Toxicology最新文献

Mycotoxins are potential environmental risk factors for neurodegenerative diseases. These toxins penetrate the central nervous system via a compromised blood-brain barrier, which may cause oxidative stress and neuroinflammation, these can also contribute to amyloid-beta (Aβ) plaque accumulation, Tau protein hyperphosphorylation, and neurofibrillary tangle formation. Mycotoxins also activate microglia, cause neuronal apoptosis, and disrupt central nervous system function. This study examines the evidence linking mycotoxin exposure to neurodegenerative disorders like Alzheimer's and Parkinson's diseases. We explore mechanisms such as oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, neuroinflammation, and direct neurotoxic effects. Epidemiological studies show regional variations in mycotoxin prevalence and corresponding neurodegenerative disease incidences, supporting this association. We also review current approaches to mitigate mycotoxin exposure and discuss the challenges and opportunities in developing strategies to prevent or slow neurodegenerative disease progression. This work highlights the need for increased awareness and research on mycotoxins as modifiable risk factors in neurological health.

Bisphenol A (BPA) is a typical environmental endocrine disruptor which have been broadly confirmed to be associated with malignant tumors, including colorectal cancer (CRC). Lipid metabolism reprogramming performed important biological effects in cancer progression. While the role of lipid metabolism in CRC progression upon BPA exposure remain elusive. Here, we found that BPA exposure enhanced de novo ceramide synthesis in vitro, along with upregulated ceramide synthase in high-BPA tumor tissue of CRC patients. Simultaneously, we demonstrated that BPA exposure exacerbated tumor biological behavior and epithelial mesenchymal transition (EMT), concurrent with elevated EMT expression of CRC tissue in high BPA group. Subsequently, the inhibition of ceramide synthase and pharmacological stimulation experiments revealed that ceramide accumulation activated EMT and exacerbated CRC progression, including Cer (d18:1/16:0) and Cer (d18:1/24:1). Collectively our findings elucidated the pathogenesis of ceramide accumulation escalating tumor progression under environmental BPA exposure, providing a strong basis for further investigation of dysregulated ceramide metabolism to boost tumor development and avoid metastatic relapse.

The environmental impact of harmful particles from tire and brake systems is a growing concern. This study investigated the health impacts of PM_2.5 emissions from brake pad wear on adult C57BL/6 mice. The mice were exposed to brake pad particles via intratracheal infusion, and various health parameters were assessed. The results showed that brake pad particle exposure significantly reduced lung function parameters such as tidal volume, peak expiratory time ratio, and peak inspiratory flow rate, while increasing the apnea index and airway stenosis index. Histological analysis revealed particle deposition, inflammatory damage, and potential fibrosis in the lungs. Additionally, inflammatory markers and fibrosis indicators were elevated in the lung tissue. Metabolomic analysis indicated changes in metabolites related to purine metabolism, protein digestion, nucleic acid metabolism, and pathways involving Caffeine, Xanthine, Inosine, and others. Gut microbiota analysis showed increased abundance of Odoribacter and Tuzzerella, and decreased abundance of Desulfovibrio and Butyricimonas. Correlation analysis further suggested a significant link between the abundance of Odoribacter and plasma metabolic changes. Overall, this study underscores the health risks associated with brake dust pollution, particularly its adverse effects on lung function and induction of lung damage and fibrosis.

Methamphetamine (METH), a synthetic stimulant, has seen an escalating abuse situation globally over the past decade. Although the molecular mechanism underlying METH-induced neurotoxicity has been explored, the dysfunction of brain-derived neurotrophic factor (BDNF) neuroprotection in the context of METH neurotoxicity remains insufficiently understood. Our previous studies have found that METH induced neurotoxicity and BDNF expression in rat primary neurons, necessitating further research into this paradox. Specifically, BDNF-dependent tyrosine receptor kinase B (TrkB) endocytosis was crucial for BDNF to confer neuroprotection in neurons. Therefore, we investigated the effect and molecular mechanism of METH on TrkB endocytosis. This work attempted to explain the potential reasons why BDNF did not exert neuroprotection in the context of METH exposure. In the current study, excessive apoptosis, elevated BDNF and reduced huntingtin-associated protein 1 (HAP1) expression were observed in the hippocampus of METH users. METH also induced cell degeneration, cytotoxicity, and BDNF expression and release in HT-22 cells in both a concentration- (0.25, 0.5, 1, 2, and 4 mM) and time-dependent manner (3, 6, 12, 24, and 48 h). Furthermore, following 24 h of exposure to METH (2 mM), apoptosis, impaired TrkB endocytosis, and reduced HAP1 expression were evident in HT-22 cells and organotypic hippocampal slices from mice. Notably, overexpression of HAP1 attenuated METH-induced cell degeneration, cytotoxicity, apoptosis, and TrkB endocytosis disruption in HT-22 cells. These findings suggest that HAP1 is a key molecule in the disruption of BDNF-mediated neuroprotective signaling by METH, and that targeting HAP1-mediated TrkB endocytosis may represent a promising therapeutic avenue for METH-induced neurotoxicity.

Malathion is an organophosphate compound widely used as an insecticide in the agriculture sector and is toxic to humans and other mammals. Although several studies have been conducted at different levels in different animal models. But there is no work has been conducted on the toxicological correlation from cellular to behavioral level in surviving species model. Addressing this gap through further research is essential for a comprehensive understanding of malathion's impact on biological systems, facilitating better risk assessment and management strategies. Current research systemically evaluated the effects of malathion on the central nervous system and peripheral immune cells using immunological techniques in the BALB/c mice models. For this, animals were placed inside an inhalation chamber containing malathion (dose of 89.5 mg/ml/m³) for a specific exposure time. The group exposed for 6 minutes has shown a significant change in plasma-neurotransmitter (serotonin, dopamine) levels and decreased expression of Tyrosine hydroxylase in striatum and SNPC region of brain. The depolarized mitochondria and increased level of cleaved caspase-3 level and mature neurons in DG, CA1 and CA3 were also observed in the brain. Peripheral blood analysis illustrated a decrease in total leukocyte count and an increased level of early apoptosis at the same time point. From neurobehavioral results a significant locomotor hyperactivity, restlessness, and risk-taking behavior was observed. Taken together, results from the current study indicate that exposure to malathion at prolonged time durations induces neuronal and immune cell toxicity, and its toxicity may be mediated via changes in neurotransmitter levels and metabolite concentrations.

N⁶-methyladenosine (m⁶A) modification and LncRNAs play crucial regulatory roles in various pathophysiological processes, yet roles of m⁶A modification and the relationship between m⁶A modification and LncRNAs in cadmium-induced oxidative damage of pancreatic β-cells have not been fully elucidated. In this study, m⁶A agonist entacapone and inhibitor 3-deazadenosine were used to identify the effects of m⁶A on cadmium-induced oxidative damage as well as LncRNA changes. Our results indicate that elevated levels of m⁶A modification by entacapone can rescue the cell viability and attenuate the cell apoptosis, while the inhibition levels of m⁶A modification can exacerbate the cell death. Furthermore, the elevation of m⁶A modification can recover cadmium-induced oxidative damage to pancreatic β-cells, which characterized as inhibition the ROS accumulation, MDA contents, protein expressions of Nrf2 and Ho-1, while elevation the expressions of Sod1 and Gclc. On the contrary, the reduction levels of m⁶A modification can exacerbate the cadmium-induced oxidative damage. More importantly, six significantly differentially expressed LncRNAs were selected according to our preliminary sequencing data (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE253072) and there is a clear correlation between the levels of these LncRNAs and m⁶A modification after cadmium treatment. Interestingly, the intervention of m⁶A modification levels can significantly affect the levels of these LncRNAs. In detail, the stimulation of m⁶A modification reversed the changes of cadmium-induced LncRNAs, while the m⁶A modification inhibition can significantly exacerbate the changes of cadmium-induced LncRNAs. In conclusion, our data revealed critical roles of m⁶A modification in cadmium-induced LncRNAs and oxidative damage. Our findings point to a new direction for future studies on the molecular mechanisms of pancreatic β-cell damage induced by cadmium.

Air pollution is associated with increased risk of neurodegenerative and neuropsychiatric conditions. While animal models have increased our understanding of how air pollution contributes to brain pathologies - including through oxidative stress, inflammatory, and stress hormone pathways - investigation of underlying mechanisms remains limited due to a lack of human-relevant models that incorporate systemic processes. Our objective was to establish an ex vivo approach that enables assessment of the roles of plasma mediators in pollutant-induced effects in the brain. As a proof-of-concept for application in the human context, we assessed whether such effects reproduced in vivo responses to pollutant exposure. Primary rat hippocampal neurons and microglia were each treated with plasma collected from rats immediately or 24 h after ozone inhalation (0 or 0.8 ppm) ± pre-treatment with the glucocorticoid synthesis inhibitor metyrapone. Microglia were further challenged with lipopolysaccharide to evaluate modification of inflammatory responses. Plasma from the ozone-exposed group produced transcriptional changes (inflammatory, antioxidant, glucocorticoid-responsive) in neurons, some of which were glucocorticoid-dependent. Ex vivo and hippocampal responses were strongly correlated, establishing the in vivo relevance of the model. Plasma from the ozone-exposed group modified inflammatory responses to lipopolysaccharide challenge in microglia, demonstrating the model's utility to assess functional changes resulting from pollutant exposure. This study establishes that an ex vivo approach can reproduce ozone-induced effects in the brain. The model was sensitive to specific plasma mediators and temporal effects, and enabled assessment of functional responses. This approach may serve to investigate mechanisms underlying effects of pollutants on the human brain.

Non-dioxin-like polychlorinated biphenyls (NDL-PCBs), as well as dioxin-like PCBs, are endocrine disruptors that persist in human and animal tissues worldwide. Due to their lipophilicity and resistance to enzymatic degradation, PCBs accumulate in fat deposits contributing to the onset of endocrine and metabolic diseases. Aquaporins (AQPs) are transmembrane channel proteins that allow the transport of water and small solutes. In particular, the aquaglyceroporins AQP3, AQP7, and AQP9 mediate the release and the uptake of glycerol in adipose tissue. Here, we investigate the modulation of these AQPs by NDL-PCBs and the following effects on lipid metabolism in mature 3T3-L1 adipocytes exposed for 48 h to PCB 101, 153, or 180 (1 μM). NDL-PCBs modulated protein expression of AQP3 and AQP7, involved in glycerol release, and AQP9, implicated in glycerol uptake. This modulation induced a greater accumulation of glycerol in treated adipocytes indirectly evaluated by its reduction in the culture media. Interestingly, only PCB 153 altered the expression of enzymes involved in glycerol metabolism and lipid accumulation (i.e. Pparg, Fabp4, Gyk, Dgat1, and Agpat9). These modifications indicated an increase of adipocyte lipid accumulation confirmed by Oil Red O staining. The role of AQPs in the increased cellular accumulation of glycerol was confirmed using phloretin, an AQP9 inhibitor, that reverted the PCB 153 effect. Our results show the involvement of AQPs in PCB 153-induced dysfunction of glycerol metabolism and lipid storage in adipocytes, contributing to better defining the mechanisms underlying its known obesogenic effect.

Gasoline exhaust particles (GEP) are risk factors for cardiovascular disease. Activating transcription factor 3 (ATF3) is a transcription factor known to form a heterodimer with AP-1 transcription factors for its target gene expression. However, the involvement of ATF3 in GEP-induced gene expression in human umbilical vein endothelial cells (HUVECs) has not been investigated. In this study, we found that GEP, at IC₅₀ value of 59 μg/ml, induced the expression of ATF3, which led to the expression of matrix metalloproteinase 1 (MMP1) in HUVECs. GEP induce an interaction between c-Jun and ATF3, and c-Jun depletion attenuates GEP-induced MMP1 expression. Depletion of NADPH oxidase 4 (Nox4) suppressed GEP-induced reactive oxygen species (ROS) generation and the subsequent upregulation of ATF3 and MMP1, suggesting that Nox4-derived ROS play a role as upstream regulators of GEP-induced ATF3 expression and MMP1 upregulation. Furthermore, Nox4 depletion attenuated the interaction between ATF3 and c-Jun and their binding to the AP-1 binding site of the MMP1 promoter. Taken together, these findings demonstrate that GEP induce the expression of MMP1 by generating Nox4-dependent ROS, which subsequently increase ATF3 expression and its interaction with c-Jun. This leads to their binding to the promoter region of MMP1 and its transcription. These findings suggest that Nox4-derived ROS and ATF3 are critical for GEP-induced MMP1 expression.

Observational studies have shown that cadmium exposure increases the risk of cardiovascular disease, but the underlying mechanism is still unclear. Atherosclerotic plaque can cause vascular obstruction, which is important for the death from cardiovascular disease. Cell damage and monocyte adhesion are two early events in atherosclerotic plaque formation that can be induced by cadmium exposure, but the mechanism remains to be determined. This study was carried out to investigate the toxicity of cadmium in HUVECs and the effect of cadmium on the adhesion of THP-1 cells, and further explored the possible mechanisms. Rhodamine staining, DCFH-DA staining, Hoechst33258 staining, morphological observation and western blot were used to detect mitochondrial membrane potential, ROS, apoptosis, cell adhesion, signaling pathways and cell adhesion factors respectively. The results indicated that cadmium exposure increased the level of ROS, activated MAPK signaling pathway and resulted in cellular oxidative stress in HUVECs. Exposure to cadmium made nuclear shrinkage, activated DNA damage response pathways and mitochondria-mediated intrinsic apoptosis pathway in HUVECs. Cadmium exposure activated the NLRP3 inflammasome and NF-κB signaling pathway, led to the upregulation of inflammatory cytokines in HUVECs. In addition, cadmium exposure also upregulated the adhesion factors including ICAM-1, VCAM-1 and E-Selectin via NF-κB signaling pathway and resulted in the adhesion of THP-1 cells. The present study elucidated that cadmium could damage the HUVECs and promote the adhesion of THP-1 cells, which clarified the toxicity of cadmium in HUVECs and revealed the possible mechanism for the occurrence of cardiovascular disease induced by cadmium.