matrix for early-life biomonitoring.

INTRODUCTION: Alzheimers disease (AD) is a multifactorial disorder, yet current research largely focuses on downstream biomarkers with limited attention to environmental contributors. Experimental studies suggest that per and polyfluoroalkyl substances (PFAS) may contribute to neuroimmune and neurodegenerative pathways relevant to AD. OBJECTIVE: To examine associations between PFAS exposure and neuroimmune and AD related plasma biomarkers in cognitively unimpaired rural adults. METHODS: In a cross sectional pilot study (n=48), serum concentrations of 33 PFAS were measured, including four legacy compounds (PFOS, PFHxS, PFOA, PFNA). Plasma neuroimmune related (ITGB2, SMOC1, TREM2, GFAP) and AD related biomarkers (Ab42/40, ptau217) were detected using proteomic analysis. RESULTS: PFOS showed moderate associations with ITGB2, SMOC1, and Ab42/40 in unadjusted analyses, which attenuated after adjustment for age. PFOA and PFNA demonstrated consistent inverse associations with TREM2 before and after adjustment. DISCUSSION: Findings suggest possible compound specific PFAS associations with immune and amyloid related biomarkers, supporting further investigation in longitudinal and PFAS mixture based studies.

Evaluation of unintended immunotoxicity represents an important component of nonclinical safety assessment, as perturbation of immune function may increase susceptibility to infection, impair vaccine responses, and disrupt immune homeostasis. Regulatory guidance, including the ICH S8 Immunotoxicity Guideline, recommends a weight-of-evidence approach in which observations from conventional toxicological endpoints are integrated with functional immune assays to support interpretation of immune system effects. The present study applied an integrated immunotoxicity evaluation framework to examine concordance among structural, functional, and cellular immune endpoints in male Sprague-Dawley rats using a well-characterized immunosuppressive reference compound. Hematological evaluation revealed leukopenia characterized primarily by lymphocyte depletion. Reductions in spleen and thymus weights were accompanied by histopathological evidence of lymphoid depletion in multiple immune tissues, including spleen, thymus, lymph nodes, Peyers patches, and bone marrow. Functional immune competence was assessed through hemagglutination antibody response to sheep red blood cells and delayed-type hypersensitivity assays, both of which demonstrated marked suppression of adaptive immune responses. Flow cytometric immunophenotyping further demonstrated substantial reductions in B-cell populations and decreases in CD4 and CD8 T-cell counts, whereas NK cell populations were comparatively less affected. The concordance of hematological alterations, lymphoid tissue changes, impaired functional immune responses, and lymphocyte subset depletion provides integrated evidence of immune system perturbation. These findings demonstrate that complementary immunotoxicity endpoints collectively support hazard characterization of immune system effects under GLP conditions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/713556v1_ufig1.gif" ALT="Figure 1"> View larger version (72K): org.highwire.dtl.DTLVardef@beaf9dorg.highwire.dtl.DTLVardef@fb9f10org.highwire.dtl.DTLVardef@187ff06org.highwire.dtl.DTLVardef@1780dc2_HPS_FORMAT_FIGEXP M_FIG C_FIG

Silver has been used as a biocide for centuries, mostly in health-oriented applications. However, as a biocide, silver is toxic not only to its intended targets, mainly bacteria and fungi, but also to all living cells. Because of this toxicity, it is desirable to use forms of silver that maximize the required biocidal activity while minimizing the amount of silver that will be released in the environment at the end of life of the product. Silver nano objects are a good compromise for such requirements. The high surface to volume ratio allows for good reactivity and thus good biocidal activity, while the small amount of silver present in nano objects allows for a limited environmental release at the product end of life. In this work, we tested three types of silver nano objects. The first type, polyvinylpyrrolidone-coated silver nanoparticles (nAg-PVP) were used as a control nanoparticle, as this type of nanoparticle is now widespread. We also manufactured and tested maltodextrin-coated silver nanoparticles (nAg-MD) and micrometric (20 {micro}m in two dimensions and a few nanometers in the third one) silver flakes ({micro}AgSF). For these three silver nano objects, we investigated the biocidal activity by stringent tests using both Staphylococcus aureus and Escherichia coli as target bacteria. In addition, we investigated toxicity on mammalian macrophages or keratinocytes cell lines, as well as on an insect hemocyte cell line. Our results showed that the two innovative silver nano objects (nAg-MD and even more {micro}AgSF), showed both a better bactericidal activity and a lesser toxicity than the reference nAg-PVP nanoparticles. In addition, we also checked that beyond toxicity, the silver nano objects did not induce an inflammatory reaction, making them safer to use.

The ubiquitously occurring food contaminants altenuene (ALT) and tentoxin (TEN) are recognized as emerging Alternaria mycotoxins, yet substantial data gaps remain when it comes to their toxicological behavior and toxicokinetic characteristics. This study aimed to compare and generate quantitative data on their hepatic metabolism and to obtain semi-quantitative insights into their metabolite profiles. To this end, primary rat and human hepatocytes were incubated with 10 {micro}M ALT or TEN over multiple time points up to 4 h. Both substrate depletion and metabolite identification revealed pronounced interspecies differences. The extent of ALT metabolism was significant, with an 88% and 57% decrease in rat and human hepatocytes after 4 h, respectively. In contrast, TEN showed extensive biotransformation in rats (67%) but only modest turnover in humans (27%) over the same period. Hepatocellular clearances were consistently higher for ALT than TEN, with hepatic extraction ratios indicating intermediate extraction for ALT and low extraction for TEN. High-resolution mass spectrometry combined with targeted analysis of selected metabolites annotated phase II conjugation as the predominant metabolic pathway for ALT and phase I oxidative metabolism for TEN, including mono- and double-metabolized species for the latter. Overall, these results provide a comprehensive characterization of ALT- and TEN-metabolism in hepatocytes, offering a foundation for future studies on their toxicological relevance and impact on human health.

Micro and nanoplastics are pollutants which concentration in different biotopes increases continuously over time, which poses the question of their potential effects on health. In animals, these micro and nanoplastics are recognized as particulate materials and thus handled by macrophages, which are therefore a key cell type to study. Most studies have used an experimental scheme in which the cells are exposed to a single dose of plastics, with a readout made immediately after exposure. However, this classical experimental scheme does not take into account the impact of biopersistence, nor the potential cellular adaptation that may take place when cells are exposed repeatedly to a low dose of plastics. We thus used a repeated exposure scheme, in order to better take into account these phenomena. Within this frame, we compared the macrophages responses to a persistent nanoplastic, i.e. polystyrene nanoparticles and to a biodegradable nanoplastic, i.e. polylactide, by a combination of proteomic and targeted experiments. Our results show that under this repeated exposure scheme, the proteome changes were of a lesser (for PS) or similar (for PLA) extent than under the acute exposure mode, indicating cell adaptation. However, PLA particles induced mitochondrial dysfunction and depression of response to bacterial molecules perceived as danger signals, such as lipopolysaccharide. Polystyrene nanoparticles also induced a slight alteration of the immune functions of macrophages. This indicates harmful effects even in the repeated exposure scheme.

Bats are exposed to a variety of pollutants, including cadmium (Cd), that can impair immune function and potentially increase viral shedding and burden. Despite this, little is known about the impacts of heavy metals on bats. This study aimed to determine the impacts of Cd exposure on bat T and B cell immune responses in naive and coronavirus infected bats and determine the impact of Cd on viral replication in Jamaican fruit bat (JFB; Artibeus jamaicensis) cells. To determine the impact of Cd exposure on adaptive immune responses, splenocyte cultures from naive and BANAL-52 coronavirus infected JFB were treated with 0, 1, and 10 {micro}M Cd and stimulated overnight with concanavalin A. RNA was extracted, a SYBR Green qPCR was used to assess gene expression. To determine if Cd exposure increased viral replication, two JFB kidney cell clones were treated with 0, 1, 10, and 50 {micro}M of CdCl2 overnight and then infected with Cedar virus (CedV). Supernatants were collected and viral titers determined. Several transcripts were upregulated in both naive and virus infected JFB splenocytes treated with Cd. B cell transcripts were significantly upregulated in a dose-dependent manner and T cell transcripts were also increased in Cd treated splenocytes. Assessment of transcripts associated with T cell subsets suggest a predominant Th2 response in Cd treated splenocytes. Viral replication was not significantly different in Cd treated kidney clones compared to the non-treated cells. These studies provide evidence that JFB adaptive immune responses are altered when exposed to low Cd concentrations.

The foodborne mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME) have been associated with several adverse effects, including cytotoxicity, genotoxicity, endocrine disruption, and immunomodulation. As these endpoints are typically observed in vitro at micromolar concentrations, the question arises whether such levels are attainable in exposed humans. To address this data gap in chemical risk assessment, a physiologically based kinetic (PBK) model was developed to predict internal exposure doses to AOH and AME in humans. As input parameters, kinetic constants for hepatic glucuronidation were obtained in vitro by incubating Sprague Dawley rat and human liver S9 fractions with 0.5-50 M AOH and 0.5-20 M AME, demonstrating rapid biotransformation in both species. Intestinal absorption of AME and physicochemical parameters were estimated using quantitative structure-activity relationship (QSAR) models. Sensitivity analysis identified parameters describing hepatic glucuronidation and gastrointestinal uptake as among the most influential, confirming the importance of their reliable estimation. The PBK model was evaluated against available rodent toxicokinetic data and subsequently extrapolated to humans. Ultimately, the currently available exposure estimates published by EFSA in 2016 were applied to predict target tissue concentrations, which were compared to points of departure (PoDs) for relevant toxicological endpoints. Even in the most susceptible group of male toddlers, predicted internal concentrations (10-4 M range) were approximately four orders of magnitude below the respective PoDs. Consequently, under the applied exposure assumptions and considering the compounds as isolated chemicals, AOH and AME are not expected to reach systemic or tissue concentrations associated with the investigated effects.

The early developmental environment plays a critical role in the etiology of cardiovascular diseases (CVDs), but underlying molecular mechanisms are poorly understood. Exposure to per and polyfluoroalkyl substances (PFAS) are linked to various CVDs, but effects of developmental PFAS exposures on the human heart remain unclear. Using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), the objective of this study was to investigate the effects of PFAS exposure during cardiac differentiation on gene expression and function of cardiomyocytes. We exposed two hiPSC lines (one male and one female donor) to perfluorooctanoic acid (PFOA), a common and ubiquitous PFAS (0.05, 0.5, 5, 50, 100, 150, 200 M), followed by assessment of cellular number and pluripotency marker expression. PFOA exposure for 72 hours had no significant effects on hiPSC pluripotency, and modest inhibition of proliferation was observed only at the highest concentration. hiPSCs were then differentiated into ventricular cardiomyocytes in the continued presence or absence of PFOA (0, 0.5, 5, 50 M) using an established small molecules protocol. Optical mapping studies using voltage and calcium-sensitive dyes revealed dose and cell line-specific effects of PFOA on cardiomyocyte voltage and calcium dynamics that were still present 10 days after cessation of exposure. Patch clamping studies demonstrated small but significant reductions in repolarizing IKr currents with 5{micro}M PFOA exposure in cardiomyocytes from both donors. Using RNA-seq, we found that exposure to PFOA led to significant changes in transcriptional pathways related to lipids and lipoproteins in the female hiPSC-CM. In the male hiPSC-CM, we observed significant effects on developmental pathways and calcium homeostasis. Thus, we found that environmentally relevant PFOA exposure during cardiomyocyte differentiation affects the electrophysiological properties and transcriptome of hiPSC-CM even after cessation of exposure, with effects that differ by donor cell line. These findings provide direct experimental evidence that transient developmental exposure to PFOA can durably reprogram human cardiomyocyte function, supporting a developmental origin of PFAS-associated cardiovascular risk. Impact StatementThese studies demonstrate that exposure to environmentally relevant levels of PFOA during the differentiation of hiPSCs into cardiomyocytes alters cardiac gene expression and function, with effects that persist beyond cessation of exposure.

Ethylene oxide is a widely used industrial chemical,yet evidence linking its exposure to Parkinsons disease remains limited.Using data from participants in the United States,we examined whether exposure to ethylene oxide is associated with Parkinson's disease.This cross-sectional study included 8,430 adults from the National Health and Nutrition Examination Survey (NHANES) collected between 2013 and 2020.Information on demographic characteristics,socioeconomic factors,lifestyle behaviors,body mass index,sedentary time and major chronic conditions was analyzed. Levels of hemoglobin ethylene oxide adducts,a biomarker of ethylene oxide exposure, were evaluated in relation to Parkinsons disease using statistical modeling approaches.After accounting for potential confounding factors,higher levels of ethylene oxide exposure were associated with an increased likelihood of Parkinson's disease.The association followed a positive and linear pattern.These findings provide new population-based evidence suggesting that ethylene oxide may be linked to Parkinsons disease and highlight the need for further studies to confirm causality and to better understand the biological mechanisms involved.

Per- and polyfluoroalkyl substances (PFAS) are globally recognised as emerging contaminants of concern due to their persistence, toxicity, endocrine-disrupting and immunosuppressive effects. Because of their extensive industrial use, PFAS are now widespread across ecosystems and accumulate in marine environments. Despite their ubiquity, the extent and drivers of PFAS contamination remain poorly characterised, particularly in marine systems. Odontocetes (toothed whales) are effective bioindicators of marine pollution, integrating contamination across regions, time, and trophic levels. Here, we present the first global assessment of factors influencing PFAS contamination in marine ecosystems by analysing standardised PFAS concentrations of PFNA, PFDA, PFUnDA, PFDoDA and PFOS reported for 713 liver samples across 33 odontocete species spanning 13 countries from 2000 to 2023. Using generalised linear mixed models, we evaluated the effects of genus, location, sex, life stage, and sampling year on PFAS concentrations, combining published datasets with new samples from Australia. Genus and location were the strongest predictors, suggesting that interspecific ecological and physiological traits likely contribute to PFAS accumulation. Concentrations were highest in males and younger individuals, consistent with maternal offloading and possible age-related dilution. Spatio-temporal trends indicate that PFAS contamination is widespread and increasing globally, with highest concentrations reported in the Pacific. This study provides a critical baseline for understanding global PFAS exposure in marine mammals, which underscores the need for coordinated monitoring and further research to address regional data gaps and potential unrecognised biological effects. HighlightsO_LIHigh genus-specific and spatial differences in PFAS contamination across odontocetes globally. C_LIO_LIIncreased contamination in younger/smaller individuals. C_LIO_LISex-specific trends, including higher PFAS levels in male odontocetes. C_LIO_LISpatio-temporal trends suggesting increased PFAS concentration despite global regulatory efforts, with highest concentrations in the Pacific Ocean. C_LI

INTRODUCTIONMounting evidence support exposome influences on brain function and health, complementing genome influences. Understanding the molecular imprint of exposome on brain metabolism and the biochemical communication between the body and brain can impact our fundamental understanding and treatment of neuropsychiatric diseases. METHODSLeveraging two complementary metabolomics platforms, we classified 1400 features in 514 brains from the ROSMAP collection. We evaluated the origin of these compounds using literature and databases. We correlated those metabolites with cognitive function using linear models. RESULTSWe identified over 230 non-endogenous compounds in the brain, including 103 drugs and metabolites, 120 dietary and microbial products and possibly 15 compounds from environmental exposures. Over 20 dietary and gut microbial compounds showed associations with cognition. DISCUSSIONComprehensive profiling of chemicals in the brain and the link to cognitive function provides foundational work to connect body and brain in the study of AD and related dementias.

Railway catenary sparking generates airborne ultrafine particles (UFPs) that may pose health risks due to their metallic composition and ability to penetrate deep into the alveolar region of the lungs. Copper, widely used in wires and pantographs, is a major component of these emissions, making copper-rich particles common in railway environments such as subways. However, exposure levels and health impacts remain poorly characterized, and localized hotspots may represent an underrecognized risk in densely populated areas. This study investigated the toxicity of copper UFPs under realistic dosimetry and deposition conditions. Copper UFPs were generated using a spark discharge generator and applied to two in vitro lung models: a 3D co-culture of Calu-3 epithelial cells, THP-1-derived macrophages, and EA.hy926 endothelial cells, and a monoculture of A549 alveolar epithelial cells. Cells were exposed at the air-liquid interface (ALI) using an automated platform to mimic inhalation exposure and UFPs deposition. Copper deposition ranged from 6.5 to 41 ng/cm2, within occupationally relevant levels. A549 cells showed cytotoxic responses consistent with previous studies, whereas the 3D co-culture model revealed broader adverse effects, including inflammation, impaired epithelial barrier integrity, oxidative stress, and early DNA damage. Inflammatory activation also differed between models: A549 cells mainly exhibited transcriptional responses, while the 3D model showed significant secretion of IL-6 and IL-8, associated with interferon signaling. These findings highlight the potential health risks of copper UFPs from railway systems and emphasize the need for improved characterization of UFP exposure in environmental and occupational railway settings.