Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used halogen-containing organophosphate flame retardant with potential neurotoxicity, but its effects on cardiac autonomic function remain largely unexplored. This study investigated TDCIPP's impact on heart rate variability (HRV) and the underlying molecular mechanisms. Young adult male rats were treated with TDCIPP (0, 13.3, 40, 120, or 360 mg/kg/day) by gavage for 114 days. TDCIPP exposure significantly reduced multiple HRV parameters including SDRR (by 58%-62%, p < 0.005), CVRR (by 57%-64%, p < 0.01), RMSSD (by 55%-63%, p < 0.05), and SD2 (by 59%-65%, p < 0.01) across all dose groups, indicating impaired cardiac autonomic function with a possible threshold-like pattern instead of a typical dose-dependent response. Further analyses revealed that TDCIPP decreased choline acetyltransferase (ChAT) activity (by 28%-53%, p < 0.001) and mRNA expression (by 22%-48%, p < 0.05 to p < 0.001) dose-dependently without affecting protein levels, while acetylcholinesterase (AChE) activity remained unchanged. Acetylcholine levels were significantly reduced in the 40 and 360 mg/kg/day groups (by 31% and 42%, respectively, p < 0.05). Molecular docking analysis demonstrated that TDCIPP binds to the choline binding site of ChAT, forming a hydrogen bond with His334, the same residue critical for choline binding. This suggests TDCIPP impairs cardiac autonomic function by disrupting cholinergic neurotransmission through putative competitive inhibition of ChAT activity. This novel mechanism differs from that of chlorpyrifos and provides new insights into how environmental flame retardants may impact cardiovascular health.

Neonicotinoids (NEOs) are the most widely used insecticides worldwide and have been detected in various biological samples. While NEO neurotoxicity has been demonstrated in animal studies, epidemiological evidence in humans remains limited, and the underlying mechanisms are not fully elucidated. In this study, urinary concentrations of six parent NEOs and four metabolites were quantified in 1150 older adults from Shenzhen, China. Quantile-based g-computation, weighted quantile sum regression, and Bayesian kernel machine regression were employed to assess the joint effects of NEO mixture on cognitive impairment. Co-exposure to NEOs was positively associated with the risk of cognitive impairment (OR = 1.65, 95% CI: 1.05-2.60, P = 0.03). Imidacloprid (IMI), dinotefuran (DIN), and thiacloprid (THD) were recognized as the major contributors to the overall effect. Moreover, integrative network toxicology and molecular docking analyses identified eight core targets as potential mediators in NEO-induced neurotoxicity (HSP90AA1, TP53, JUN, EGFR, JAK2, STAT3, MET, and PIK3R1), suggesting coordinated disruptions in neuroactive ligand-receptor interactions, kinase-regulated signaling pathways, inflammatory responses, apoptosis processes, and synaptic function. Although mitochondrial DNA copy number (mtDNA-CN) has been implicated in cognitive aging, no significant mediating effect was observed in the exposure-outcome relationship. These findings warrant validation in large-scale cohorts and experimental studies.

Tri(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a commonly used organophosphate ester that has the potential to adversely affect human health. Although previous studies have closely associated TDCIPP with cognitive impairment, the underlying mechanisms remain unclear. To elucidate the neurotoxic effects of TDCIPP and its mechanistic contribution to cognitive impairment in 3 ×Tg-AD mice, a multi-omics approach incorporating proteomics, untargeted metabolomics, and 16S ribosomal RNA (rRNA) gene sequencing was employed to evaluate the impact of TDCIPP exposure on neurobehavioral function. TDCIPP exposure promoted cognitive impairment in 3 ×Tg-AD mice. Proteomic analyses revealed that this promotion is associated with disturbances in the hippocampal mitochondrial autophagy pathway. Furthermore, TDCIPP may interfere with the PINK1/Parkin-mediated mitophagy pathway at the functional level, without altering PINK1 protein abundance. Untargeted metabolomic analysis of urine samples demonstrated that TDCIPP exposure altered the metabolic profile of 3 ×Tg-AD mice, with 58 metabolites upregulated and 11 downregulated. Additionally, 16S rRNA sequencing revealed substantial modifications in gut microbiome composition following exposure to TDCIPP. Notably, significant correlations were identified between the perturbed bacterial genera and the differential metabolites. In conclusion, exposure to TDCIPP promotes cognitive impairment in 3 ×Tg-AD mice, which is associated with the interference with the PINK1/Parkin-mediated mitophagy pathway, as well as alterations in the urinary metabolome and gut microbiota. These findings suggest the potential to mitigate such cognitive impairment by targeting the microbiota-gut-brain axis.

Simultaneous benzene, toluene, and xylene (BTX) exposure is a common phenomenon in the workplace and the environment, but has not been well defined by time-resolved molecular events leading to BTX-induced neurotoxicity in multicellular settings. To address these points, we derived an in vitro tri-culture system using SH-SY5Y with a supportive glial compartment (HMC3 + U87) and combined dose-dependent phenotypic profiling with time-resolved transcriptomic, proteomic and metabolic studies after 4, 12, 24, 36 and 48 h of BTX treatment. Working concentrations (IC10, IC20 and IC30) were determined at the end of an initial 24 h dose-response step. Although BTX reduced cell viability in both monoculture and co-culture models, no significant differences in viability were observed between the two models at matched doses. Conversely, the co-culture model had increased sensitivity to sub-lethal toxic responses, which was evidenced by the higher levels of ROS and more obvious concentration-dependent responses to inflammatory, injury and the apoptosis-related markers. Transcriptional pathway dynamics were shown through time-course transcriptomics: initial enrichment of the cell cycle, DNA replication, and p53 signaling; mid-stage metabolic re-programming consisting of HIF-1 signaling, glycolysis/gluconeogenesis and pentose phosphate pathway; and later-stage enrichment of oxidative phosphorylation and Parkin pathways Time-course proteomics and metabolomics respectively indicated a temporal shift into mitochondrial energy dysfunction, proteostasis dysregulation, and neurodegeneration-associated modules. The integrative multi-omics analysis revealed oxidative phosphorylation, Parkinsonism, and thermogenesis as the convergent pathways. Additional evidence of early transcriptional compensation followed by a reduction of mitochondrial and neurofunctional proteins was obtained by time-resolved qPCR and western blot validation. Such results indicate a sequence of BTX neurotoxicity and provide a biologically meaningful multi-omics scheme to study mechanisms underlying and identify biomarkers.

Alzheimer's disease (AD) is a complex disease with unknown etiology and pathogenesis. We described a combined analysis of murine proteomics and microbiomics to find potential therapeutic targets of different doses of xanthohumol (Xn), with the goal of providing a biological basis for the treatment of early AD. Xn improved the spatial learning and memory ability of APP/PS1 mice; this was associated with an increased number of newborn neurons in the subgranular zone (SGZ) and dentate gyrus (DG) and a decreased inflammatory response. 108 proteins were significantly changed after 0.5 mg/kg Xn treatment while only 72 proteins changed by 5 mg/kg Xn. Eight significant microbiota were modulated by different doses of Xn at line discriminant analysis (LDA) score 3.0, but only three of which were regulated by 0.5 mg/kg Xn at LDA score 4.0. In addition, Xn treatment could significantly regulate the pathways of neurodegeneration- multiple diseases in the hippocampus and the penicillin and cephalosporin biosynthesis and atrazine degradation pathways in the gut. Interestingly, Nefl protein validated by correlation analysis was found in the common signaling pathway. 0.5 mg/kg Xn was able to reverse the correlation between hippocampal proteins and gut microbiota. Xn treatment significantly improved cognitive function in AD transgenic mice. Different doses of Xn caused significant differences in protein expression and flora composition and abundance, suggesting that the doses of Xn should be selected with caution, and low dose may be better in the prevention of AD.

Exposure to polycyclic aromatic hydrocarbons (PAHs) and tobacco smoke is widespread and linked to various adverse health outcomes. Their potential to disturb the neurological system has raised much concern, particularly among older adults. Thus, we conducted a case-control study to assess the associations between co-exposure to PAHs and nicotine, and the risk of cognitive impairment and oxidative stress in older adults. A total of 384 adults aged 60 years and older were recruited from 2017 to 2018 in Shenzhen, China. Morning spot urine samples were collected for the analysis of 6 mono-hydroxylated PAHs, 8 nicotine metabolites, and a typical biomarker for oxidative stress, 8-hydroxy-2 '-deoxyguanosine (8-OHdG). The Mini-Mental State Examination was used to assess the cognitive function of participants. Quantile-based g-computation (QGC), weighted quantile sum regression, and Bayesian kernel machine regression were used to analyze the associations between the exposure mixture and outcomes. QGC showed co-exposure to PAHs and nicotine were positively associated with cognitive impairment risk (OR: 1.66, 95% CI: 1.36-2.03, P <0.001) and 8-OHdG ((3:11.19, 95% CI: 3.90-18.48, P < 0.001). The primary contributors to cognitive impairment risk were (S)-nicotine-N-(3-glucuronide (NicGluc), cotinine N-(3-D-glucuronide (CotGluc) and (S)-cotinine N-oxide (CNO) and Cotinine (Cot), with no-linear doseresponse relationships. However, 8-OHdG did not mediate the association between PAHs, nicotine and cognitive impairment risk.

Acrylamide (ACR) is a pervasive environmental and workplace contaminant with established neurotoxic effects but unclear pathogenic mechanisms. In this study, we screened for potential ACR binding targets associated with neurotoxicity and identified the astrocytic glutamate transporter EAAT2. Molecular docking and dynamics simulations revealed that ACR interacts stably with the glutamate-binding pocket of EAAT2, potentially impairing transport function. After exposing SH-SY5Y human neuroblastoma cells to ACR (0-500 μg/mL) for 1, 3, or 5 days, a significant decrease in EAAT2 expression was indeed observed. Concurrently, it induced significant time- and dose-dependent reductions in viable cell numbers, increases in Tau phosphorylation (AT8, pS396, pS262), and the accumulation of insoluble Tau oligomers, as well as the downregulation of neurotrophic signaling factors BDNF and TrkB. Moreover, in transwell co-cultures of mature SY5Y cells and U251 astrocytes, ACR administration (111 μg/mL, 72 h) resulted in reactive transformation of astrocytes, extracellular glutamate accumulation and enhanced neuronal calcium influx via extrasynaptic NMDA receptors. This resulted in downstream neurotoxic responses including BDNF/TrkB suppression, caspase-3 activation, Tau hyperphosphorylation and secondary neuronal injury. Astrocytic overexpression of SLC1A2 (EAAT2) significantly reversed all of these pathogenic responses. Taken together, these findings suggest that ACR induces neuronal excitotoxicity by interfering with astrocytic EAAT2-mediated regulation of extracellular glutamate, leading to extrasynaptic NMDAR overactivation, intracellular calcium overload, and Tau-related neurodegeneration. The EAAT2 is a potential therapeutic target for mitigating ACR-induced neurotoxicity and associated sequelae such as cognitive impairment.

Bisphenol A (BPA) and its bisphenol analogs (BPs) serve as key precursors in the manufacturing of polycarbonate plastics and epoxy resins. However, due to BPA' s detrimental health effects, there has been a growing global consensus to restrict its use. The elderly, being particularly susceptible to neurodegenerative disorders, represent a population of concern; yet, research exploring the association between BPs exposure and neurodegenerative diseases in the elderly remains scarce. In this study, the urinary levels of six BPs among 267 participants from the Shenzhen aging-related disorder cohort in China during 2017-2018 were measured. Cognitive status was evaluated using the Mini-Mental State Examination (MMSE), and the impact of sociodemographic factors, lifestyle habits, and dietary practices was analyzed through the Extreme Gradient Boosting (XGBoost) classifier. In this study, BPA was the highest urinary level of bisphenol compound detected in the high-risk group (2.10 ng/mL, 95.2 %). Significant differences in BPs levels were observed to the degree of education, tea consumption frequency, meat intake frequency, and distance of main road groups (P < 0.05). Notably, the absence of a significant positive correlation between BPF and BPA levels in high-risk groups for cognitive impairment implies more findings may be needed to fully evaluate BPF' s actual human exposure levels. The XGBoost models have further revealed that BPA analogs exposure and certain housing characteristics were substantial contributors to the potential impact on cognitive impairment during aging not only BPA. (c) 2025 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

The intricate relationships between cognitive function and a broad spectrum of trace elements and physiological and biochemical indices remain unclear. This study aimed to employ a path analysis model to investigate the effects of multiple trace elements and physiological and biochemical factors on mild cognitive impairment (MCI) among elderly Chinese. A total of 5768 residents aged 60 years and older were recruited in Shenzhen, China. Cognitive function was evaluated using the Mini-Mental State Examination and the Mini-Cognitive Assessment. Concentrations of 18 trace elements in urine were quantified with adjustments for urinary creatinine levels. Physiological and biochemical indices were acquired at community health centers. Based on the multiple logistic regression analysis, only selenium exhibited significant negative correlations with MCI (p-trend = 0.035). Serum albumin (ALB), triglyceride (TG), bone mineral density (BMD) and mitochondrial DNA copy number (mtDNAcn) exhibited negative correlations with high risk of MCI, whereas serum uric acid (SUA) and fasting blood glucose (FBG) were positively correlated with a higher risk of MCI. In addition, the path analysis model demonstrated that cobalt had direct effect on cognitive function, whereas iron, manganese, selenium, zinc, and copper affected it indirectly. Furthermore, the model identified that mtDNAcn directly affected cognitive function, while the other four physiological and biochemical indicators, including ALB, TG, BMD and SUA, had both direct and interactive indirect effects on it. Trace elements and physiological and biochemical indices exerted both direct and indirect effects on MCI. Specifically, trace elements might indirectly affect cognitive function through physiological and biochemical indices, which interact with each other.

Domoic acid (DA), a structural glutamate analog inducing neuroexcitotoxicity through AMPA/kainate receptor activation, poses significant risks for Amnesic Shellfish Poisoning. This study examined DA contamination in 300 shellfish samples from Shenzhen's South China Sea during 2021-2022, assessing acute and chronic health risks through point and probabilistic estimations. Samples included 50 razor clams, 125 scallops, 75 oysters, and 50 molluscs across 10 administrative districts. Scallops had the highest DA detection rate (48.8%) and peak concentration (9460.73 mu g/kg). DA levels fluctuated seasonally, peaking in autumn. Point estimates revealed acute exposure in males and children exceeded the acute reference dose (ArfD, 30 mu g/kg bw/day), while probabilistic estimates showed <1% of the population surpassed this threshold. Chronic health risks were estimated at 1.73-4.36% of the population. This study establishes the inaugural systematic risk characterization of acute/chronic domoic acid (DA), underscoring the need for monitoring harmful algal blooms and providing evidence-based recommendations on shellfish consumption for coastal residents.

Depression is a mood disorder characterized by persistent emotional and behavioral dysregulation. Oxidative stress-induced neuronal damage is increasingly recognized as a critical risk factor contributing to the pathogenesis of depression. However, the potential molecular mechanisms and therapeutic targets underlying brain homeostasis disruption induced by neuroinflammatory responses remain unclear. The polyphenolic compound curcumin has been shown to exert neuroprotective effects and partially alleviate depression-related behavioral symptoms through its anti-oxidative properties. However, the molecular mechanisms and therapeutic targets underlying curcumin's ability to ameliorate oxidative stress-induced behavioral abnormalities in specific brain regions remain insufficiently defined. In this study, we demonstrate that chronic administration of corticosterone (CORT) induces pronounced depression- and anxiety-like behaviors in mice, accompanied by marked oxidative stress, neuroinflammation, and disrupted synaptic plasticity within the medial prefrontal cortex (mPFC). Curcumin treatment significantly ameliorated these behavioral and neuropathological abnormalities by enhancing antioxidant capacity, suppressing inflammatory cytokine production and restoring dendritic architecture. Transcriptomic profiling and network pharmacology identified the p53-DDIT4-NF-κB signaling as a key signaling hub underlying these effects. Pharmacological inhibition of p53 with pifithrin-α (PFT-α) mimicked the antidepressant-like effects of curcumin, whereas activation with NSC697923 abolished them. These findings support curcumin may serve as a promising strategy for anti-oxidative stress and anti-neuroinflammation in depression via targeting p53-DDIT4-NF-κB signaling.

In recent years, neonicotinoids (NEOs) as a new type of insecticide have been increasingly used worldwide, causing significant impacts on human health. This study collected urine samples from 1147 elderly individuals (including 714 in the control group and 433 in the hypertension group) in Shenzhen, China, and detected the concentrations of six types of NEOs and four metabolites of NEOs (mNEOs). The aim of this study is to investigate the association between NEOs exposure and hypertension and dyslipidemia. After measurement, we find that the lowest detection rate (DR) among NEOs is imidacloprid (IMI), at only 39.3%. The NEO with the highest urine median concentration is dinotefuran (DIN) (1.31 μg/L), while the mNEO with the highest median concentration is DM-ACE (2.74 μg/L). Through univariate analysis, we found that DM-THM may promote the development of hypertension, while logistic regression indicated that IMI-OF could be a risk factor for hypertension. As prototypes of these two metabolites, thiamethoxam (THM) and IMI may also be risk factors for hypertension. Linear regression analysis revealed a negative correlation between the concentration of thiamethoxam (THD) and low-density lipoprotein (LDL) level, while DIN was positively correlated with triglyceride (TG) level and negatively correlated with high-density lipoprotein (HDL) level. Mediation effect analysis showed that THD may influence the risk of hypertension in the elderly by affecting LDL level. Based on this study, we believe that exposure to NEOs may increase the risk of hypertension in the elderly population.

Systematic studies on the associations between co-exposure to multiple metals and chronic kidney disease (CKD), as well as the underlying mechanisms, remain insufficient. This study aimed to provide a comprehensive perspective on the risk of CKD induced by multiple metal co-exposures through the integration of occupational epidemiology and adverse outcome pathway (AOP). The study participants included 401 male mine workers whose blood metal, β2-microglobulin (β2-MG), and cystatin C (Cys-C) levels were measured. Generalized linear models (GLMs), quantile g-computation models (qgcomp), least absolute shrinkage and selection operator (LASSO), and bayesian kernel machine regression (BKMR) were utilized to identify critical nephrotoxic metals. The mean concentrations of lead, cadmium, mercury, arsenic, and manganese were 191.93, 3.92, 4.66, 3.11, 11.35, and 16.33 µg/L, respectively. GLM, LASSO, qgcomp, and BKMR models consistently identified lead, cadmium, mercury, and arsenic as the primary contributors to kidney toxicity. Based on our epidemiological analysis, we used a computational toxicology method to construct a chemical-genetic-phenotype-disease network (CGPDN) from the Comparative Toxicogenomics Database (CTD), DisGeNET, and GeneCard databases, and further linked key events (KEs) related to kidney toxicity from the AOP-Wiki and PubMed databases. Finally, an AOP framework of multiple metals was constructed by integrating the common molecular initiating events (reactive oxygen species) and KEs (MAPK signaling pathway, oxidative stress, mitochondrial dysfunction, DNA damage, inflammation, hypertension, cell death, and kidney toxicity). This is the first AOP network to elucidate the internal association between multiple metal co-exposures and CKD, providing a crucial basis for the risk assessment of multiple metal co-exposures.

BackgroundAs the important factors in cognitive function, dietary habits and metal exposures are interactive with each other. However, fewer studies have investigated the interaction effect of them on cognitive dysfunction in older adults.Methods2,445 registered citizens aged 60–85 years from 51 community health centers in Luohu District, Shenzhen, were recruited in this study based on the Chinese older adult cohort. All subjects underwent physical examination and Mini-cognitive assessment scale. A semi quantitative food frequency questionnaire was used to obtain their food intake frequency, and 21 metal concentrations in their urine were measured.ResultsElastic-net regression model, a machine learning technique, identified six variables that were significantly associated with cognitive dysfunction in older adults. These variables included education level, gender, urinary concentration of arsenic (As) and cadmium (Cd), and the frequency of monthly intake of egg and bean products. After adjusting for multiple factors, As and Cd concentrations were positively associated with increased risk of mild cognitive impairment (MCI) in the older people, with OR values of 1.19 (95% CI: 1.05–1.42) and 1.32 (95% CI: 1.01–1.74), respectively. In addition, older adults with high frequency of egg intake (≥30 times/month) and bean products intake (≥8 times/month) had a reduced risk of MCI than those with low protein egg intake (<30 times/month) and low bean products intake (<8 times/month), respectively. Furthermore, additive interaction were observed between the As exposure and egg products intake, as well as bean products. Cd exposure also showed additive interactions with egg and bean products intake.ConclusionsThe consumption of eggs and bean products, as well as the levels of exposure to the heavy metals Cd and As, have been shown to have a substantial influence on cognitive impairment in the elderly population.

Exposure to tobacco smoke and essential metals is linked with metabolic syndrome (MS). However, the joint effect of them on MS in older adults and the underlying mechanisms are still unclear. This large-scale study measured the urinary concentrations of 8 nicotine metabolites and 8 essential metals in 4564 older adults from Shenzhen, China. The biomarker of insulin resistance, triglyceride-glucose index (TyG), was also calculated. Restricted cubic splines (RCS), Bayesian kernel machine regression and quantile-based g-computation were used to access the single and joint effects of urinary nicotine metabolites and essential metals on MS and insulin resistance. Mediation analysis was performed to investigate the role of TyG in these relationships.Single urinary nicotine metabolite and essential metal had non-linear relationships with MS in RCS. The overall effect of urinary nicotine metabolites and essential metals was positively associated with MS. Urinary zinc (52.2 %) and copper (20.1 %) were the major contributors to MS, whereas molybdenum had a negative association with MS. TyG mediated 64.7 % of the overall effect of urinary nicotine metabolites and essential metals on MS. Overall, the mixture of urinary nicotine metabolites and essential metals had a dose-response relationship with MS. Insulin resistance was as a crucial mediated pathway in this association.

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been consistently identified in various environmental media and biological specimens. Current understanding of the in vivo toxicities of TDCIPP is limited, especially for potential for neurotoxic and cognitive impairment effects. To better evaluate the potential adverse effect of the chemical on learning and memory, Sprague Dawley (SD) rats were administered TDCIPP via gavage at doses of 40, 120, and 360 mg/kg/day for a period of 90 days. Quantitative proteomic analysis, immunohistochemistry, and Western blotting were employed to assess alterations in proteins following exposure to TDCIPP. An open field test and the Morris Water Maze were used to assess anxiety and spatial learning memory capacity. Administration of TDCIPP induced anxiety and cognitive impairments in rats. Additionally, a noteworthy decrease in the number of neurons was observed in the hippocampal CA3 and dentate gyrus (DG) regions. Proteomic and bioinformatic analyses revealed dysregulation of numerous hippocampal proteins, particularly those associated with synapses (PKN1) or oxidative stress (GSTM4, NQO1, and BMAL1), which was further confirmed by Western blot analysis. In sum, the cognitive impairment of rats caused by TDCIPP exposure was associated with dysregulation of synaptic and oxidative stress-related proteins.

Alzheimer’s disease (AD) has an increasing prevalence, complicated pathogenesis and no effective cure. Emerging evidences show that flavonoid compounds such as xanthohumol (Xn) could play an important role as a dietary supplement or traditional Chinese herbal medicine in the management of diseases such as AD. This study aims to analyze the target molecules of Xn in the prevention and treatment of AD, and its potential mechanism from the perspective of metabolites. APP/PS1 mice 2- and 6-months old were treated with Xn for 3 months, respectively, the younger animals to test for AD-like brain disease prevention and the older animals to address therapeutic effects on the disease. Memantine (Mem) was selected as positive control. Behavioral tests were performed to assess the course of cognitive function. Urine samples were collected and analyzed by high-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) coupled with online Compound Discoverer software. Morris Water Maze (MWM) tests showed that Xn, like Mem, had a therapeutic but not a preventive effect on cognitive impairment. The expression levels of urinary metabolites appeared to show an opposite trend at different stages of Xn treatment, downregulated in the prevention phase while upregulated in the therapy phase. In addition, the metabolic mechanisms of Xn during preventive treatment were also different from that during therapeutic treatment. The signaling pathways metabolites nordiazepam and genistein were specifically regulated by Xn but not by Mem in the disease prevention stage. The signaling pathway metabolite ascorbic acid was specifically regulated by Xn in the therapeutic stage. In conclusion, dietary treatment with Xn altered the urinary metabolite profile at different stages of administration in APP/PS1 mice. The identified potential endogenous metabolic biomarkers and signal pathways open new avenues to investigate the pathogenesis and treatment of AD.

In recent years, carbonized silicon nanoparticles (SiC NPs) have found widespread scientific and engineering applications, raising concerns about potential human health risks. SiC NPs may induce pulmonary damage through sustained inflammatory responses and oxidative stress, with unclear toxicity mechanisms. This study uses an in vitro co-culture model of alveolar macrophages (NR8383) and alveolar epithelial cells (RLE-6TN) to simulate the interaction between airway epithelial cells and immune cells, providing initial insights into SiC NP-triggered inflammatory responses. The research reveals that increasing SiC NP exposure prompts NR8383 cells to release high mobility group box 1 protein (HMGB1), which migrates into RLE-6TN cells and activates the receptor for advanced glycation end-products (RAGE) and Toll-like receptor 4 (TLR4). RAGE and TLR4 synergistically activate the MyD88/NF-κB inflammatory pathway, ultimately inducing inflammatory responses and oxidative stress in RLE-6TN cells, characterized by excessive ROS generation and altered cytokine levels. Pretreatment with RAGE and TLR4 inhibitors attenuates SiC-induced HMGB1 expression and downstream pathway proteins, reducing inflammatory responses and oxidative damage. This highlights the pivotal role of RAGE-TLR4 crosstalk in SiC NP-induced pulmonary inflammation, providing insights into SiC NP cytotoxicity and nanomaterial safety guidelines.

Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases, such as Alzheimer’s disease (AD). This study delves into the intricate role of miR-671/CDR1as regulation in the etiology of AD-like lesions triggered by chronic Pb exposure in adult mice. To emulate the chronic effects of Pb, we established a rodent model spanning 10 months of controlled Pb administration, dividing 52 C57BL/6J mice into groups receiving varying concentrations of Pb (1, 2, or 4 g/L) alongside an unexposed control. Blood Pb levels were monitored using serum samples to ensure accurate dosing and to correlate with observed toxicological outcomes. Utilizing the Morris water maze, a robust behavioral assay for assessing cognitive functions, we documented a dose-dependent decline in learning and memory capabilities among the Pb-exposed mice. Histopathological examination of the hippocampal tissue revealed tell-tale signs of AD-like neurodegeneration, characterized by the accumulation of amyloid plaques and neurofibrillary tangles. At the molecular level, a significant upregulation of AD-associated genes, namely amyloid precursor protein (APP), β-secretase 1 (BACE1), and tau, was observed in the hippocampal tissue of Pb-exposed mice. This was accompanied by a corresponding surge in the protein levels of APP, BACE1, amyloid-β (Aβ), and phosphorylated tau (p-tau), further implicating Pb in the dysregulation of these key AD markers. The expression of CDR1as, a long non-coding RNA implicated in AD pathogenesis, was found to be suppressed in Pb-exposed mice. This observation suggests a potential mechanistic link between Pb-induced neurotoxicity and the dysregulation of the CDR1as/miR-671 axis, which warrants further investigation. Moreover, our study identified a dose-dependent alteration in the intracellular and extracellular levels of the transcription factor nuclear factor-kappa B (NF-κB). This finding implicates Pb in the modulation of NF-κB signaling, a pathway that plays a pivotal role in neuroinflammation and neurodegeneration. In conclusion, our findings underscored the deleterious effects of Pb exposure on the CNS, leading to the development of AD-like pathology. The observed modulation of NF-κB signaling and miR-671/CDR1as regulation provides a plausible mechanistic framework for understanding the neurotoxic effects of Pb and its potential contribution to AD pathogenesis.

Parabens and triclosan (TCS) have been extensively applied in personal care products (PCPs) as preservatives and antibacterial agents. However, their potentiality to disrupt the neurological system has induced increasing concern. The elderly population is at a higher risk of neurodegenerative disorder, although research on its association with PCP exposure remains scarce. Here, we measured the urinary levels of four parabens, TCS, and an oxidative stress marker among 540 participants from the Shenzhen aging-related disorder cohort during 2017-2018. The Mini-Mental State Examination (MMSE) was used to assess the cognitive status of participants. Their demographic, dietary, and behavioral factors were collected via questionnaire survey. Among the four paraben analogs, the median concentration of methyl parabens (MeP) was the highest (Low-risk group: 1.21 ng/ mL, High-risk group: 1.64 ng/mL). TCS and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were detected in more than 90% of the samples. Weighted quantile sum regression and quantile-based g-computation showed that the combined effect of all analytes was positively associated with the level of 8-OHdG. BtP, EtP and MeP were identified as the major contributors to the joint effect. After stratification by gender, females exhibited more pronounced changes in urinary 8-OHdG level than males. However, the positive correlation between co-exposure to parabens and TCS and cognitive impairment was not significant (p > 0.05) in both models, which warrants investigation with the larger sample size.