Inhalation exposure to polystyrene nanoplastics induces chronic obstructive pulmonary disease-like lung injury in mice through multi-dimensional assessment.

Nanoplastics are widely distributed in indoor and outdoor air and can be easily inhaled into human lungs. However, limited studies have investigated the impact of nanoplastics on inhalation toxicities, especially on the initiation and progression of chronic obstructive pulmonary disease (COPD). To fill the gap, the present study used oronasal aspiration to develop mice models. Mice were exposed to polystyrene nanoplastics (PS-NPs) at three concentrations, as well as the corresponding controls, for acute, subacute, and subchronic exposure. As a result, PS-NPs could accumulate in exposed mice lungs and influence lung organ coefficient. Besides, PS-NPs induced local and systemic oxidative stress, inflammation, and protease-antiprotease imbalance, resulting in decreased respiratory function and COPD-like lesions. Meanwhile, PS-NPs could trigger the subcellular mechanism to promote COPD development by causing mitochondrial dysfunctions and endoplasmic reticulum (ER) stress. Mechanistically, ferroptosis played an important role in the COPD-like lung injury induced by PS-NPs. In summary, the present study comprehensively and systematically indicates that PS-NPs can damage human respiratory health and increase the risk for COPD.

HIF-1α/m6A/NF-κB/CCL3 axis-mediated immunosurveillance participates in low level benzene-related erythrohematopoietic development toxicity.

Defective erythropoiesis is one of the causes of anemia and leukemia. However, the mechanisms underlying defective erythropoiesis under a low-dose environment of benzene are poorly understood. In the present study, multiple omics (transcriptomics and metabolomics) and methods from epidemiology to experimental biology (e.g., benzene-induced (WT and HIF-1α + ) mouse, hiPSC-derived HSPCs) were used. Here, we showed that erythropoiesis is more easily impacted than other blood cells, and the process is reversible, which involves HIF-1 and NF-kB signaling pathways in low-level benzene exposure workers. Decreased HIF-1α expression in benzene-induced mouse bone marrow resulted in DNA damage, senescence, and apoptosis in BMCs and HSCs, causing disturbances in iron homeostasis and erythropoiesis. We further revealed that HIF-1α mediates CCL3/macrophage-related immunosurveillance against benzene-induced senescent and damaged cells and contributes to iron homeostasis. Mechanistically, we showed that m6A modification is essential in this process. Benzene-induced depletion of m6A promotes the mRNA stability of gene NFKBIA and regulates the NF-κB/CCL3 pathway, which is regulated by HIF-1α/METTL3/YTHDF2. Overall, our results identified an unidentified role for HIF-1α, m6A, and the NF-kB signaling machinery in erythroid progenitor cells, suggesting that HIF-1α/METTL3/YTHDF2-m6A/NF-κB/CCL3 axis may be a potential prevention and therapeutic target for chronic exposure of humans to benzene-associated anemia and leukemia.

Ferritinophagy Mediated by Oxidative Stress-Driven Mitochondrial Damage Is Involved in the Polystyrene Nanoparticles-Induced Ferroptosis of Lung Injury.

Nanoplastics are a common type of contaminant in the air. However, no investigations have focused on the toxic mechanism of lung injury induced by nanoplastic exposure. In the present study, polystyrene nanoplastics (PS-NPs) caused ferroptosis in lung epithelial cells, which could be alleviated by ferrostatin-1, deferoxamine, and N-acetylcysteine. Further investigation found that PS-NPs disturbed mitochondrial structure and function and triggered autophagy. Mechanistically, oxidative stress-derived mitochondrial damage contributed to ferroptosis, and autophagy-dependent ferritinophagy was a pivotal intermediate link, resulting in ferritin degradation and iron ion release. Furthermore, inhibition of ferroptosis using ferrostatin-1 alleviated pulmonary and systemic toxicity to reverse the mouse lung injury induced by PS-NPs inhalation. Most importantly, the lung-on-a-chip was further used to clarify the role of ferroptosis in the PS-NPs-induced lung injury by visualizing the ferroptosis, oxidative stress, and alveolar-capillary barrier dysfunction at the organ level. In summary, our study indicated that ferroptosis was an important mechanism for nanoplastics-induced lung injury through different lung cells, mouse inhalation models, and three-dimensional-based lung-on-a-chip, providing an insightful reference for pulmonary toxicity assessment of nanoplastics.

Metabolic risk factors link unhealthy lifestyles to the risk of colorectal polyps in China.

Colorectal cancer is the second leading cause of global cancer-related deaths, and its precursor lesions are colorectal polyps (CAP). The study aimed to explore the effect of combinations of unhealthy lifestyles on CAP and investigate the mediation role of metabolic disorder in this process. A total of 1299 adults were recruited from a hospital in Jiangsu, China, including 811 cases and 488 adults without diseases. The information on demographic characteristics and lifestyles was collected through questionnaires and the medical record system. Serum biochemical parameters were determined using the automatic biochemical analyzer. Adjusted regression analysis showed that unhealthy lifestyles, including smoking, overnight meals, daily water intake, staying up late, and exercise associated with the risk of CAP. Furthermore, metabolic biomarkers, including BMI, triglycerides, and uric acid, were associated with the risk of CAP. Also, unhealthy lifestyle scores were positively associated with BMI, triglycerides, and CAP. The mediation effect of metabolic biomarkers, such as BMI and triglycerides on the association of unhealthy lifestyle scores with CAP was significant. Available data demonstrate the adverse effect of combinations of unhealthy lifestyle factors on CAP, and metabolic disorders to potentially mediate the association of unhealthy lifestyles with the risk of CAP.

Sentinel supervised lung-on-a-chip: A new environmental toxicology platform for nanoplastic-induced lung injury.

Nanoplastics are prevalent in the air and can be easily inhaled, posing a threat to respiratory health. However, there have been few studies investigating the impact of nanoplastics on lung injury, especially chronic obstructive pulmonary disease (COPD). Furthermore, cell and animal models cannot deeply understand the pollutant-induced COPD. Existing lung-on-a-chip models also lack interactions among immune cells, which are crucial in monitoring complex responses. In the study, we built the lung-on-a-chip to accurately recapitulate the structural features and key functions of the alveolar-blood barrier while integrating multiple immune cells. The stability and reliability of the lung-on-a-chip model were demonstrated by toxicological application of various environmental pollutants. We Further focused on exploring the association between COPD and polystyrene nanoplastics (PS-NPs). As a result, the cell viability significantly decreased as the concentration of PS-NPs increased, while TEER levels decreased and permeability increased. Additionally, PS-NPs could induce oxidative stress and inflammatory responses at the organ level, and crossed the alveolar-blood barrier to enter the bloodstream. The expression of α1-antitrypsin (AAT) was significantly reduced, which could be served as early COPD checkpoint on the lung-chips. Overall, the lung-on-a-chip provides a new platform for investigating the pulmonary toxicity of nanoplastics, demonstrating that PS-NPs can harm the alveolar-blood barrier, cause oxidative damage and inflammation, and increase the risk of COPD.

Characterization of lymphocyte subsets and intestinal short-chain fatty acids in benzene-induced immunosuppressive mice.

Exposure to benzene causes immunosuppression, but the mechanism has not been clarified. In this study, mice were subcutaneously injected with different concentrations (0, 6, 30 and 150 mg/kg) of benzene for four weeks. The lymphocytes of bone marrow (BM), spleen and peripheral blood (PB) and the level of short-chain fatty acids (SCFAs) in mouse intestine were measured. The results showed that benzene exposure led to a reduction in CD3+ and CD8+ lymphocytes in mouse BM, spleen and PB, and CD4+ lymphocytes were increased in mouse spleen but decreased in mouse BM and PB after 150 mg/kg benzene exposure. In addition, Pro-B lymphocytes were reduced in mouse BM in the 6 mg/kg group. Besides, the levels of IgA, IgG, IgM, IL-2, IL-4, IL-6, IL-17a, TNF-α and IFN-γ in mouse serum were reduced after benzene exposure. Furthermore, the levels of acetic, propionic, butyric and hexanoic acid were reduced in mouse intestine, and the AKT-mTOR signaling pathway was activated in mouse BM cells after benzene exposure. Our results demonstrate that benzene induced immunosuppression in mice, and the B lymphocytes in BM are more sensible to benzene-induced toxicity. The reduction in mouse intestinal SCFAs as well as the activation of AKT-mTOR signaling may be related to the occurrence of benzene immunosuppression. Our study provides new insight for further mechanistic research on benzene-induced immunotoxicity.

Multi-omics analysis revealed NMBA induced esophageal carcinoma tumorigenesis via regulating PPARα signaling pathway.

As widespread environmental carcinogens causing esophageal carcinoma (EC), the effects of N-nitrosamines on human health hazards and accurate toxicity mechanisms have not been well-elucidated. In this study, we explored the tumorigenic mechanism of N-nitrosomethylbenzylamine (NMBA) exposure using both cell and rat models. It was found that NMBA (2 µM) exposure for 26 weeks induced malignant transformation of normal esophageal epithelial (Het-1A) cells. After then proteomics analysis showed that lipid metabolism disorder predominantly participated in the process of NMBA-induced cell malignant transformation. Further the integrated proteomics and lipidomics analysis revealed that the enhancement of fatty acid metabolism promoted the EC tumorigenesis induced by NMBA through facilitating the fatty acid-associated PPARα signaling pathway. The animal studies also revealed that accelerated fatty acid decomposition in the progression of NMBA-induced EC models of rats was accompanied by the activation of the PPARα pathway. Overall, our findings depicted the key dynamic molecular alteration triggered by N-nitrosamines, and provided comprehensive biological perspectives into the carcinogenic risk assessment of N-nitrosamines.

Hearing loss and hypertension among noise-exposed workers: a pilot study based on baseline data.

This study aimed to assess the prevalence of noise-induced hearing loss (NIHL) and hypertension, and the association between NIHL and hypertension using occupational physical examination data of 42,588 noise-exposed workers from local enterprises in Yangzhou between 2015 and 2017. The average binaural high-frequency threshold on average (BHFTA), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were 23.09 ± 11.32 dB, 126.85 ± 15.94 mm Hg and 79.94 ± 11.61 mm Hg. The prevalence of NIHL and hypertension were 24.38% and 25.40%. An increased risk of NIHL and hypertension was observed in the groups of males, aged >35 years, noise exposure time >5 years, noise exposure level >85 dB(A) and smoking. 32.25% NIHL workers had hypertension. NIHL workers were at higher risk of hypertension (adjusted OR = 1.07, 95%CI = 1.02-1.13). This study shows that the noise-exposed workers have high risk of developing NIHL and hypertension.

N-nitrosamines-mediated downregulation of LncRNA-UCA1 induces carcinogenesis of esophageal squamous by regulating the alternative splicing of FGFR2.

Concerns are raised over the risk to digestive system's tumors from the N-nitrosamines (NAs) exposure in drinking water. Albeit considerable studies are conducted to explore the underlying mechanism responsible for NAs-induced esophageal squamous cell carcinoma (ESCC), the exact molecular mechanisms remain largely unknown, especially at the epigenetic regulation level. In this study, it is revealed that the urinary concentration of N-Nitrosodiethylamine is higher in high incidence area of ESCC, and the lncRNA-UCA1(UCA1) is significantly decreased in ESCC tissues. In vitro and in vivo experiments further show that UCA1 is involved in the malignant transformation of Het-1A cells and precancerous lesions of the rat esophagus induced by N-nitrosomethylbenzylamine (NMBzA). Functional gain and loss experiments verify UCA1 can affect the proliferation, migration, and invasion of ESCC cells in vitro and in vivo. Mechanically, through binding to heterogeneous nuclear ribonucleoprotein F (hnRNP F) protein, UCA1 regulates alternative splicing of fibroblast growth factor receptor 2 (FGFR2), which promotes the FGFR2IIIb isoform switching to FGFR2 IIIc isoform, and the latter activates epithelial-mesenchymal transition via PI3K-AKT signaling pathways impacting tumorigenesis. Therefore, NAs-mediated downregulation of UCA1 promotes ESCC progression through targeting hnRNP F/FGFR2/PI3k-AKT axis, which provides a new chemical carcinogenic target and establishes a previously unknown mechanism for NAs-induced ESCC.

Microcystin-LR Combined with Cadmium Exposures and the Risk of Chronic Kidney Disease: A Case-Control Study in Central China.

Increasing evidence indicates that exposure to microcystin-LR (MC-LR) can cause kidney damage. However, the association between MC-LR exposure and chronic kidney disease (CKD) risk in humans has not been studied. Therefore, we conducted a population-based case-control study involving 135 CKD cases and 135 matched controls in central China and analyzed the effects of MC-LR alone as well as combined with the known risk factor cadmium (Cd). Compared to the lowest quartile of MC-LR exposure, the highest quartile had a 6.56-fold (95% confidence interval [CI]: 2.46, 17.51) significantly increased risk for CKD, displaying a dose-response relationship (ptrend < 0.001). Our animal study also showed that MC-LR exposure induced kidney injury via the PI3K/AKT/mTOR signaling pathway. Comparing the highest Cd quartile to the lowest, the adjusted odds ratio for CKD was 3.88 (95% CI: 1.47, 10.28), exhibiting a dose-response relationship (ptrend < 0.006). Furthermore, a positive additive interaction was observed between MC-LR and Cd (relative excess risk due to interaction = 1.81, 95% CI: 0.42, 3.20; attributable proportion of interaction = 0.70, 95% CI: 0.35, 1.05). Our study firstly revealed that MC-LR exposure is an independent risk factor for CKD and has a synergistic relationship with Cd. MC-LR and Cd exposures are associated with CKD risk in a dose-response manner.

Let-7e-5p, a promising novel biomarker for benzene toxicity, is involved in benzene-induced hematopoietic toxicity through targeting caspase-3 and p21.

Benzene is a common industrial chemical and environmental pollutant. However, the mechanism of hematotoxicity caused by exposure to low doses of benzene is unknown. Let-7e-5p pathway regulatory networks were constructed by bioinformatics analysis using a benzene-induced aplastic anemia (BIAA) mouse model. The MTT assay, EdU staining, flow cytometric analysis, dual luciferase reporter gene assay, and RIP assay were utilized to evaluate the effects of benzoquinone (1,4-BQ) on let-7e-5p pathway. This study consisted of 159 workers with a history of low-level benzene exposure and 159 workers with no history of benzene exposure. After the confounding factors were identified, the associations between let-7e-5p expression and hematotoxicity were assessed by multiple linear regression. Furthermore, we used four machine learning algorithms (decision trees, neural network, Bayesian network, and support vector machines) to construct a predictive model for detecting benzene-causing hematotoxicity in workers. In this study, compared with respective controls, let-7e-5p expression was decreased in BIAA mice and benzene-exposed workers. After 1,4-BQ exposure, let-7e-5p overexpression negatively regulated caspase-3 and p21 expression, protected cells from apoptosis, and facilitated cell proliferation. RIP assays, and dual luciferase reporter gene assays confirmed that let-7e-5p could target p21 and caspase-3 and regulate the cell cycle and apoptosis. The support vector machines classifier achieved the best prediction of benzene-induced hematotoxicity (prediction accuracy = 88.27, AUC = 0.83) by statistically characterizing the internal dose of benzene exposure and the oxidative stress index, as well as the expression levels of let-7e-5p pathway-related genes in benzene-exposed workers. Let-7e-5p may be a potential therapeutic target of benzene-induced hematotoxicity, provide a basis for evaluating the health hazards of long-term and low-dose benzene exposure in workers, and supply a reference for revising occupational health standards.

Metabolomic transition trajectory and potential mechanisms of N-nitrosomethylbenzylamine induced esophageal squamous cell carcinoma in rats.

Esophageal squamous cell carcinoma (ESCC) is an environment-relevant malignancy with a high mortality. Nitrosamines, a class of nitrogen-containing environmental carcinogens, are widely suggested as a risk factor for ESCC. However, how nitrosamines affect metabolic regulation to promote ESCC tumorigenesis is largely unknown. In this study, the transition trajectory of serum metabolism in the course of ESCC induced by N-nitrosomethylbenzylamine (NMBA) in rats was depicted by an untargeted metabolomic analysis, and the potential molecular mechanisms were revealed. The results showed that the metabolic alteration in rats was slight at the basal cell hyperplasia (BCH) stage, while it became apparent when the esophageal lesion developed into dysplasia (DYS) or more serious conditions. Moreover, serum metabolism of severe dysplasia (S-DYS) showed more similar characteristics to that of carcinoma in situ (CIS) and invasive cancer (IC). Aberrant nicotinate (NA) and nicotinamide (NAM) metabolism, tryptophan (TRP) metabolism, and sphingolipid metabolism could be the key players favoring the malignant transformation of esophageal epithelium induced by NMBA. More particularly, NA and NAM metabolism in the precancerous stages and TRP metabolism in the cancerous stages were demonstrated to replenish NAD+ in different patterns. Furthermore, both the IDO1-KYN-AHR axis mediated by TRP metabolism and the SPHK1-S1P-S1PR1 axis by sphingolipid metabolism provided an impetus to create the pro-inflammatory yet immune-suppressive microenvironment to facilitate the esophageal tumorigenesis and progression. Together, these suggested that NMBA exerted its carcinogenicity via more than one pathway, which may act together to produce combination effects. Targeting these pathways may open up the possibility to attenuate NMBA-induced esophageal carcinogenesis. However, the interconnection between different metabolic pathways needs to be specified further. And the integrative and multi-level systematic research will be conducive to fully understanding the mechanisms of NMBA-induced ESCC.

LncRNA RPL34-AS1 suppresses the proliferation, migration and invasion of esophageal squamous cell carcinoma via targeting miR-575/ACAA2 axis.

BACKGROUND: Long noncoding RNAs (lncRNAs) are abnormally expressed in a broad type of cancers and play significant roles that regulate tumor development and metastasis. However, the pathological roles of lncRNAs in esophageal squamous cell carcinoma (ESCC) remain largely unknown. Here we aimed to investigate the role and regulatory mechanism of the novel lncRNA RPL34-AS1 in the development and progression of ESCC. METHODS: The expression level of RPL34-AS1 in ESCC tissues and cell lines was determined by RT-qPCR. Functional experiments in vitro and in vivo were employed to explore the effects of RPL34-AS1 on tumor growth in ESCC cells. Mechanistically, fluorescence in situ hybridization (FISH), bioinformatics analyses, luciferase reporter assay, RNA immunoprecipitation (RIP) assay and western blot assays were used to detect the regulatory relationship between RPL34-AS1, miR-575 and ACAA2. RESULTS: RPL34-AS1 was significantly down-regulated in ESCC tissues and cells, which was negatively correlated with overall survival in ESCC patients. Functionally, upregulation of RPL34-AS1 dramatically suppressed ESCC cell proliferation, colony formation, invasion and migration in vitro, whereas knockdown of RPL34-AS1 elicited the opposite function. Consistently, overexpression of RPL34-AS1 inhibited tumor growth in vivo. Mechanistically, RPL34-AS1 acted as a competing endogenous RNA (ceRNA) of miR-575 to relieve the repressive effect of miR-575 on its target ACAA2, then suppressed the tumorigenesis of ESCC. CONCLUSIONS: Our results reveal a role for RPL34-AS1 in ESCC tumorigenesis and may provide a strategy for using RPL34-AS1 as a potential biomarker and an effect target for patients with ESCC.

High expression of HIF-1α alleviates benzene-induced hematopoietic toxicity and immunosuppression in mice.

Benzene exposure can cause pancytopenia and immunosuppression, leading to serious diseases such as aplastic anemia (AA) or acute myeloid leukemia (AML), but the underlying mechanism has not been fully elucidated. Hypoxia-inducible factor 1 (HIF-1) is an important transcription factor that regulates many downstream target genes. In this study, we reported a novel mechanism by which high expression of HIF-1α alleviated benzene toxicity. Mice with high expression of HIF-1α (HIF-1α+) were obtained by the Tet-on system and doxycycline induction, and they and wild-type (WT) mice were exposed to 150 mg/kg benzene for 0, 1, 3, 7, 10, 14, and 28 days. Dynamic changes in hematopoietic and immune-related indicators and the role of HIF-1α were explored. The level of white blood cells in mice reached the highest level on the third day, and immunity was activated and then suppressed within 10 days. Significant pancytopenia and immunosuppression occurred at 14 days and were more pronounced at 28 days. The levels of HIF-1α, EPO, VEGF, RORγt, and IL-17 in WT mice gradually decreased with increasing benzene exposure days, while the levels of Foxp3 and IL-10 increased. These changes were alleviated in HIF-1α+ mice. High expression of HIF-1α increased the levels of EPO and VEGF, which helped to maintain the stability of the hematopoietic microenvironment. Simultaneously, it attenuated benzene-induced immunosuppression by alleviating the Th17/Treg imbalance. HIF-1α is expected to be a new target for benzene-induced diseases such as AA and AML.

The association between neurodevelopmental and behavioral problems and tobacco smoke exposure among 3-17 years old children.

Children being exposed to tobacco smoke can lead to poor developmental and behavioral problems. We aimed to explore the correlation between neurodevelopmental and behavioral problems (NBPs) and tobacco smoke exposure (TSE) among children aged 3-17 years. In this study, data were obtained from the 2018-2019 U.S. National Survey of Children's Health (NSCH). Children in the range of 3-17 years old were taken as the research subjects, and their parents were surveyed through questionnaires. TSE status was defined as one of three groups: no tobacco smoke exposure (no TSE), someone smoking but not inside the house (no home TSE), and someone smoking inside the house (home TSE). NBPs mainly included behavioral or conduct problems, intellectual disability, learning disability, speech or other language disorders, and developmental delay. We used the sampling weights provided by the NSCH to weight the data in order to obtain an unbiased population estimate. One-way ANOVA and Chi-square tests were performed to examine the difference of each variable. Logistic regression analysis and stratified analysis were carried out to investigate the association between NBPs and TSE. A total of 48,783 children were included in this study, with an average age of 10.1 years. In total 17.9% of all the participants were preschool children, 35.1% were school-age children, and 47.0% were school-age adolescents. More than 85.0% of children lived with no TSE. Over 90.0% of children were healthy in each NBP. Children living with home TSE and no home TSE showed significant adjusted odds ratios (aORs) compared with no TSE in four NBPs besides intellectual disability. The stratified analysis found aORs were higher for NBPs in preschool children compared to the school-age children and school-age adolescents. Male children living with home TSE showed higher aORs in moderate/severe NBP conditions. Our study indicated it is necessary to protect the health of young children from TSE by intervention measures.

The role of N6-methyladenosine methylation in environmental exposure-induced health damage.

The health risks caused by environmental pollution have long been of substantial concern. With the development of epigenetics, a large number of studies have demonstrated that N6-methyladenosine (m6A) modification is involved in the regulation of various important life activities associated with various diseases. Recent studies have revealed that m6A plays a key role in health damage caused by environmental exposure by regulating post-transcriptional gene expression. Therefore, our study outlined the effects of environmental pollutant exposure on m6A methylation and its regulator levels. Moreover, we found that m6A methylation modifications were involved in the development of various health damages by regulating important life activities in vivo, such as reactive oxygen species imbalance, apoptosis, epithelial-mesenchymal transition (EMT), and inflammatory processes. More importantly, we delved into the regulatory mechanisms of m6A methylation dysregulation in environmental pollution-induced diseases. Finally, by examining the published literature, we found that methyltransferase-like protein 3 (METTL3) and fat mass- and obesity-associated protein (FTO) were potentially used as biomarkers of health damage induced by particulate matter exposure and heavy metal exposure, respectively. The current studies on regulators of METTL3 and FTO were more promising to bring new perspectives for the treatment of environmental health-related diseases.

Fluorescence imaging of FEN1 activity in living cells based on controlled-release of fluorescence probe from mesoporous silica nanoparticles.

Flap endonuclease 1 (FEN1) is a structure-specific nuclease, which catalyzes the removal of 5' overhanging DNA flap from a specific DNA structure. FEN1 has been considered as an important biomarker for cancer diagnosis since it is over-expressed in various types of human tumor cells and closely related to cancer development. Nanoprobes gradually become basic tools for analyzing biomarkers variations in vivo. Here, we utilized aminoated mesoporous silica nanoparticles (NH2-MSNs) with a rich porous structure as the fluorescence nanoprobes to entrap the rhodamine 6G (Rh6G) molecules. Then gold nanoparticles linked specific single-stranded DNA (AuNPs-ssDNA) as a molecular gate was used to coat the NH2-MSNs surface. The fluorescence signal was weak when the fluorescence molecules were blocked by the AuNPs-ssDNA. In the presence of FEN1, it recognized and cleaved the specific ssDNA to release the Rh6G from NH2-MSNs, which resulted in recovered fluorescence signals. Thus, the sensitive detection of FEN1 activity was realized by controlled-release of Rh6G. The fluorescence signal showed a good linear relationship with the logarithm of FEN1 activity ranging from 0.05 to 1.75 U with a detection limit of 0.03 U. Moreover, confocal imaging demonstrated that the proposed biosensor could distinguish tumor cells from normal cells. Therefore, this technique contributes to clinical diagnostic and therapeutic monitoring.

Lipid metabolism disorders contribute to hepatotoxicity of ICR mice induced by nitrosamines exposure.

Health risks caused by crucial environmental carcinogens N-nitrosamines triggered ubiquitous attention. As the liver exerted vital function through metabolic process, lipid metabolism disorders have been confirmed as potential drivers for toxicological effects, and the mechanisms of lipid regulation related to hepatotoxicity induced by N-nitrosamines remained largely unclear. In this study, we comprehensively explored the disturbance of hepatic lipid homeostasis in mice induced by nitrosamines. The results implied that nitrosamines exposure induced hepatotoxicity accompanied by liver injury, inflammatory infiltration, and hepatic edema. Lipidomics profiling analysis indicated the decreased levels of phosphatidic acids (PA), phosphatidylcholines (PC), phosphatidylethanolamines (PE), lyso-phosphatidylcholines (LPC), lyso-phosphatidylethanolamines (LPE), diacylglycerols (DAG) and triacylglycerols (TAG), the elevation of ceramides (Cer) and decomposition of free fatty acids (FFA) in high-dose nitrosamines exposure group. Importantly, nitrosamines exposure promoted fatty acid oxidation (FAO) by facilitating fatty acid uptake and decomposition, together with the upregulation of genes associated with FAO accompanied by the activation of inflammatory cytokines TNF-α, IL-1ß and NLRP3. Furthermore, fatty acid translocase CD36-mediated fatty acid oxidation was correlated with the enhancement of oxidative stress in the liver caused by nitrosamines exposure. Overall, our results contributed to the new strategies to interpret the early toxic effects of nitrosamines exposure.

Ferroptosis is involved in the benzene-induced hematotoxicity in mice via iron metabolism, oxidative stress and NRF2 signaling pathway.

Benzene is a pollutant that widely exists in the environment and in occupational workplaces. Its exposure is closely associated with hematological disorders and even leukemia, which poses a significant threat to public health. Thus, the underlying mechanisms should be explored. In the current study, it was investigated whether ferroptosis plays a role in benzene hematopoietic toxicity and related mechanisms. Mice were subcutaneously injected with benzene at 150 mg/kg b.w. to establish a hematotoxicity model. Four weeks later, the mice exposed to benzene exhibited a decrease in white blood cells, red blood cells, and hemoglobin level, as well as reduction in frequency of hematopoietic stem and progenitor cells (HS/PCs) and the colony forming abilities of CFU-G, CFU-M, CFU-GM, and CFU-GEMM. Simultaneously, apart from ferroptosis features in the mitochondrial morphology, decreased ATP and mitochondrial membrane potential, alterations in biochemical indices and gene expression were also observed, such as increased intracellular iron and lipid peroxidation, glutathione (GSH) depletion, and reduced glutathione peroxidase (GSH-Px) level, and upregulated PTGS2. Meanwhile, markedly altered expression of SLC7A11, GPX4, GCLC, NOX1, TFRC, FTH1, and FTL hinted that redox imbalance and dysfunction of iron uptake and storage are vital to induce ferroptosis. Additionally, decreased cytoplasmic NRF2 and increased nuclear NRF2 were also found, suggesting the activation of the NRF2 pathway. More importantly, inhibition of ferroptosis with ferrostatin-1 (Fer-1) or deferoxamine (DFO) partially relieved the hematopoietic injuries. Our findings imply that dysregulation in the system Xc-/GPX4 axis, iron metabolism, and activation of the NRF2 pathway play a crucial role in benzene-induced ferroptosis, and reveals that taking ferroptosis as a target may be a potential intervention strategy for benzene-induced hematotoxicity.