NeuroToxicology

IntroductionMetal exposure has been associated with higher risk of neurodegenerative disorders such as Alzheimers disease (AD). We examined the potential link between welding-related metal co-exposure (e.g., Fe, Mn, Pb) and AD-related structural and neurobehavioral metrics. MethodsSubjects with (welders; n=42) or without (controls; n=31) a history of welding were examined. Metal exposure was estimated by exposure questionnaires and whole blood metal levels. Brain metal accumulations were estimated by MRI R1 (Mn) and R2* (Fe) in the caudate, putamen, globus pallidus, red nucleus (RN), and hippocampus. AD-related structural differences were assessed by volume and diffusion tensor imaging metrics in the hippocampus, and neurobehavioral aspects by learning/memory task scores. ResultsCompared to controls, welders displayed higher blood metal levels (ps <0.004) and R2* values in the caudate and RN (ps<0.024). Caudate R2* values were associated with blood Fe (p=0.043), whereas RN R2* values were correlated with blood Pb (p=0.003). Welders had higher hippocampal mean diffusivity (MD; p=0.011) and lower Story Recall scores (p=0.049), but no difference in volume or domain-wise learning/memory performance (ps>0.117). Group differences in hippocampal MD and Story Recall scores were greater with higher RN R2* values (ps<0.016). Moreover, RN R2* values reflected an indirect link between blood Pb and hippocampal MD (p=0.036) across both groups. DiscussionWelders had hippocampal structural and learning/memory performance differences similar to those in AD-at-risk populations. These AD-like differences in welders may, in part, be linked to Pb exposure reflected by higher RN R2* levels at the brain level.

Alzheimers disease (AD) is one of the most prevalent neurodegenerative disorders and one of the leading causes of death in individuals over the age of 65. Most cases of AD develop sporadically, however, there are several risk factors that have been identified which significantly increases an individuals risk for developing AD. The most prominent of these is Apolipoprotein E4 (APOE4), which can potentially result in an up to 10-fold greater risk of developing AD. The presence of APOE4 alone, however, cannot be solely responsible for AD as the disease may occur even in the absence of APOE4. Therefore, there must be other contributing factors such as exposure to environmental toxins including heavy metals and pesticides, which have independently been shown to contribute to AD. Nano- and microplastics (NMPs) are plastic particles less than 1 m and 5 mm in size, respectively, and have only recently been identified as a major environmental pollutant with serious health concerns. Given the adverse health effects that are increasingly being associated with NMPs exposure, we sought to understand how the combination of APOE4 and NMPs exposure may work synergistically to promote cognitive dysfunction and alter key regulatory pathways to impact overall health. Following an acute (3 week) exposure to pristine spherical fluorescently-labeled 0.1 and 2 {micro}m polystyrene (PS) NMPs, we found significant sex-dependent alterations in locomotor and recognition memory in APOE4 mice, but not in APOE3 controls. We additionally found that exposure to PS-NMPs resulted in sex and genotype specific alterations in astrocytic and microglial markers in the brain, and in CYP1A1, a major metabolizer of environmental polycyclic aromatic hydrocarbons, in the liver. These results suggest PS-NMPs may interact with the APOE4 allele to promote cognitive dysfunction and alter immune and metabolic pathways which may contribute to disease-like states.

BackgroundChlordecone (CLD) is a persistent organochloride pesticide formerly used against banana weevil. It is detectable in blood samples from a large proportion of the population in the French Caribbean Islands. Several experimental studies have demonstrated acute neurotoxicity of CLD, but the effect of a subchronic exposure to CLD remains to be studied. MethodsYoung adult male mice were injected intraperitoneally with 3 mg/kg CLD (n=34) or vehicle (n=22), twice a week, for eight weeks. Behavior, regional brain accumulation, and effects on the dopaminergic system were studied. In addition, functional ultrasound imaging (fUSi) was used to probe the visual, somatosensory and dopaminergic pathways. ResultsCLD was detected in all brain regions (5-15 mg/kg) after two-month exposure, without any marked impact on behavior (anxiety, motor coordination, memory). The dopaminergic system was mostly unaffected, despite slight decreases in the number of TH-positive neurons and the expression of VMAT2, quantified in a subset of animals. fUSi highlighted a decreased response to the visual stimulation in CLD-exposed animals, in contrast to the sensorimotor response, which was found unaltered. ConclusionThe two-month-long, systemic, exposure to an intermediate dose of CLD resulted in a mostly unaffected phenotype, with a normal behavior and a largely intact dopaminergic system. Interestingly, functional ultrasound imaging was able to detect an altered visual response, which has also been noted in Parkinsons disease. This study position functional ultrasound imaging as a promising technique to capture early signs of neurotoxicity, opening up opportunities for "toxico-fUS" in the field of neurotoxicology. HighlightsHigh CLD neurotropism confirmed in mice by LC-MS/MS. Sub-chronic chlordecone exposure suggests possible early signs of parkinsonism. Functional UltraSound reveals impairment of brain areas linked to vision and hearing.

BackgroundThe increasing awareness that environmental exposure may lead to sporadic neurological disorders has implicated rotenone to the etiology of some neurodegenerative diseases. However, the risk associated with rotenone toxicity remains controversial as a limited amount of research has studied its effects on brain health. ObjectivesThis work assessed the risk of rotenone exposure to mice of different ages, gender, and duration by examining in vivo effects on brains. MethodsUsing a mouse model, the impact of rotenone exposure was determined by analyzing the cellular phenotype in the murine brain. ResultsOur results highlight the neurological susceptibility to long-term rotenone exposure in younger ages. For such, younger mice exhibit seizures and convulsions, resulting in shorter lifespan. At the cellular level, rotenone exposure specifically alters the migrating neuroblast populations in the dentate gyrus and causes disorganized pyramidal neurons in the CA3 within the hippocampus. Our findings, albeit the absence of transgenerational inheritance, demonstrated age-related outcomes from rotenone exposure. DiscussionWe demonstrated that rotenone exposure specifically influences the population of neuroblasts and pyramidal neurons residing in the hippocampus, a brain region important for learning/memory and associated with convulsive seizure. Our understanding of how exactly rotenone affected region-specific neuronal cells and the molecular mechanism behind exposure risk is still limited. From the perspective of public health, our in vivo study highlights age-related susceptibility to rotenone toxicity. Future investigations in environmental epidemiology should determine whether age and duration of exposure to rotenone in human subjects pertains to the development of seizures or other neurological abnormalities over time.

Lead (Pb) continues to be a public health burden, in the US and around the world, and yet the effects of historical and current exposure levels on neurogenesis are not fully understood. Here we examine the effects of a range of environmentally relevant Pb concentrations (0.16M, 1.26M, and 10M Pb) relative to control on neural differentiation in the SH-SY5Y cell model. Pb exposure began on Day 5 and continued throughout differentiation at Day 18. We assessed morphological measures related to neurogenesis at several time points during this process, including the expression of proteins key in neural differentiation ({beta}-tubulin III and GAP43), cell number and size, as well as the development of neurites. The bulk of detectable changes occurred with 10M Pb exposure, most notably that of {beta}-tubulin III and GAP43 expression. Effects with the 0.16M and 1.26M Pb exposure conditions increased as differentiation progressed, with significant reductions in cell and nuclear size as well as the number and length of neural projections by Day 18. Best benchmark concentration (BMC) analysis revealed many of these metrics to be susceptible to levels of Pb at or below historically relevant levels. This work highlights the disruption of neurite formation and protein expression as potential new mechanisms by which environmentally relevant Pb exposure impacts neurogenesis and morphology and perturb cognitive health throughout the life course.

BackgroundAlzheimers disease (AD) is characterized by the presence of amyloid-{beta} plaques, neurofibrillary tangles, and neuroinflammation. Previously, we reported serum levels of dichlorodiphenyldichloroethylene (DDE), the primary metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were significantly higher in AD patients compared to age-matched controls and that DDT exposure worsened AD pathology in animal models. ObjectiveHere, we investigated the effect of DDT on neuroinflammation in primary mouse microglia (PMG) and C57BL/6J mice. MethodsEffects of DDT on inflammation and disease-associated microglia were determined in primary mouse microglia and C57BL/6J mice. ResultsPMG exposed to DDT (0.5-5.0 {micro}M) elicited a [~]2-3-fold increase in Il-1b mRNA levels, with similar concentration-dependent upregulation in Il-6, Nos2, and Tnfa. These effects were blocked by the sodium channel antagonist tetrodotoxin, demonstrating the role of DDT-microglial sodium channel interactions in mediating this response. Additionally, NOS2 protein levels increased by [~]1.5-2-fold, while TNFa was elevated by 2-4-fold. C57BL/6J male and female mice exposed to DDT (30 mg/kg) demonstrated significantly increased mRNA levels of Nos2, Il-1b, and Il-6 in the frontal cortex (1.5-2.3-fold), and Nos2, Il-1b, and Tnfa (1.5-1.8-fold) in the hippocampus. Furthermore, microglial homeostatic genes, Cx3cr1, P2ry12, and Tmem119, were downregulated, while stage 1 disease-associated microglia genes were upregulated both in vitro and in vivo. Notably, Apoe and Trem2 were only upregulated in the frontal cortex and hippocampus of females. ConclusionThese data indicate that DDT increases neuroinflammation, which may result from direct actions of DDT on microglia, providing a novel pathway by which DDT may contribute to AD risk.

BackgroundThe formation of hyperphosphorylated tau (p-tau) protein tangles in neurons is a pathological marker of Alzheimers disease (AD). Exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) has been associated with increased risk of AD. ObjectivesTo determine if there was a connection between DDT exposure and tau toxicity we investigated whether exposure to DDT can exacerbate tau protein toxicity in C. elegans. In addition, we examined the association between p-tau protein and metabolism in a human population study and in a transgenic C. elegans strain neuronally expressing a mutant tau protein fragment that is prone to aggregation. MethodsIn the human population study, we used a metabolome-wide association framework to determine the association between p-tau measured in the cerebrospinal fluid (CSF) and metabolomic features measured in both plasma (n = 142) and CSF (n = 78) using high-resolution metabolomics (HRM). Using the same HRM method, we determined changes in metabolomic features in the transgenic C. elegans strain compared to its control strain. Metabolites associated with p-tau in both species were analyzed for overlap. We also examined the effect of DDT and aggregating tau protein on growth, swim behavior, mitochondrial function, metabolism, learning, and lifespan in C. elegans. ResultsPlasma and CSF-derived features associated with p-tau level were related to drug, amino acid, fatty acid and mitochondrial metabolism pathways. Five metabolites overlapped between plasma and C. elegans, and 4 between CSF and C. elegans. DDT exacerbated the inhibitory effect of aggregating tau protein on growth and basal respiration. In the presence of aggregating tau protein, DDT induced more curling and was associated with reduced levels of amino acids but increased levels of uric acid and adenosylselenohomocysteine. Developmental exposure to DDT blunted the lifespan reduction caused by aggregating tau protein. ConclusionThe model organism C. elegans can complement human studies by providing a means to study mechanisms of environmental toxicants. Specifically, our C. elegans data show that DDT exposure and tau protein aggregation both inhibit mitochondrial function and DDT exposure can exacerbate the mitochondrial inhibitory effects of tau protein aggregation providing a plausible explanation for the observed human associations.

Environmental factors shape organismal health through complex interactions known as the exposome. However, the interactions between chemical and non-chemical exposome factors remain largely unclear. Here, a dopaminergic reporter strain of Caenorhabditis elegans and a field isolated rhabditid nematode were used in a behavioral arena to assess natural variation in locomotory behavior in response to silica nanoparticles as a chemical exposome factor, and ambient temperature conditions (15 {degrees}C, 20 {degrees}C, and 25 {degrees}C) as non-chemical factors. Our results reveal that in the C. elegans strain lower temperature (15 {degrees}C) mitigates silica-induced locomotion deficits, while higher temperature (25 {degrees}C) exacerbates neurotoxicity, suggesting a temperature-dependent response. Notably, the wild rhabditid isolate showed distinct behavioral responses compared to the laboratory strain, highlighting the importance of species-specific ecological backgrounds in toxicological studies. This study provides a conceptual basis for integrating environmental factors and natural diversity into exposome research: Phenotype exposome maps, as presented here, broaden the identification of ecotoxicological hazards of nanomaterials across species. Author summaryIncorporating wild rhabditid species with unknown genotypes into neurotoxicology research broadens the traditional model-organism framework by extending beyond C. elegans to encompass a wider range of naturally occurring neuronal and behavioral variation. This phenotype-driven approach enables the detection of both conserved and species-specific responses to neurotoxicants, independent of prior genomic knowledge. Observed differences in locomotor behavior across nematode species may reflect underlying diversity in neural architecture or compensatory mechanisms, offering insights into the functional plasticity of nervous systems. By adopting a comparative perspective grounded in the ecological context, this strategy enhances the environmental relevance of neurotoxicity studies and promotes more inclusive ecological risk assessment through the use of field isolated nematodes in controlled laboratory settings. SynopsisWild nematodes and C. elegans differ in pollutant responses, highlighting the need for broader toxicology models. HighlightsO_LIWe report comparative testing of Caenorhabditis elegans and a wild rhabditid isolate in a behavioral arena. C_LIO_LIC. elegans and the wild isolate were assessed under multiple exposome conditions: silica nanoparticles and ambient temperatures (15-25 {degrees}C). C_LIO_LIField isolated rhabditid nematodes showed distinct behavioral responses to chemical and temperature exposures compared to C. elegans. C_LIO_LIThis study highlights the importance of including wild nematode isolates alongside C. elegans for ecological hazard identification of emerging pollutants like silica nanoparticles. C_LIO_LIWe culture wild nematode isolates under standardized laboratory conditions to probe the limits of C. elegans as a toxicology model and enhance its real-world relevance. C_LI

BackgroundLead (Pb) exposure is ubiquitous and has permanent developmental effects on childhood intelligence and behavior and adulthood risk of dementia. The hippocampus is a key brain region involved in learning and memory, and its cellular composition is highly heterogeneous. Pb acts on the hippocampus by altering gene expression, but the cell type-specific responses are unknown. ObjectiveExamine the effects of perinatal Pb treatment on adult hippocampus gene expression, at the level of individual cells, in mice. MethodsIn mice perinatally exposed to control water (n=4) or a human physiologically-relevant level (32 ppm in maternal drinking water) of Pb (n=4), two weeks prior to mating through weaning, we tested for gene expression and cellular differences in the hippocampus at 5-months of age. Analysis was performed using single cell RNA-sequencing of 5,258 cells from the hippocampus by 10x Genomics Chromium to 1) test for gene expression differences averaged across all cells by treatment; 2) compare cell cluster composition by treatment; and 3) test for gene expression and pathway differences within cell clusters by treatment. ResultsGene expression patterns revealed 12 cell clusters in the hippocampus, mapping to major expected cell types (e.g. microglia, astrocytes, neurons, oligodendrocytes). Perinatal Pb treatment was associated with 12.4% more oligodendrocytes (P=4.4x10-21) in adult mice. Across all cells, differential gene expression analysis by Pb treatment revealed cluster marker genes. Within cell clusters, differential gene expression with Pb treatment (q<0.05) was observed in endothelial, microglial, pericyte, and astrocyte cells. Pathways up-regulated with Pb treatment were protein folding in microglia (P=3.4x10-9) and stress response in oligodendrocytes (P=3.2x10-5). ConclusionBulk tissue analysis may be confounded by changes in cell type composition and may obscure effects within vulnerable cell types. This study serves as a biological reference for future single cell studies of toxicant or neuronal complications, to ultimately characterize the molecular basis by which Pb influences cognition and behavior.

The prevalence of neurodegenerative diseases and mental health disorders has been increasing over the past few decades. While genetic and lifestyle factors are important to the etiology of these illnesses, the pathogenic role of environmental factors, especially toxicants such as pesticides encountered over the life span, is receiving increased attention. As an environmental factor, organophosphates pose a constant threat to human health due to their widespread use as pesticides, their deployment by rogue militaries, and their use in terrorist attacks. The standard organophosphate-antidotal regimen provides modest efficacy against lethality, although morbidity remains high, and there is little evidence that it attenuates long-term neurobehavioral sequelae. Here we show that a novel intranasally administered treatment strategy with specific gangliosides can prevent the organophosphate-related alterations in important neurotrophin pathways that are involved in cognition and depression. We found that a single toxic dose of the organophosphate diisopropylfluorophosphate (DFP) in mice leads to persistent decreases in the neurotrophins NGF and BDNF and their receptors, TrkA and TrkB. Moreover, seven days of repeated intranasal administration of gangliosides GM1 or GD3 24 hours after the DFP injection prevented the neurotrophin receptor alterations. As NGF and BDNF signaling are involved in cognitive function and depression symptoms, respectively, intranasal administration of GM1 or GD3 can prevent the organophosphate-related alterations in those brain functions. Our study thus supports the potential of a novel therapeutic strategy for neurological deficits associated with a class of poisons that endangers millions of people worldwide. Highlights O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/646417v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@edf17dorg.highwire.dtl.DTLVardef@1895982org.highwire.dtl.DTLVardef@538e99org.highwire.dtl.DTLVardef@1b700d3_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIA single exposure to DFP, which causes cognitive deficits, dysregulates NGF and BDNF signaling C_LIO_LIGM1 or GD3 24 hours after DFP injection prevents the alteration of the neurotrophin signaling C_LIO_LIIntranasal ganglioside treatment provides neuroprotective effects against persistent organophosphate toxicity C_LI

Glyphosate-based herbicides (GBHs), the most recognized of which is Roundup, are the most extensively used herbicides worldwide. GBHs were initially considered safe for animals since the primary target of the active ingredient, glyphosate, is only found in plants. Recent studies show that glyphosate can affect a range of animal physiologies; however, it remains poorly characterized as to whether animal GBH effects are mediated by glyphosate itself or are in response to toxic effects of the adjuvants and surfactants found in GBH formulations. Here we expose embryonic zebrafish to environmentally relevant doses of glyphosate or Roundup and compare effects on two systems in the larvae: cellular bioenergetics, since glyphosate can affect mitochondrial function, and behaviour, as a systems-level readout of lasting developmental changes. We showed that exposure of embryonic zebrafish to low levels of glyphosate resulted in decreased mitochondrially-mediated basal respiration and hypoactive swimming behavior in larval stage, whereas exposure to Roundup in this same treatment paradigm had the opposite effect, causing increased cellular respiration and increased locomotion. In addition, we also explored generational effects of F1 embryonic glyphosate or Roundup exposure in the F2, and showed that offspring born to zebrafish exposed to low-level glyphosate or Roundup during embryogenesis both exhibited reduced mitochondrially-mediated basal respiration and altered locomotion. Combined, these data show that embryonic exposure to glyphosate or the full formulation of GBHs caused differential effects on mitochondrial function and behaviours in vertebrates, with potential lasting effects on future generations. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/510731v1_fig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@93431borg.highwire.dtl.DTLVardef@1aa602org.highwire.dtl.DTLVardef@1890cf5org.highwire.dtl.DTLVardef@b1c655_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Graphical abstract.Zebrafish (F1 generation) were exposed to glyphosate or Roundup from zero to 48 hours, with behaviour and mitochondrial bioenergetics assessed at larval timepoints (2- and 5-dpf). Offspring of glyphosate and Roundup exposed fish (F2 generation) behaviour and mitochondrial bioenergetics were assessed to the same paradigm as F1 fish at 5-dpf. Changes to core metabolic parameters and locomotion was observed in both F1 and F2 generations. C_FIG

Interest is growing in the potential role of manganese (Mn) in Alzheimers Disease (ADRD). This nested pilot study of a ferroalloy workers cohort was aimed to investigate the effects of long-term occupational Mn exposure on cognitive function through {beta}-amyloid (A{beta}) modification and brain deposition, as well as metabolomic, lipidomic and proteomic profiling. We examined 6 male exposed workers (median age 63, exposure duration 31 yrs), and 5 historical controls (median age 60) who had undergone brain PET scan imaging showing higher A{beta} deposition among the exposed compared to the controls (p < 0.05). The average annual cumulative respirable Mn of the ferroalloy workers was 329.23 {+/-} 516.39 {micro}g/m3 (geometric mean 118.59). Average Mn level in plasma of the exposed subjects (0.704 {+/-} 0.2 ng/mL) was significantly higher than the controls (0.397 {+/-} 0.18). Pathway analyses using LC-MS/MS results revealed impacted metabolomic pathways such as olfactory signaling, mitochondrial fatty acid beta-oxidation, biogenic amine synthesis, SLC-mediated transmembrane transport, and glycerophospholipid and choline metabolism in the Mn exposed group. Single molecule arrays (Simoa) analysis revealed notable modifications of AD-related plasma biomarkers; protein microarray (chip) showed significant changes (p < 0.05) in the levels of some plasma antibodies targeting autoimmune and neuronal associated proteins such as A{beta} (25-35), GFAP, Serotonin, Human NOVA1, and Human Siglec-1/CD169 among the Mn exposed individuals. This data provides evidence on Mn-induced alterations of pathways and biomarkers associated with cognitive neurodegenerative diseases.

Parabens, particularly methylparaben (MP) and ethylparaben (EP), are extensively used preservatives in cosmetics, foods, and pharmaceuticals. Although considered safe at low concentrations, recent evidence questions their biological inertness under chronic exposure. This study evaluated the developmental, biochemical, and behavioral effects of continuous dietary MP and EP exposure in Drosophila melanogaster, an established in vivo model for toxicological screening. Flies were chronically exposed to MP (0.5-2%) or EP (0.5-1.5%) throughout development and adulthood. Developmental timing, lifespan, oxidative-stress markers (MDA, FRAP, total protein), and locomotor performance (negative geotaxis in adults, crawling in larvae) were quantified. Paraben exposure significantly delayed development ([~]15% increase in eclosion time), reduced median lifespan (up to 50% decrease at 2% MP), and elevated oxidative damage ({uparrow}MDA, {downarrow}FRAP) in a dose-dependent manner. Protein content declined more rapidly with age, suggesting oxidative degradation or proteolysis. Both adult climbing and larval crawling performances were impaired, linking biochemical stress to neuromuscular dysfunction. MP produced stronger oxidative and behavioral effects than EP. Feeding controls confirmed that observed deficits were not due to nutritional differences. Chronic MP and EP exposure induces systemic toxicity in D. melanogaster, integrating endocrine disruption and redox imbalance as plausible mechanisms. Given conserved stress and hormonal pathways, these findings reinforce the need to re-evaluate low-dose paraben safety limits and highlight Drosophila as a rapid, ethically viable platform for screening environmental preservatives and safer substitutes.

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.

Micro- and nano-plastic (MNP) particles are a ubiquitous environmental contaminant that are increasingly bioaccumulating in human tissues, particularly the brain. MNPs induce mitochondrial defects, oxidative stress, inflammatory responses and neurotoxicity in cellular and organismal models. This raises the possibility that MNP exposure could cause or exacerbate neurological conditions associated with these pathological phenomena. Parkinsons Disease (PD), a common movement disorder characterised by degeneration of striatal dopaminergic neurons, and associated with mitochondrial dysfunction, represents such a condition. We therefore hypothesised that MNP exposure might interact with PD risk mutations affecting mitochondrial fidelity. We used a fruit fly model of PRKN-dependent PD associated with defects in mitophagy, a mitochondrial quality control pathway, to test this hypothesis. We found that ingestion of MNPs at concentrations tolerated by wild-type controls selectively enhanced PD-relevant phenotypes - including progressive dopaminergic neurodegeneration, movement defects, and sleep disruption - in this model of PD. Our data suggest that defects in mitochondrial quality control can increase vulnerability to MNP exposure, and more broadly, that MNPs may synergistically interact with existing genetic risk factors to worsen neurological disease.

BackgroundMethylglyoxal (MGO), a highly reactive by-product of glycolysis, has been associated with cognitive decline and Alzheimers disease, though the mechanistic role of MGO remains unclear. Moreover, conflicting findings exist regarding MGOs toxicity on the blood-brain barrier (BBB). This study investigated whether MGO can cross the BBB under physiologically relevant conditions and whether MGO affects BBB permeability. MethodsMice were intravenously injected with highly purified home-made MGO or PBS, and MGO concentration was measured at five timepoints in the cerebral cortex up to 4 hours after injection. MGO toxicity was screened on a human brain endothelial cell line (hCMEC/D3) using a live/dead assay prior to the study of selected MGO concentrations and on hiPSC-derived brain microvascular endothelial cells (EECM-BMECs). EECM-BMECs were cultured on Transwell(R) inserts, and barrier function was assessed by sodium fluorescein permeability and transendothelial passage of 13C3-MGO quantified by UPLC-MS/MS. ResultsMGO levels in the mouse cortex did not increase post-injection. MGO was not toxic to hCMEC/D3 cells, and it had no impact on barrier properties of EECM-BMECs. After 1-hour exposure, [~]13% of total 13C3-MGO was recovered in its free form, and only [~]1% of supplemented MGO was recovered from the abluminal side. ConclusionMGO does not cross the BBB in vivo and does not affect barrier properties of a human in vitro model of the BBB. In vitro MGO passage across the BBB is minimal. These findings suggest that circulating MGO is unlikely to directly affect neuronal function via BBB disruption or enter the brain in its free from.

Alzheimers disease (AD) arises from complex multilevel interactions between genetic, epigenetic, and environmental factors. Recent studies suggest that exposure to the environmental and occupational toxicant formaldehyde (FA) may play a significant role in AD development. However, the effects of FA exposure on A{beta} and tau pathologies in human neural cell 3D culture systems remain unexplored. To investigate FAs role in AD initiation, we differentiated 3D-cultured immortalized human neural progenitor ReN cells (ReNcell VM) into neurons and glial cells, followed by FA treatment. FA exposure for 12 weeks resulted in a dose-dependent increase in A{beta}40, A{beta}42, and phosphorylated tau levels. To further examine FAs role in AD progression, we established a 3D human neural cell culture AD model by transfecting ReN cells with AD-related mutant genes, including mutant APP and PSEN1, which recapitulate key AD pathological events. Our findings demonstrate that FA exposure significantly elevated A{beta}40, A{beta}42, and phosphorylated tau levels in this 3D-cultured AD model. These results suggest that FA exposure contributes to the initiation and progression of AD pathology in 3D-cultured human neural cells.

Proper brain development is based on the orchestration of key neurodevelopmental processes, including the formation and function of neural networks. If at least one key neurodevelopmental process is affected by a chemical, an adverse outcome is expected. To allow a higher testing throughput than the guideline animal experiments, a developmental neurotoxicity (DNT) in vitro testing battery (DNT IVB) has been set up that includes a variety of assays, which model several key neurodevelopmental processes. Gap analyses of the DNT IVB revealed the need of a human-based assay to assess neural network formation and function (NNF). Therefore, here we established the human NNF (hNNF) assay. A co-culture comprised of human-induced pluripotent stem cell (hiPSC)- derived excitatory and inhibitory neurons, as well as primary human astroglia, was differentiated for 35 days on micro-electrode arrays (MEA) and spontaneous electrical activity, together with cytotoxicity, was assessed on a weekly basis after washout of the compounds 24 h prior to measurements. In addition to the characterization of the test system, the assay was challenged with 28 compounds, mainly pesticides, identifying their DNT potential by evaluation of specific spike-, burst- and network parameters. This approach confirmed the suitability of the assay for screening environmental chemicals. Comparison of benchmark concentrations (BMC) with an NNF in vitro assay (rNNF) based on primary rat cortical cells, revealed differences in sensitivity. Together with the successful implementation of hNNF data into a postulated stressor-specific adverse outcome pathway (AOP) network associated with a plausible molecular initiating event for deltamethrin, this study suggests the hNNF assay as a useful complement to the current DNT IVB.

BackgroundAcute poisoning is a major public health concern and a significant cause of hospital mortality worldwide. Poisoning-related mortality is influenced by demographic and socioeconomic factors, with suicide being the predominant cause in many regions. This study examines poisoning-related deaths in relation to demographic and other relevant factors over a five-year period in Isfahan, Iran. Material and MethodsA retrospective cross-sectional study was conducted on acute poisoning-related deaths recorded at the Clinical Toxicology Department, the referral poisoning center at Khorshid Hospital, Isfahan, Iran, from March 20, 2019, to March 20, 2023. Data were collected on demographic characteristics, cause of poisoning, type of substance, route of exposure, duration of hospitalization, history of suicide attempts, and addiction. Statistical analyses were performed to assess associations between demographic variables and poisoning outcomes. ResultsAmong the 306 poisoning-related deaths, 81.4% were males with a median age of 42 years. Suicide accounted for 63.07% of cases, followed by accidental poisoning (18.95%) and substance abuse (17.97%). The most common substances involved were methadone (20.56%), aluminum phosphide (18.63%), and paraquat (17.32%). Ingestion was the primary route of exposure (94.44%). Significant associations were found between gender and route of exposure (P=0.043) as well as substance abuse history (P=0.024). ConclusionSuicide was the leading cause of poisoning-related death. Mortality is observed more in patients with methadone, aluminum phosphide, and paraquat poisoning. Preventive measures, including stricter regulation of pesticide sales, monitoring of addiction treatment programs, and enhanced mental health support, are essential to reduce mortality and morbidity from acute poisoning.

BackgroundThe Minamata Convention on Mercury (Article 4) prohibits the manufacture, import or export of skin-lightening products containing mercury concentrations above 1 g/g. However, there is a lack of knowledge surrounding the global prevalence of mercury-added skin-lightening products. ObjectiveThe objective of this study was to increase our understanding of worldwide human mercury exposure and associated health risks from the use of skin-lightening products. MethodsA systematic search of peer-reviewed scientific literature was performed in four databases (PubMed, Web of Science Core Collection, Scopus, and Toxline). The initial search in July of 2018 identified 1,711 unique scientific articles, of which 34 were ultimately deemed eligible for inclusion after iterative screens at the title, abstract, and whole text levels. A second search was performed in November of 2020 using the same methods, of which another 7 scientific articles were included. All papers were organized according to four data groups 1) "Mercury in products", 2) "Usage of products", 3) "Human biomarkers of exposure"; and 4) "Health impacts", prior to data extraction and synthesis. ResultsThis review was based on data contained within 41 peer-reviewed scientific papers from 22 countries worldwide published between 2000 and 2020. In total, we captured mercury concentration values from 787 skin-lightening product samples (overall pooled central median mercury level was 0.49 g/g, IQR: 0.02 - 5.9) and 1,042 human biomarker measurements from 863 individuals. We also synthesized usage information from 3,898 individuals, and self-reported health impacts associated with using mercury-added products from 832 individuals. DiscussionThis review suggests that mercury widely exists as an active ingredient in many skin-lightening products worldwide, and that users are at risk of variable, and often high exposures. These synthesized findings help increase our understanding of the health risks associated with the use of these products.