Study on the role of CCM3 gene and lead exposure induced neurotoxicity through neurovascular units.

This study aimed to determine the toxic effects of vascular CCM3 gene deficiency and lead (Pb) exposure on the nervous system. Lentiviral transfection was performed to generate a stable strain of brain microvascular endothelial cells with low CCM3 expression. MTT assay assessed the survival rate of cells exposed to Pb, determining the dose and duration of Pb exposure in vitro. Proteomic analysis was performed on the differentially expressed proteins in bEnd3 and HT22 cells and flow cytometry was used to detect cell apoptosis. Finally, urine samples from pregnant and postpartum women were subjected to ICP-MS to detect Pb levels and HPLC to detect neurotransmitter metabolites. Based on the proteomic analysis of bEnd3 (CCM3-/-) cells co-cultured with HT22 cells, it was determined that HT22 cells and CCM3 genes interfered with bEnd3 cell differential proteins,2 including apoptosis and ferroptosis pathways. Electron microscopy observation, ICP-MS iron ion loading detection, and WB determination of protein GPX4 expression confirmed that HT22 cells undergo apoptosis, while bEnd3 cells undergo multiple pathways of iron death and apoptosis regulation. Furthermore, a linear regression model showed the interaction between maternal urine Pb levels, the rs9818496 site of the CCM3 SNP in peripheral blood DNA, and the concentration of the neurotransmitter metabolite 5-HIAA in maternal urine (F=4.198, P < 0.05). bEnd3 cells with CCM3 gene deficiency can induce HT22 cell apoptosis through iron death and apoptosis pathways under Pb exposure in a combined cell culture Pb exposure model, and CCM3 gene deficiency in endothelial cells and Pb exposure interacts with neural cell HT22. Epidemiological studies on maternal and newborn infants further confirmed the interaction between urine Pb levels in mothers and the SNP rs9818496 site of the CCM3 gene in peripheral blood DNA.

Pollution levels and probability risk assessment of potential toxic elements in soil of Pb-Zn smelting areas.

Soil pollution around Pb-Zn smelters has attracted widespread attention around the world. In this study, we compiled a database of eight potentially toxic elements (PTEs) Pb, Zn, Cd, As, Cr, Ni, Cu, and Mn in the soil of Pb-Zn smelting areas by screening the published research papers from 2000 to 2023. The pollution assessment and risk screening of eight PTEs were carried out by geo-accumulation index (Igeo), potential ecological risk index (PERI) and health risk assessment model, and Monte Carlo simulation employed to further evaluate the probabilistic health risks. The results suggested that the mean values of the eight PTEs all exceeded the corresponding values in the upper crust, and more than 60% of the study sites had serious Pb and Cd pollution (Igeo > 4), with Brazil, Belgium, China, France and Slovenia having higher levels of pollution than other regions. Besides, PTEs in smelting area caused serious ecological risk (PERI = 10912.12), in which Cd was the main contributor to PREI (86.02%). The average hazard index (HI) of the eight PTEs for adults and children was 7.19 and 9.73, respectively, and the average value of total carcinogenic risk (TCR) was 4.20 × 10-3 and 8.05 × 10-4, respectively. Pb and As are the main contributors to non-carcinogenic risk, while Cu and As are the main contributors to carcinogenic risk. The probability of non-carcinogenic risk in adults and children was 84.05% and 97.57%, while carcinogenic risk was 92.56% and 79.73%, respectively. In summary, there are high ecological and health risks of PTEs in the soil of Pb-Zn smelting areas, and Pb, Cd, As and Cu are the key elements that cause contamination and risk, which need to be paid attention to and controlled. This study is expected to provide guidance for soil remediation in Pb-Zn smelting areas.

Integrative investigation of hematotoxic effects induced by low doses of lead, cadmium, mercury and arsenic mixture: In vivo and in silico approach.

The effect of the lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As) mixture (MIX) on hematotoxicity development was investigated trough combined approach. In vivo subacute study (28 days) was performed on rats (5 per group): a control group and five groups orally exposed to increasing metal(loid) mixture doses, MIX 1- MIX 5 (mg/kg bw./day) (Pb: 0.003, 0.01, 0.1, 0.3, 1; Cd: 0.01, 0.03, 0.3, 0.9, 3; Hg: 0.0002, 0.0006, 0.006, 0.018, 0.06; As: 0.002, 0.006, 0.06, 0.18, 0.6). Blood was taken for analysis of hematological parameters and serum iron (Fe) analysis. MIX treatment increased thrombocyte/platelet count and MCHC and decreased Hb, HCT, MCV and MCH values compared to control, indicating the development of anemia and thrombocytosis. BMDIs with the narrowest width were identified for MCH [pg] (6.030E-03 - 1.287E-01 mg Pb/kg bw./day; 2.010E-02 - 4.290E-01 mg Cd/kg bw./day; 4.020E-04 - 8.580E-03 mg Hg/kg bw./day; 4.020E-03 - 8.580E-02 mg As/kg bw./day). In silico analysis showed target genes connected with MIX and the development of: anemia - ACHE, GSR, PARP1, TNF; thrombocytosis - JAK2, CALR, MPL, THPO; hematological diseases - FAS and ALAD. The main extracted pathways for anemia were related to apoptosis and oxidative stress; for thrombocytosis were signaling pathways of Jak-STAT and TPO. Changes in miRNAs and transcription factors enabled the mode of action (MoA) development based on the obtained results, contributing to mechanistic understanding and hematological risk related to MIX exposure.

Influence of lead-induced toxicity on the inflammatory cytokines.

Lead (Pb2+) is a hazardous heavy metal that is pervasive in the human environment as a result of anthropogenic activity, and poses serious health risks, particularly in children. Due to its innumerable unique physical and chemical properties, it has various applications; therefore, it has become a common environmental pollutant. Lead may cause oxidative stress, and accumulating evidence indicates that oxidative stress influences the pathophysiology of lead poisoning, also called plumbism. The immune system is continually exposed to various environmental pathogens and xenobiotics, including heavy metals such as lead, and appears to be one of the most vulnerable targets. After being exposed to lead, cells are subjected to oxidative stress as a result of reactive oxygen species (ROS) production. When the generation and consumption of ROS are out of equilibrium, various cell structures, particularly phospholipids are disrupted leading to lipid peroxidation. Various inflammatory signalling pathways are activated as a consequence, along with reduced disease resistance, inflammation, autoimmunity, sensitization and disruption of the cell-mediated and humoral immune systems. Lead negatively affects the metabolism of cytokines, including the interleukins IL-2, IL-1b, IL-6, IL-4, IL-8, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN), as well as the expression and functioning of inflammatory enzymes such as cyclooxygenases. However, the cause of toxicity depends on the kind of lead, dosage, route of entry, exposure period, age, host and genetic predisposition.

Evaluation of the effect of cannabidiol on the THLE-2 liver cell line exposed to lead.

Environmental and soil pollution increase the likelihood of human exposure to toxic metals. Therefore, there is a need for new methods and substances to protect individuals against the harmful effects caused by toxic metals. The study is the first to aim at determining the protective effect of cannabidiol (CBD) against oxidative stress and inflammation induced by toxic metal exposure in Transformed Human Liver Epithelial-2 (THLE-2) cell lines representing healthy liver cells. The IC50 value was determined by exposing THLE-2 human liver healthy cell line to different molarities of lead (Pb) using the XTT kit. The protective efficacy of CBD was assessed by adding 5 µM CBD in addition to the Pb doses determined at IC50 levels to the Pb groups created in cell lines. The levels of GSH, MDA, MPO, CAT, TNF-α, IL-1ß, and IL-6 in cell lines were determined using ELISA kits. The inhibition of toxic metal entry into the cells by CBD was assessed through ICP-MS analysis. The IC50 value for Pb was determined as 10 µM in 2D cell lines and 25 µM in 3D cell lines. It was observed that the application of 5 µM concentration of CBD, along with the determined IC50 doses for Pb, increased the cell proliferation rate. Furthermore, the decrease in GSH and CAT levels and the increase in MDA, MPO, TNF-α, IL-1ß, and IL-6 levels observed in cell lines treated only with Pb were reversed with the application of CBD. The ICP-MS analysis revealed that CBD reduced the cellular uptake of Pb. The reversal of oxidative stress and inflammation induced by Pb, the increase in cell proliferation, and the reduction in the cellular uptake of toxic metals by CBD can be considered as strong evidence for the protective use of CBD in Pb exposures.

Lead exposure exacerbates liver injury in high-fat diet-fed mice by disrupting the gut microbiota and related metabolites.

Lead (Pb) is a widespread toxic endocrine disruptor that could cause liver damage and gut microbiota dysbiosis. However, the causal relationship and underlying mechanisms between the gut microbiota and Pb-induced liver injury are unclear. In this study, we investigated the metabolic toxicity caused by Pb exposure in normal chow (Chow) and high-fat diet (HFD) mice and confirmed the causal relationship by fecal microbial transplantation (FMT) and antibiotic cocktail experiments. The results showed that Pb exposure exacerbated HFD-induced hepatic lipid deposition, fibrosis, and inflammation, but it had no significant effect on Chow mice. Pb increased serum lipopolysaccharide (LPS) levels and induced intestinal inflammation and barrier damage by activating TLR4/NFκB/MLCK in HFD mice. Furthermore, Pb exposure disrupted the gut microbiota, reduced short-chain fatty acid (SCFA) concentrations and the colonic SCFA receptors, G protein-coupled receptor (GPR) 41/43/109A, in HFD mice. Additionally, Pb significantly inhibited the hepatic GPR109A-mediated adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway, resulting in hepatic lipid accumulation. FMT from Pb-exposed HFD mice exacerbated liver damage, disturbed lipid metabolic pathways, impaired intestinal barriers, and altered the gut microbiota and metabolites in recipient mice. However, mice exposed to HFD + Pb and HFD mice had similar levels of these biomarkers in microbiota depleted by antibiotics. In conclusion, our study provides new insights into gut microbiota dysbiosis as a potential novel mechanism for human health related to liver function impairment caused by Pb exposure.

Alleviating the adverse effects of Cd-Pb contamination through the application of silicon fertilizer: Enhancing soil microbial diversity and mitigating heavy metal contamination.

The use of silicon fertilizer (SF) as a means of remediating cadmium (Cd) and lead (Pb) pollution has proven to be beneficial. However, the mechanism via which SF enhances soil quality and crop productivity under Cd- and Pb-contaminated soil (S) remains unclear. This study investigated the impacts of chemical fertilizer, mineral SF (MSF), and organic SF (OSF) on microbial community structure, activity of nutrient acquisition enzymes, and growth of tobacco in the presence of S condition. SF significantly reduced the contents of Cd and Pb in soil under S condition by 6.92-42.43% and increased plant height and leaf area by 15.27-81.77%. Moreover, the use of SF was observed to increase the efficiency of soil carbon and phosphorus cycling under S condition by 6.88-23.08%. Concurrently, SF was found to play a crucial role in facilitating the establishment of a complex, efficient, and interdependent molecular ecological network among soil microorganisms. In this context, Actinobacteriota, Bacteroidota, Ascomycota, and Basidiomycota were observed to be integral components of this network. SF was found to have a substantial positive impact on the metabolic functions and organismal systems of soil microorganisms. Moreover, the combined utilization of the Mantel test and partial least squares path model provided empirical evidence supporting the assertion that the administration of SF had a positive impact on both soil nutrient acquisition enzyme activity and tobacco growth, which was attributed to the enhancement of soil microbial diversity resulting from the application of SF. Furthermore, compared with MSF, OSF has advantages in reducing soil Pb and Cd content, promoting tobacco agronomic traits, increasing the number of key microbial communities, and maintaining the structural stability of microbial networks. The aforementioned findings, therefore, suggest that the OSF played a pivotal role in alleviating the adverse impacts of S, thereby demonstrating its efficacy in this particular process.

Flooding regimes alleviate lead toxicity and enhance phytostabilization of salix: Evidence from physiological responses and iron-plaque formation.

Aggravated metal pollution in wetland and riparian zones has become a global environmental issue, necessitating the identification of sustainable remediation approaches. Salix exhibits great potential as a viable candidate for metal(loid) remediation. However, the underlying mechanisms for its effectiveness in different flooding regimes with Pb pollution have not been extensively studied. In this study, fast-growing Salix×jiangsuensis 'J172' was selected and planted in different Pb polluted soils (control, 400 and 800 mg ∙ kg-1) under non-flooded and flooded (CF: continuous flooding and IF: intermittent flooding) conditions for 60 days. This study aimed to explore the effects of flooding on Salix growth performance, physiological traits, and the relationship between Pb uptake/translocation and root Fe plaques. Salix×jiangsuensis 'J172' exhibited excellent tolerance and adaptation to Pb pollution with a tolerance index (TI) exceeding 0.6, even at the highest Pb levels. Moreover, the TIs under flooded conditions were higher than that under non-flooded conditions, suggesting that flooding could alleviate Pb toxicity under co-exposure to Pb and flooding. Leaf malondialdehyde (MDA) exhibited a dose-dependent response to Pb exposure; however, CF or IF mitigated the oxidative damage induced by Pb toxicity with decreased MDA content (2.2-11.9%). The superoxide dismutase and peroxidase activities were generally enhanced by flooding, but combined stress (flooding and Pb) significantly decreased catalase activity. Pb was predominantly accumulated in Salix roots, and flooding markedly increased root Pb accumulation by 19.2-173.0% compared to non-flooded condition. Additionally, a significant positive correlation was observed between the iron (Fe) content of the root plaque and root Pb accumulation, indicating that the formation of Fe plaque on the root surface could enhance the phytostabilization of Pb in Salix. The current findings highlight that fast-growing woody plants are suitable for phyto-management of metal-polluted wetlands and can potentially minimize the risk of metal mobility in soils.

Prenatal and childhood lead exposure is prospectively associated with biological markers of aging in adolescence.

Few studies have related early life lead exposure to adolescent biological aging, a period characterized by marked increases in maturational tempo. We examined associations between prenatal and childhood lead exposure and adolescent biological age (mean 14.5 years) utilizing multiple epigenetic clocks including: intrinsic (IEAA), extrinsic (EEAA), Horvath, Hannum, PhenoAge, GrimAge, Skin-Blood, Wu, PedBE, as well as DNA methylation derived telomere length (DNAmTL). Epigenetic clocks and DNAmTL were calculated via adolescent blood DNA methylation measured by Infinium MethylationEPIC BeadChips. We constructed general linear models (GLMs) with individual lead measures predicting biological age. We additionally examined sex-stratified models and lead by sex interactions, adjusting for adolescent age and lead levels, maternal smoking and education, and proportion of cell types. We also estimated effects of lead exposure on biological age using generalized estimating equations (GEE). First trimester blood lead was positively associated with a 0.14 increase in EEAA age in the GLMs though not the GEE models (95%CI 0.03, 0.25). First and 2nd trimester blood lead levels were associated with a 0.02 year increase in PedBE age in GLM and GEE models (1st trimester, 95%CI 0.004, 0.03; 2nd trimester, 95%CI 0.01, 0.03). Third trimester and 24 month blood lead levels were associated with a -0.06 and -0.05 decrease in Skin-Blood age, respectively, in GLM models. Additionally, 3rd trimester blood lead levels were associated with a 0.08 year decrease in Hannum age in GLM and GEE models (95%CI -0.15, -0.01). There were multiple significant results in sex-stratified models and significant lead by sex interactions, where males experienced accelerated biological age, compared to females who saw a decelerated biological age, with respect to IEAA, EEAA, Horvath, Hannum, and PedBE clocks. Further research is needed to understand sex-specific relationships between lead exposure and measures of biological aging in adolescence and the trajectory of biological aging into young adulthood.

In silico prediction aided preparation of antioxidant soybean peptides by enzymatic hydrolysis for ameliorating lead exposure-induced toxicity.

Food derived bioactive peptides are prominent dietary supplements to protect against oxidative stress induced by lead (Pb) exposure. This study aimed to develop a new strategy for rapid preparation of highly active antioxidant soybean polypeptides (ASPs) against Pb toxicity. In silico enzymatic hydrolysis simulation and antioxidant activity prediction showed that pepsin, chymotrypsin and bromelain can produce peptides with the highest activity. The preparation process was then optimized, and the obtained ASP showed good antioxidant and metal-chelating activities in vitro. An in vivo study showed that ASP exerted prominent protective effects against Pb-induced cognitive impairment and tissue damage in mice by reducing Pb deposition and enhancing the antioxidant capacity in tissues and was superior to Vc, DMSA or their combination in some aspects. ASP composition analysis demonstrated that its prominent antioxidant activity might be attributed to the high proportion of amino acid residues E, L, P and V in the peptide sequence and L, V and A at the C- and N-termini. In conclusion, in silico prediction could facilitate the preparation of ASP. And the ASP prepared with the new strategy exerted prominent protective effects against Pb toxicity.

Multipollutant reciprocal neurological hazard from smoke particulate matter and heavy metals cadmium and lead in brain nerve terminals.

Heavy metals, Cd2+ and Pb2+, and carbonaceous air pollution particulate matter are hazardous neurotoxicants. Here, a capability of water-suspended smoke particulate matter preparations obtained from poplar wood (WPs) and polypropylene fibers (medical facemasks) (MPs) to influence Cd2+/Pb2+-induced neurotoxicity, and vice versa, was monitored using biological system, i.e. isolated presynaptic rat cortex nerve terminals. Combined application of Pb2+ and WPs/MPs to nerve terminals in an acute manner revealed that smoke preparations did not change a Pb2+-induced increase in the extracellular levels of excitatory neurotransmitter L-[14C]glutamate and inhibitory one [3H]GABA, thereby demonstrating additive result and no interference of neurotoxic effects of Pb2+ and particulate matter. Whereas, both smoke preparations decreased a Cd2+-induced increase in the extracellular level of L-[14C]glutamate and [3H]GABA in nerve terminals. In fluorimetric measurements, the metals and smoke preparations demonstrated additive effects on the membrane potential of nerve terminals causing membrane depolarisation. WPs/MPs-induced reduction of spontaneous ROS generation was mitigated by Cd2+ and Pb2+. Therefore, a potential variety of multipollutant heavy metal-/airborne particulate-induced effects on key presynaptic processes was revealed. Multipollutant reciprocal neurological hazard through disturbance of the excitation-inhibition balance, membrane potential and ROS generation was evidenced. This multipollutant approach and data contribute to up-to-date environmental quality/health risk estimation.

Maternal prenatal lead levels and neonatal brain volumes: Testing moderations by maternal depressive symptoms and family income.

There is considerable evidence that prenatal lead exposure is detrimental to child cognitive and socio-emotional development. Further evidence suggests that the effects of prenatal lead on developmental outcomes may be conditional upon exposure to social stressors, such as maternal depression and low socioeconomic status. However, no studies have examined associations between these co-occurring stressors during pregnancy and neonatal brain volumes. Leveraging a sample of 101 mother-infant dyads followed beginning in mid-pregnancy, we examined the main effects of prenatal urinary lead levels on neonatal lateralized brain volumes (left and right hippocampus, amygdala, cerebellum, frontal lobes) and total gray matter. We additionally tested for moderations between lead and depressive symptoms and between lead and family income relative to the federal poverty level (FPL) on the same neurodevelopmental outcomes. Analyses of main effects indicated that prenatal lead was significantly (ps < 0.05) associated with reduced right and left amygdala volumes (ßs = -0.23- -0.20). The testing and probing of cross-product interaction terms using simple slopes indicated that the negative effect of lead on the left amygdala was conditional upon mothers having low depressive symptoms or high income relative to the FPL. We interpret the results in the context of trajectories of prenatal and postnatal brain development and susceptibility to low levels of prenatal lead in the context of other social stressors.

Arsenic, lead and cadmium concentration in food and estimated daily intake in the Cuban population and the health risks using a Total Diet Study.

This study estimates the intake of arsenic, lead and cadmium by the adult population (aged 18-91) of Cuba. The food consumption indices were obtained through 24-h dietary recall surveys applied to 450 people between October 2020 and March 2021. The Estimated Dietary Intake (EDI) of t-As (54.6 µg/day), Pb (118.5 µg/day) and Cd (35.1 µg/day) complied with Cuban legislation but was higher than the EDI for Cd established by the CONTAM Panel. The Target Hazard Quotients for the three contaminants were: iAs (0.220), Pb (0.409) and Cd (0.424), making the value of the Total Target Hazard Quotient 1.05, which indicates potential health risks for the population. Additionally, associated carcinogenic risks were: iAs (1.0·10-4), Pb (7.2·10-4) and Cd (25.9·10-4). Therefore, 10, 72 and 259 persons per 100,000 inhabitants are likely prone to developing cancer due to the ingestion of iAs, Pb and Cd, respectively.

Environmental exposure to lead and cadmium are associated with triglyceride glucose index.

The triglyceride glucose (TyG) index was suggested as a novel reliable surrogate marker for insulin resistance and related cardiovascular-metabolic diseases. We aimed to evaluate the association between the TyG index and environmental exposure to lead (Pb), mercury (Hg), and cadmium (Cd). A total of 9645 adults who enrolled in the Korea National Health and Nutrition Examination Survey in 2005, 2008-2013, and 2016 were included. Fasting plasma glucose and triglyceride levels were used to calculate the TyG index. Multivariate logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). We noted an increasing trend in the TyG index with increment of blood Pb and Cd concentrations. Participants in the highest quartile of blood Pb and Cd concentrations had higher TyG index values than those in the lowest quartile, with ORs (95% CIs) of 1.32 (1.07-1.63) and 1.29 (1.04-1.59) for Pb and Cd, respectively. Strong associations between blood Pb and Cd concentrations and the TyG index were found in men. Blood Hg concentrations did not show a significant association with the TyG index. Our study suggests that public health strategies for cardiovascular-metabolic disorder prevention should be directed toward individuals exposed to priority heavy metals.

Physical activity can reduce the risk of blood cadmium and blood lead on stroke: Evidence from NHANES.

The detrimental impact of heavy metals on cardiovascular well-being is a global concern, and engaging in suitable physical activity has been shown to confer cardiovascular advantage. Nevertheless, the potential of exercise to mitigate the deleterious effects of heavy metals on stroke remains uncertain. We conducted a cross-sectional survey to assess the influence of blood cadmium and blood lead on stroke occurrence, while also examining the role of physical activity. Weighted multivariate regression analysis was employed to examine the potential correlation, while subgroup and interaction analyses were used to investigate the sensitivity and robustness of the results. After controlling risk factors, it revealed a positive correlation between blood cadmium and lead levels and the occurrence of stroke. Specifically, a 50% increase in blood cadmium was associated with a 28% increase in stroke incidence, while a 50% increase in blood lead was associated with a 47% increase in stroke incidence. To estimate the non-linear relationship, we employed restricted cubic models. The results demonstrate a gradual decrease in the slope of the model curve as the intensity of physical activity increases, implying that engaging in physical activity may contribute to a reduction in the occurrence of stroke caused by blood cadmium and lead. Our findings suggest that blood cadmium and lead could be considered an autonomous risk factor for stroke within the general population of the United States. Moreover, engaging in physical activity has the potential to mitigate the potential detrimental consequences associated with exposure to heavy metals.

Assessment of human health risks associated with airborne arsenic, nickel and lead exposure in particulate matter from vehicular sources in Sao Paulo city.

Air pollution is a critical public health concern. The present study assessed the risk to human health of airborne Potentially Toxic Elements (PTE) arsenic, nickel and lead exposure in particulate matter (PM10-2.5) in Sao Paulo, Brazil. Statistical analysis was performed using R Software and the risk assessment for human health was carried out according to the methods of the United States Environmental Protection Agency. The results for mean annual concentration of PTE (ng m-3) were within the limits stipulated for air-quality by international agencies (arsenic <6, nickel <20 and lead <150). Airborne arsenic and lead showed higher mean concentrations during the winter than the other seasons (p < 0.05). However, the results showed a greater health risk for the adult population and during the winter season. These findings highlight the importance of air pollution as a risk factor for population health.

Pb induces the release of CXCL10 and CCL2 chemokines via mtROS/NF-κB activation in BV-2 cells.

Lead (Pb), a well-known environmental pollutant, could cause damage of microglia, the resident macrophages vitally regulating inflammation in brain. Previous studies have found that Pb exposure induces typical pro-inflammatory factors release, such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), but what effects of Pb treatment below the dose causing these factors release are unknown. Thus, cytokines assay was performed to identify the factors released from Pb-treated BV-2 cells at 2.5 µM, causing no effects on TNF-α, IL-1ß, and IL-6 release and cell death. Cytokines assay identified low doses of Pb exposure mainly induce an increase in specific chemokines, including CXCL10, CCL2, and CXCL2, which were confirmed by ELISA. Subsequent assessment found Pb could damage mitochondria function and generate mitochondrial reactive oxygen species (mtROS), and Mito TEMPO, a specific inhibitor of mtROS, suppressed Pb-caused upregulation of CXCL10 and CCL2, but not CXCL2. Finally, we determined that mtROS mediated Pb-induced activation of NF-κB pathway, as Mito TEMPO treatment inhibited P-p65/p65 escalation during Pb treatment. Inhibition of NF-κB pathway by Bay11-7821 suppressed the release of CXCL10 and CCL2. Collectively, low dose of Pb induces the release of CXCL10 and CCL2 chemokines, but not TNF-α and IL-1ß, via mtROS/NF-κB activation in BV-2 cells.

Proteome signatures of joint toxicity to arsenic (As) and lead (Pb) in human brain organoids with optic vesicles.

Arsenic (As) and lead (Pb) are toxins found in the natural surroundings, and the harmful health outcomes caused by the co-exposure of such toxins have become a considerable problem. However, the joint neurotoxicity of As and Pb to neurodevelopment and the underlying mechanisms remain unclear. Pluripotent stem cell-derived human brain organoids are emerging animal model alternatives for understanding neurological-related diseases. Therefore, we utilized brain organoids with optic vesicles (OVB-organoids) to systematically analyze the neurotoxicity of As and Pb. After 24 h of As and/or Pb exposure, hematoxylin-eosin staining revealed that As and Pb exposure could cause disorders in the structure of the ventricular zone and general cell disarrangement in OVB-organoids. Immunostaining displayed that OVB-organoids are more susceptible to As and Pb co-exposure than independent exposure in apoptosis, proliferation, and cell differentiation. Meanwhile, even though As and Pb could both hinder cell proliferation, contrary to Pb, As could induce an increasing proportion of mitotic (G2/M) cells. The proteome landscape of OVB-organoids illustrated that Pb synergized with As in G2/M arrest and the common role of As and Pb in carcinogenesis. Besides, proteomics analyses suggested the consequential role of autophagy and Wnt pathway in the neurotoxicity of As and Pb co-exposure. Overall, our findings provide penetrating insights into the cell cycle, carcinogenesis, autophagy, and Wnt pathway underlying the As and Pb binary exposure scenarios, which could enhance our understanding of the mixture neurotoxicity mechanisms.

Study on the combined toxicity of DEHP and lead on the blood system of rats.

Di(2-ethylhexyl) phthalate (DEHP) is a commonly used phthalate ester compound, while lead is a persistent and bioaccumulative heavy metal. Both can be exposed to the body through a variety of ways, which may have an impact on the blood system. In this study, we examined the impact of co-exposure to DEHP (0, 10, 100 mg/kg) and Pb (0, 5, 50 mg/kg) on the blood system of male SD rats. The study revealed that continuous exposure to DEHP and Pb for 20 days resulted in a decrease in leukocytes and lymphocytes, while an increase in neutrophils and monocytes. Co-exposure led to a significant decrease in the spleen coefficients. Furthermore, the combined exposure could increase the ratio of bone marrow cells in G1 phase, and decrease the ratio of cells in S phase and G2 phase. Cytokine testing showed that combined exposure affects the secretion of hematopoietic factors and may cause bone marrow cell apoptosis. Single or combined exposure to DEHP and Pb can cause oxidative stress in serum and bone marrow. Overall, these results indicate that the co-exposure of DEHP and Pb adversely affected the blood system of rats, mainly due to the induction of oxidative stress and ultimately affects the secretion of cytokines. The combined effect of the two substances is primarily antagonistic. These results have important implications for the risk assessment of combined pollution and provide valuable theoretical guidance.