The widespread use of neonicotinoid pesticides has severely impacted honey bees, driving population declines. Gut microbiota are increasingly recognized for their role in mitigating pesticide toxicity. This study evaluated the ability of Gilliamella sp. G0441, a core microbiome member of the Asian honey bee (Apis cerana), to confer resistance to the toxicity of a neonicotinoid nitenpyram. Newly emerged Asian honey bees were first colonized with gut microbiota in the source colony, then divided into four treatments: SS (fed sucrose solution throughout), SN (fed sucrose solution, then exposed to nitenpyram), GS (fed Gilliamella, then sucrose solution), and GN (fed Gilliamella, then exposed to nitenpyram), and their responses-mortality, food consumption, body weight, and sucrose sensitivity-were assessed. The protective effects of Gilliamella administration on the host were further validated using a microbiota-free bee model. Gilliamella supplementation significantly mitigated nitenpyram-induced appetite suppression, weight loss, impaired learning, and gut microbiota disruption. Mechanistic analyses revealed that nitenpyram disrupted brain metabolism via the intestinal MAPK pathway, reducing ascorbate and aldarate metabolism. Prophylactic Gilliamella treatment reversed these effects, restored metabolic balance, and modulated esterase E4 expression, enhancing pesticide resistance. This study underscores Gilliamella's vital role in honey bee resilience to neonicotinoids, offering insights into the microbiota-gut-brain axis (MGBA) as a pathway for enhancing pesticide tolerance and ecological health.

The small GTPase Ras is an intracellular signaling hub required for long-term potentiation (LTP) in the hippocampus and for memory formation. Genetic alterations in Ras signaling (i.e., RASopathies) are linked to cognitive disorders in humans. However, it remains unclear how Ras controls synaptic plasticity, and whether different Ras isoforms play overlapping or distinct roles in neurons. Using genetically modified mice, we show here that H-Ras (the most abundant isoform in the brain) does not promote LTP, but instead long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). Mechanistically, H-Ras is activated locally in spines during mGluR-LTD via c-Src, and is required to trigger Erk activation and de novo protein synthesis. Furthermore, H-Ras deletion impairs object recognition as well as social and spatial memory. Conversely, K-Ras is the isoform specifically required for LTP. This functional specialization correlates with a differential synaptic distribution of the two isoforms H-Ras and K-Ras, which may have important implications for RASopathies and cognitive function.

Recently, more and more epidemiological studies have examined the impact of exposure to persistent organic pollutants (POPs) on depression, but the results are inconsistent. Thus, we conducted a systematic review and meta-analysis to better understand the effects of POPs exposure on the risk of depression in the general population. We searched PubMed, Embase, Web of Science, and Scopus databases for studies before March 20, 2024. Random-effects meta-analysis was applied to calculate pooled relative risk (OR) and 95% confidence intervals (CIs). We also assessed potential heterogeneity and publication bias across studies and conducted sensitivity analysis. A total of 26 studies were included, and the results indicated that exposure to ΣPBDEs, PBDE-47, and PBDE-99 increased the risk of depression, with OR of 1.37 (95 % CI = 1.06-1.79), 1.30 (95% CI = 1.08-1.56), 1.46 (95 % CI = 1.00-2.12) respectively. On the contrary, the exposure assessment results of PFOS showed a negative correlation with the risk of depression. There is no association between exposure to ΣPFAS, ΣPCBs, and ΣOCPs and increased risk of depression. More standardized studies and more samples are needed in the future to confirm the findings of this study. This finding could provide theoretical references for the prevention and management of depression and offer insights for the risk assessment of POPs exposure.

Chlorpyrifos (CPF) is one of the organophosphorus pesticides widely used throughout the world. Epidemiological studies suggested a link between CPF exposure and neurologic disorders, while the molecular mechanisms remain inconclusive. In the present study, we investigated the impacts of chlorpyrifos-oxon (CPO), the major toxic CPF metabolite, on cell apoptosis, and explored possible mechanism associated with endoplasmic reticulum (ER) stress in SH-SY5Y cells. Results showed that CPO exposure induced dose-dependent apoptosis and expression of ER stress-related proteins in SH-SY5Y cells. Pretreatment with 4-PBA (an ER stress inhibitor) effectively inhibited the expression of GRP78, GRP94, p-IRE1α, and XBP1-s, and apoptotic events. Pretreatment with STF-083010 (an IRE1α inhibitor) partially attenuated CPO-induced apoptosis. In addition, CPO exposure significantly evoked the generation of reactive oxygen species (ROS) which could be eliminated by pretreatment of 4-PBA. Of note, buffering the ROS generation with antioxidant NAC had little impact on the expression of p-IRE1α, and only partially attenuated CPO-induced apoptosis. In contrast, co-pretreatment with NAC and STF-083010 effectively inhibited CPO-induced apoptotic events. Collectively, our results indicate that CPO exposure exerts neuronal cytotoxicity via ER stress downstream-regulated IRE1α/XBP1 signaling pathway and ROS generation-triggered apoptosis. These findings highlight the role of ER stress in CPF-induced neurotoxicity, and provide a promising target for the intervention of organophosphate-associated neurodegenerative diseases.

Niemann-Pick disease Type C (NPC) is caused by mutations in the cholesterol transport protein NPC1 leading to the endolysosomal accumulation of the lipid and to psychiatric alterations. Using an NPC mouse model (Npc1nmf164) we show aberrant mGluR5 lysosomal accumulation and reduction at plasma membrane in NPC1 deficient neurons. This phenotype was induced in wild-type (wt) neurons by genetic and pharmacological NPC1 silencing. Extraction of cholesterol normalized mGluR5 distribution in NPC1-deficient neurons. Intracellular accumulation of mGluR5 was functionally active leading to enhanced mGluR-dependent long-term depression (mGluR-LTD) in Npc1nmf164 hippocampal slices. mGluR-LTD was lower or higher in Npc1nmf164 slices compared with wt when stimulated with non-membrane-permeable or membrane-permeable mGluR5 agonists, respectively. Oral treatment with the mGluR5 antagonist 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP) reduced mGluR-LTD and ameliorated psychiatric anomalies in the Npc1nmf164 mice. Increased neuronal mGluR5 levels were found in an NPC patient. These results implicate mGluR5 alterations in NPC psychiatric condition and provide a new therapeutic strategy that might help patients suffering from this devastating disease.

Developmental dyslexia, a complex neurodevelopmental disorder, not only affects children's academic performance but is also associated with increased healthcare costs, lower employment rates, and reduced productivity. The pathogenesis of dyslexia remains unclear and it is generally considered to be caused by the overlap of genetic and environmental factors. Systematically exploring the close relationship between exposure to environmental compounds and susceptibility genes in the development of dyslexia is currently lacking but high necessary.

In this study, we systematically compiled 131 publicly reported susceptibility genes for dyslexia sourced from DisGeNET, OMIM, and GeneCards databases. Comparative Toxicogenomics Database database was used to explore the overlap between susceptibility genes and 95 environmental compounds, including metals, persistent organic pollutants, polycyclic aromatic hydrocarbons, and pesticides. Chemical bias towards the dyslexia risk genes was taken into account in the observation/expectation ratios > 1 and the corresponding P value obtained by hypergeometric probability test.

Our study found that the number of dyslexia risk genes targeted by each chemical varied from 1 to 109. A total of 35 chemicals were involved in chemical reactions with dyslexia-associated genes, with significant enrichment values (observed/expected dyslexia risk genes) ranging from 1.147 (Atrazine) to 66.901 (Dibenzo(a, h)pyrene).

The results indicated that dyslexia-associated genes were implicated in certain chemical reactions. However, these findings are exploratory, and further research involving animal or cellular experiments is needed.

The toxicology field is concerned with the impact of organophosphorus (OP) compounds on human health. These compounds have been linked to an increased risk of neurological disorders, including neurodegenerative and neurodevelopmental diseases. This article aims to review studies on the role of OP compounds in developing these neurological disorders and explore how genetic variations can affect susceptibility to the neurotoxicity of these pesticides. Studies have shown that exposure to OP compounds can lead to the development of various neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD), autism, intellectual disability, and other developmental neurotoxicities. Apart from inhibiting the cholinesterase enzyme, OP compounds are believed to cause other pathological mechanisms at both the extracellular level (cholinergic, serotonergic, dopaminergic, glutamatergic, and GABAergic synapses) and the intracellular level (oxidative stress, mitochondrial dysfunction, inflammation, autophagy, and apoptosis) that contribute to these disorders. Specific genetic polymorphisms, including PON1, ABCB1, NOS, DRD4, GST, CYP, and APOE, have increased the risk of developing OP-related neurological disorders.

Alzheimer's disease (AD) is a progressive and neurodegenerative illness which results in alterations in cognitive development. It is characterized by loss/dysfunction of cholinergic neurons, and formation of amyloid plaques, and formation of neurofibrillary tangles, among other changes, due to hyperphosphorylation of tau-protein. Exposure to pesticides in humans occurs frequently due to contact with contaminated food, water, or particles. Organochlorines, organophosphates, carbamates, pyrethroids and neonicotinoids are associated with the most diagnosed incidents of severe cognitive impairment. The aim of this study was to determine the effects of these pesticides on the phosphorylation of tau protein, and its cognitive implications in the development of AD. It was found that exposure to pesticides increased the phosphorylation of tau protein at sites Ser198, Ser199, Ser202, Thr205, Ser396 and Ser404. Contact with these chemicals altered the enzymatic activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta, and protein phosphatase-2A. Moreover, it altered the expression of the microtubule associated protein tau gene, and changed levels of intracellular calcium. These changes affected tau protein phosphorylation and neuroinflammation, and also increased oxidative stress. In addition, the exposed subjects had poor level of performance in tests that involved evaluation of novelty, as test on verbal, non-verbal, spatial memory, attention, and problem-solving skills.

Accumulating evidence indicates exposure to pesticides during the crucial neurodevelopmental period increases susceptibility to many diseases, including the neurodevelopmental disorder known as autism spectrum disorder (ASD). In the last few years, it has been hypothesized that gut microbiota dysbiosis is strongly implicated in the aetiopathogenesis of ASD. Recently, new studies have suggested that the gut microbiota may be involved in the neurological and behavioural defects caused by pesticides, including ASD symptoms. This review highlights the available evidence from recent animal and human studies on the relationship between pesticides that have the potential to disturb intestinal microbiota homeostasis, and ASD symptoms. The mechanisms through which gut microbiota dysbiosis may trigger ASD-like behaviours induced by pesticides exposure during the neurodevelopmental period via the altered production of bacterial metabolites (short chain fatty acids, lipids, retinol, and amino acid) are also described. According to recent research, gut microbiota dysbiosis may be a major contributor to the symptoms of ASD associated with pesticides exposure. However, to determine the detailed mechanism of action of gut microbiota on pesticide-induced ASD behaviours, actual population exposure scenarios from epidemiological studies should be used as the basis for the appropriate exposure pattern and dosage to be used in animal studies.

Pesticides are omnipresent, and they pose significant environmental and health risks. Translational studies indicate that acute exposure to high pesticide levels is detrimental, and prolonged contact with low concentrations of pesticides, as single and cocktail, could represent a risk factor for multi-organ pathophysiology, including the brain. Within this research template, we focus on pesticides' impact on the blood-brain barrier (BBB) and neuroinflammation, physical and immunological borders for the homeostatic control of the central nervous system (CNS) neuronal networks. We examine the evidence supporting a link between pre- and postnatal pesticide exposure, neuroinflammatory responses, and time-depend vulnerability footprints in the brain. Because of the pathological influence of BBB damage and inflammation on neuronal transmission from early development, varying exposures to pesticides could represent a danger, perhaps accelerating adverse neurological trajectories during aging. Refining our understanding of how pesticides influence brain barriers and borders could enable the implementation of pesticide-specific regulatory measures directly relevant to environmental neuroethics, the exposome, and one-health frameworks.

Atrazine (ATR) is a widely applied herbicide in Asia and South America with slow natural degradation and documented deleterious effects on human and animal health, including hippocampal toxicity. However, relatively little is known about the molecular mechanisms responsible for ATR-induced hippocampal damage. Screening for differentially expressed mRNAs and microRNAs (miRNAs), and construction of potential miRNA-mRNA regulatory networks can reveal such mechanisms, so we analyzed the mRNA and miRNA expression profiles of rat hippocampus-derived H19-7 cells in response to ATR (500 μM) and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment (KEGG) analyses. Integration of miRNA sequencing (miRNA-seq) and mRNA sequencing (mRNA-seq) results identified 114 differentially expressed miRNAs (DEMIs, 40 upregulated and 74 downregulated), and 510 differentially expressed mRNAs (DEMs, 177 upregulated and 333 downregulated) targeted by these DEMIs. The top 10 hub mRNAs (Fos, Prkcb, Ncf1, Vcam1, Atf3, Pak3, Pak1, Cacna1s, Junb, and Ccl2) and 19 related miRNAs (rno-miR-194-5p, rno-miR-24-3p, rno-miR-3074, rno-miR-1949, rno-miR-218a-1-3p, rno-miR-1843a-5p, rno-miR-1843b-5p, rno-miR-296-3p, rno-miR-320-3p, rno-miR-219a-1-3p, rno-miR-122-5p, rno-miR-1839-5p, rno-miR-1843a-3p, rno-miR-215, rno-miR-3583-3p, rno-miR-194-3p, rno-miR-128-1-5p, rno-miR-1956-5p, and rno-miR-466b-2-3p) were validated by quantitative real-time PCR. GO analysis indicated that these DEMs were enriched in genes associated with synaptic plasticity and antioxidant capacity, while KEGG analysis suggested that enriched DEMs were involved in calcium signaling, axon guidance, MAPK signaling, and glial carcinogenesis. The miRNA-mRNA regulatory network identified here may provide potential biomarkers and novel strategies for the treatment of hippocampal neurotoxicity induced by ATR.

Persistent organic pollutants (POPs) are organic chemical substances that are widely distributed in environments around the globe. POPs accumulate in living organisms and are found at high concentrations in the food chain. Humans are thus continuously exposed to these chemical substances, in which they exert hepatic, reproductive, developmental, behavioral, neurologic, endocrine, cardiovascular, and immunologic adverse health effects. However, considerable information is unknown regarding the mechanism by which POPs exert their adverse effects in humans, as well as the molecular and cellular responses involved. Data are notably lacking concerning the consequences of acute and chronic POP exposure on changes in gene expression, protein profile, and metabolic pathways. We conducted a systematic review to provide a synthesis of knowledge of POPs arising from proteomics-based research. The data source used for this review was PubMed. This study was carried out following the PRISMA guidelines. Of the 742 items originally identified, 89 were considered in the review. This review presents a comprehensive overview of the most recent research and available solutions to explore proteomics datasets to identify new features relevant to human health. Future perspectives in proteomics studies are discussed.

The herbicide glyphosate is being used worldwide. Hematological toxicity caused by glyphosate exposure has been reported, but the underlying mechanisms remain unclear. In this study, classical toxicology methods and RNA sequencing were performed to explore the molecular mechanisms related to glyphosate hematotoxicity. We found that 500 mg/kg b.w. glyphosate-based herbicide (GBH) significantly decreased leukocyte, neutrophil, lymphocyte and monocyte counts, as well as inhibited colony-forming abilities of CFU-GM, CFU-G and CFU-GEMM. RNA sequencing identified 82 and 48 differentially expressed genes (DEGs) in BM cells after treatment with 250 mg/kg and 500 mg/kg GBH, respectively. Meanwhile, GO and KEGG analyses revealed that the MAPK signaling pathway, hematopoietic cell lineage and cytokine-cytokine receptor interactions were vital pathways involved in GBH-induced toxicity in BM cells. Notably, Nr4a, Fos, Thbs1 and tnfrsf19 contributed to the hematotoxicity of GBH by regulating hematopoietic stem cell functions. In summary, our efforts enhance the understanding of the glyphosate hematotoxic responses and facilitate future studies on its corresponding mechanisms.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in childhood and is caused by both genetic and environmental factors. As genetic factors are nonmodifiable, environmental factors have attracted increasing attention.

To investigate the relationships between urinary chlorpyrifos (CPF) levels, blood micronutrient levels, and ADHD prevalence in children living in rural areas of China.

This cross-sectional study collected data on CPF exposure (according to urinary levels), blood micronutrient levels, and ADHD prevalence in children aged 1-6 years in rural China. The CPF levels were determined by mass spectrometry. Blood levels of micronutrients, including zinc, iron, calcium, copper, magnesium, and vitamin D, were measured by professional detection kits. ADHD was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Descriptive statistics and univariate analysis were conducted using SPSS 21.0, and path analysis was conducted using Mplus 8.0.

Of the 738 children who met the eligibility criteria, 673 children (673/738, 91.2%) were included in the final analysis. Baseline questionnaires and urine samples were collected from all 673 subjects. A total of 672 children provided blood samples for micronutrient testing, and 651 completed the ADHD assessment. Approximately one-fifth of children (144/673, 21.4%) had detectable levels of CPF in their urine, and 6.9% (45/651) were diagnosed with ADHD. Path analysis showed that the total effect of CPF exposure on ADHD risk was 0.166 (P < 0.05), with a direct effect of 0.197 (P < 0.05) and an indirect effect of -0.031 (P < 0.05) via vitamin D. The mediating effect of urinary CPF levels on ADHD risk via vitamin D was 18.67%.

Higher levels of CPF exposure are associated with higher risk of ADHD. Additionally, increasing vitamin D levels may have a beneficial effect on the relationship between CPF exposure and ADHD risk. Our findings highlight the importance of modifying environmental factors to reduce ADHD risk and provide insight into future ADHD interventions.