The size-dependent in vivo toxicity of amorphous silica nanoparticles: A systematic review.

The extensive application of amorphous silica nanoparticles (aSiNPs) in recent years has resulted in unavoidable human exposure in daily life, thus raising widespread concerns regarding the safety of aSiNPs on human health. The particle size is one of the important characteristics of nanomaterials that could influence their toxicity. For the reason that particles with smaller sizes possess larger surface area, which may lead to higher surface activity and biological reactivity. However, due to the complexity of experimental conditions and biological systems, the relationship between the particle size and the toxic effect of aSiNPs remains unclear. Therefore, this systematic review aims to investigate how particle size influences the toxic effect of aSiNPs in vivo and to analyze the relevant experimental factors affecting the size-dependent toxicity of aSiNPs in vivo. We found that 83.8% of 35 papers included in the present review came to the conclusion that smaller-sized aSiNPs exhibited stronger toxicity, though a few papers (6 papers) put forward different opinions. The reasons for smaller aSiNPs manifested greater toxicity were summarized. In addition, certain important experimental factors could influence the size-dependent effects and in vivo toxicity of aSiNPs, such as the synthesis method of aSiNPs, disperse medium of aSiNPs, administration route of aSiNPs, species or strain of experimental animals, sex of experimental animals, aggregation/agglomeration and protein corona of aSiNPs.

Melatonin ameliorates PM2.5-induced spermatogenesis disorder by preserving H3K9 methylation and SIRT3.

There was a link between exposure to PM2.5 and male infertility. Melatonin has beneficial effects on the male reproductive processes. How PM2.5 caused spermatogenesis disturbance and whether melatonin could prevent PM2.5-induced reproductive toxicity have remained unclear. The results showed that PM2.5 could inhibit the Nrf2-mediated antioxidant pathway and distinctly increase the cell apoptosis in testes. Moreover, PM2.5 also perturbed the process of meiosis by modulating meiosis-associated proteins such as γ-H2AX and Stra8. Mechanistically, PM2.5 inhibited G9a-dependent H3K9 methylation and SIRT3-mediated p53 deacetylation, which consistent with decreased sperm count and motility rate in ApoE-/- mice. Further investigation revealed melatonin effectively alleviated PM2.5-induced meiosis inhibition by preserving H3K9 methylation. Melatonin also alleviated PM2.5-induced apoptosis by regulating SIRT3-mediated p53 deacetylation. Overall, our study revealed PM2.5 resulted in spermatogenesis disorder by perturbing meiosis via G9a-dependent H3K9 di-methylation and causing cell apoptosis via SIRT3/p53 deacetylation pathway and provided promising insights into the protective role of melatonin in air pollution associated with male infertility.

Amorphous silica nanoparticles cause abnormal cytokinesis and multinucleation through dysfunction of the centralspindlin complex and microfilaments.

BACKGROUND: With the large-scale production and application of amorphous silica nanoparticles (aSiNPs), its adverse health effects are more worthy of our attention. Our previous research has demonstrated for the first time that aSiNPs induced cytokinesis failure, which resulted in abnormally high incidences of multinucleation in vitro, but the underlying mechanisms remain unclear. Therefore, the purpose of this study was firstly to explore whether aSiNPs induced multinucleation in vivo, and secondly to investigate the underlying mechanism of how aSiNPs caused abnormal cytokinesis and multinucleation. METHODS: Male ICR mice with intratracheal instillation of aSiNPs were used as an experimental model in vivo. Human hepatic cell line (L-02) was introduced for further mechanism study in vitro. RESULTS: In vivo, histopathological results showed that the rate of multinucleation was significantly increased in the liver and lung tissue after aSiNPs treatment. In vitro, immunofluorescence results manifested that aSiNPs directly caused microfilaments aggregation. Following mechanism studies indicated that aSiNPs increased ROS levels. The accumulation of ROS further inhibited the PI3k 110ß/Aurora B pathway, leading to a decrease in the expression of centralspindlin subunits MKLP1 and CYK4 as well as downstream cytokines regulation related proteins Ect2, Cep55, CHMP2A and RhoA. Meanwhile, the particles caused abnormal co-localization of the key mitotic regulatory kinase Aurora B and the centralspindlin complex by inhibiting the PI3k 110ß/Aurora B pathway. PI3K activator IGF increased the phosphorylation level of Aurora B and improved the relative ratio of the centralspindlin cluster. And ROS inhibitors NAC reduced the ratio of multinucleation, alleviated the PI3k 110ß/Aurora B pathway inhibition, and then increased the expression of MKLP1, CYK4 and cytokinesis-related proteins, whilst NAC restored the clustering of the centralspindlin. CONCLUSION: This study demonstrated that aSiNPs led to multinucleation formation both in vivo and in vitro. ASiNPs exposure caused microfilaments aggregation and inhibited the PI3k 110ß/Aurora B pathway through excessive ROS, which then hindered the centralspindlin cluster as well as restrained the expression of centralspindlin subunits and cytokinesis-related proteins, which ultimately resulted in cytokinesis failure and the formation of multinucleation.

Association of long-term exposure to ambient air pollutants with cardiac structure and cardiovascular function in Chinese adults.

Epidemiological evidence increasingly suggests that air pollutants are intimately associated with the incidence and mortality of cardiovascular diseases (CVDs). However, studies on the association between chronic exposure to air pollutants and changes in left cardiac function and structure are limited. In our cross-sectional study, 3145 participants were enrolled from 6 provinces to explore the relationship between long-term air pollutants, cardiac structure, and cardiovascular function (e.g., blood lipids, blood pressure and pulse) in Chinese adults. Our study showed that exposure to five pollutants (NO2, O3, PM1, PM2.5 and PM10) was associated with reduced left ventricular systolic function based on EF and SV parameters. These pollutants were also associated with increased pulses, where smaller particle sizes correlated significantly with pulses. Second, except for O3, four pollutants were associated with decreased left ventricular diastolic parameters LVIDd and EDV and increased cardiac structural parameter IVSd. In addition, exposures to NO2, O3 and PM10 were positively correlated with triglycerides in blood lipids. Overall, this study showed that chronic pollutant exposure is strongly associated with impaired left ventricular function in Chinese adults.

Melatonin alleviates PM2.5 -induced glucose metabolism disorder and lipidome alteration by regulating endoplasmic reticulum stress.

Exposure to fine particulate matter (PM2.5 ) was associated with an increased incidence of liver metabolic disease. Melatonin has been shown to prevent liver glucolipid metabolism disorders. However, whether melatonin could rescue PM2.5 -induced liver metabolic abnormalities remains uncertain. This study was to evaluate the mitigating effect of melatonin on PM2.5 -accelerated hepatic glucose metabolism imbalance in vivo and in vitro. Schiff periodic acid shiff staining and other results showed that PM2.5 led to a decrease in hepatic glycogen reserve and an increase in glucose content, which was effectively alleviated by melatonin. Targeted lipidomics is used to identify lipid biomarkers associated with this process, including glycerolipids, glycerophospholipids, and sphingolipids. In addition, gene microarray and quantitative polymerase chain reaction analysis of ApoE-/- mice liver suggested that PM2.5 activated the miR-200a-3p and inhibited DNAJB9, and the targeting relationship was verified by luciferase reports for the first time. Further investigation demonstrated that DNAJB9 might motivate endoplasmic reticulum (ER) stress by regulating Ca2+ homeostasis, thus altering the protein expression of GSK3B, FOXO1, and PCK2. Meanwhile, melatonin effectively inhibited miR-200a-3p and glucose metabolism disorder. Knockout of miR-200a-3p in L02 cells revealed that miR-200a-3p is indispensable in the damage of PM2.5 and the therapeutic effect of melatonin. In summary, melatonin alleviated PM2.5 -induced liver metabolic dysregulation by regulating ER stress via miR-200a-3p/DNAJB9 signaling pathway. Our data provide a prospective targeted therapy for air pollution-related liver metabolism disorders.

Global association between atmospheric particulate matter and obesity: A systematic review and meta-analysis.

BACKGROUND: Among various air pollutants, particulate matter (PM) is the most harmful and representative pollutant. Although several studies have shown a link between particulate pollution and obesity, the conclusions are still inconsistent. METHODS: We conducted a systematic review and meta-analysis to pool the effect of PM exposure on obesity. Five databases (including PubMed, Web of Science, Scopus, Embase, and Cochrane) were searched for relevant studies up to Jan 2022. Adjusted risk ratio (RR) with corresponding 95% confidence interval (CI) were retrieved from individual studies and pooled with random effect models by STATA software. Besides, we tested the stability of results by Egger's test, Begg's test, funnel plot, and using the trim-and-fill method to modify the possible asymmetric funnel graph. The NTP-OHAT guidelines were followed to assess the risk of bias. Then the GRADE was used to evaluate the certainty of evidence. RESULTS: 26 studies were included in this meta-analysis. 19 studies have shown that PM2.5 can increase the risk of obesity per 10 µg/m3 increment (RR: 1.159, 95% CI: 1.111-1.209), while 15 studies have indicated that PM10 increase the risk of obesity per 10 µg/m3 increment (RR: 1.092, 95% CI: 1.070-1.116). Besides, 5 other articles with maternal exposure showed that PM2.5 increases the risk of obesity in children (RR: 1.06, 95% CI: 1.02-1.11). And we explored the source of heterogeneity by subgroup analysis, which suggested associations between PM and obesity tended to vary by region, age group, participants number, etc. The analysis results showed publication bias and other biases are well controlled, but most certainties of the evidence were low, and more research is required to reduce these uncertainties. CONCLUSION: Exposure to PM2.5 and PM10 with per 10 µg/m3 increment could increase the risk of obesity in the global population.

A comprehensive understanding of ambient particulate matter and its components on the adverse health effects based from epidemiological and laboratory evidence.

The impacts of air pollution on public health have become a great concern worldwide. Ambient particulate matter (PM) is a major air pollution that comprises a heterogeneous mixture of different particle sizes and chemical components. The chemical composition and physicochemical properties of PM change with space and time, which may cause different impairments. However, the mechanisms of the adverse effects of PM on various systems have not been fully elucidated and systematically integrated. The Adverse Outcome Pathway (AOP) framework was used to comprehensively illustrate the molecular mechanism of adverse effects of PM and its components, so as to clarify the causal mechanistic relationships of PM-triggered toxicity on various systems. The main conclusions and new insights of the correlation between public health and PM were discussed, especially at low concentrations, which points out the direction for further research in the future. With the deepening of the study on its toxicity mechanism, it was found that PM can still induce adverse health effects with low-dose exposure. And the recommended Air Quality Guideline level of PM2.5 was adjusted to 5 µg/m3 by World Health Organization, which meant that deeper and more complex mechanisms needed to be explored. Traditionally, oxidative stress, inflammation, autophagy and apoptosis were considered the main mechanisms of harmful effects of PM. However, recent studies have identified several emerging mechanisms involved in the toxicity of PM, including pyroptosis, ferroptosis and epigenetic modifications. This review summarized the comprehensive evidence on the health effects of PM and the chemical components of it, as well as the combined toxicity of PM with other air pollutants. Based on the AOP Wiki and the mechanisms of PM-induced toxicity at different levels, we first constructed the PM-related AOP frameworks on various systems.

Silica nanoparticles induce pulmonary autophagy dysfunction and epithelial-to-mesenchymal transition via p62/NF-κB signaling pathway.

It has been reported that silica nanoparticles (SiNPs) could cause epithelial-to-mesenchymal transition (EMT), but the specific mechanism is still unclear. Thus, the purpose of this study was to investigate the underlying mechanisms of pulmonary EMT after subacute exposure to SiNPs. The results showed intratracheal instillation of SiNPs increased the pulmonary MDA content, while decreased the activity of SOD and GSH-Px in rats. Western blot analysis demonstrated that SiNPs induced autophagy dysfunction via the upregulation of p62. Meanwhile, the inflammation cytokines (TNF-α, IL-18, IL-1ß) were released in rat lung. Immunohistochemistry and western blot assays both showed that SiNPs could regulate the related protein biomarkers of EMT through decreasing E-cadherin and increasing vimentin in a dose-dependent manner. Besides, SiNPs activated the proteins expression involved in p62/NF-κB signaling pathway, whereas the pulmonary EMT induced by SiNPs was significantly dampened after the knock down of p62. In this study, we illustrated that subacute exposure to SiNPs could trigger the autophagy dysfunction and pulmonary inflammation, further lead to EMT via activating the p62/NF-κB signaling pathway. Our findings provide new molecular evidence for SiNPs-induced pulmonary toxicity.

Melatonin ameliorates PM2.5 -induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis.

Fine particulate matter (PM2.5 ) exposure is correlated with the risk of developing cardiac fibrosis. Melatonin is a major secretory product of the pineal gland that has been reported to prevent fibrosis. However, whether melatonin affects the adverse health effects of PM2.5 exposure has not been investigated. Thus, this study was aimed to investigate the protective effect of melatonin against PM2.5 -accelerated cardiac fibrosis. The echocardiography revealed that PM2.5 had impaired both systolic and diastolic cardiac function in ApoE-/- mice. Histopathological analysis demonstrated that PM2.5 induced cardiomyocyte hypertrophy and fibrosis, particularly perivascular fibrosis, while the melatonin administration was effective in alleviating PM2.5 -induced cardiac dysfunction and fibrosis in mice. Results of electron microscopy and confocal scanning laser microscope confirmed that melatonin had restorative effects against impaired mitochondrial ultrastructure and augmented mitochondrial ROS generation in PM2.5 -treated group. Further investigation revealed melatonin administration could significantly reverse the PM2.5 -induced phenotypic modulation of cardiac fibroblasts into myofibroblasts. For the first time, our study found that melatonin effectively alleviates PM2.5 -induced cardiac dysfunction and fibrosis via inhibiting mitochondrial oxidative injury and regulating SIRT3-mediated SOD2 deacetylation. Our findings indicate that melatonin could be a therapy medicine for prevention and treatment of air pollution-associated cardiac diseases.

Evaluation of fine particulate matter on vascular endothelial function in vivo and in vitro.

Ambient fine particulate matter (PM2.5) and high-fat diet (HFD) are linked to the development of atherosclerosis. However, there is still unknown about the PM2.5-induced atherosclerosis formation on vascular endothelial injury after co-exposed to PM2.5 and HFD. Thus, the aim of this study was to evaluate the effects of PM2.5 on atherogenesis in C57BL/6 mice and endothelial cells, as well as the co-exposure effect of PM2.5 and HFD. In vivo study, C57BL/6 mice exposed to PM2.5 and fed with standard chow diet (STD) or HFD for 1 month. PM2.5 could increase vascular stiffness accessed by Doppler ultrasound, and more serious in co-exposure group. PM2.5 impaired vascular endothelial layer integrity, exfoliated endothelial cells, and inflammatory cells infiltration through H&E staining. PM2.5 reduced the expression of platelet/endothelial cell adhesion molecule-1 (PECAM-1) in vessel. Moreover, PM2.5 could induce systemic inflammation detected by Mouse Inflammation Array. In vitro study, PM2.5 triggered markedly mitochondrial damage by transmission electron microscope (TEM) and flow cytometer. Inflammatory cytokines were significantly increased in PM2.5-exposed group. The cell viability and migration of endothelial cells were significantly suppressed. In addition, PM2.5 remarkably declined the expression of vascular endothelial growth factor receptor 2 (VEGFR2) and increased the expression of somatostatin (SST) and its receptor. In conclusion, co-exposure of PM2.5 and HFD might induce systemic inflammation and endothelial dysfunction in normal mice. Moreover, PM2.5 could reduce vascular endothelial repair capacity through inhibiting the proliferation and migration of endothelial cells.

Acute exposure to PM2.5 triggers lung inflammatory response and apoptosis in rat.

Severe haze events, especially with high concentration of fine particulate matter (PM2.5), are frequent in China, which have gained increasing attention among public. The purpose of our study was explored the toxic effects and potential damage mechanisms about PM2.5 acute exposure. Here, the diverse dosages of PM2.5 were used to treat SD rats and human bronchial epithelial cell (BEAS-2B) for 24 h, and then the bioassays were performed at the end of exposure. The results show that acute exposure to diverse dosages of PM2.5 could trigger the inflammatory response and apoptosis. The severely oxidative stress may contribute to the apoptosis. Also, the activation of Nrf2-ARE pathway was an important compensatory process of antioxidant damage during the early stage of acute exposure to PM2.5. Furthermore, the HO-1 was suppression by siRNA that promoted cell apoptosis triggered by PM2.5. In other words, enhancing the expression of HO-1 may mitigate the cell apoptosis caused by acute exposure to PM2.5. In summary, our findings present the first time that prevent or mitigate the damage triggered by PM2.5 through antioxidant approaches was a promising strategy.

The relationship between long-term exposure to PM2.5 and hypertension in women：A meta-analysis.

OBJECTIVE: Gender difference and PM2.5 exposure all have effects on hypertension, change of estrogen level in different women's stage bring complex influence on blood pressure. Then we conduct this meta-analysis to investigate the association between long-term exposure (at least one year) to fine particulate matter (PM2.5) and hypertension in adult non-pregnant women. METHOD: Four major databases: PubMed, Cochrane Library, Web of Science and Embase were searched with specific search terms, and 11 studies were finally selected. The meta-analysis module of software Stata 12.0 was used for data processing with the effect values hazard ratio (HR) and odds ratio (OR) respectively. RESULTS: After sensitivity analysis, we removed a study with highly heterogeneity and finally included 10 studies. Meta-analysis results showed that exposure to PM2.5 (per 10 µg/m3 increase) was associated with hypertension in non-pregnancy adult women, HR = 1.23, 95%CI: 1.08-1.40; OR = 1.07, 95%CI: 1.00-1.14. And subgroup analysis showed that menopause, non-White and diabetes are the key risk factors of hypertension when exposed to PM2.5. CONCLUSION: This is the first meta-analysis to explore the association between PM2.5 and non-pregnancy women, and calculate OR and HR respectively for the first time. Exposure to PM2.5 could increase the risk of hypertension in non-pregnancy women, and the combined 'HR' was much higher than 'OR'.

Metabolomic characteristics of hepatotoxicity in rats induced by silica nanoparticles.

Silica nanoparticles (SiNPs) have become one of the most widely studied nanoparticles in nanotechnology for environmental health and safety. Although many studies have devoted to evaluating the hepatotoxicity of SiNPs, it is currently impossible to predict the extent of liver lipid metabolism disorder by identifying changes in metabolites. In the present study, 40 male Sprague-Dawley (SD) rats were randomly divided into control group and 3 groups with different doses (1.8 mg/kg body weight (bw), 5.4 mg/kg bw, 16.2 mg/kg bw), receiving intratracheal instillation of SiNPs. Liver tissue was taken for lipid level analysis, and serum was used for blood biochemical analysis. Then, the metabolites changes of liver tissue in rats were systematically analyzed using 1H nuclear magnetic resonance (1H NMR) techniques in combination with multivariate statistical analysis. SiNPs induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride (TG) elevation in treated groups; TG and low-density lipoprotein cholesterol (LDL-C) were significantly higher in SiNPs-treated groups of high-dose, however high-density lipoprotein cholesterol (HDL-C) showed a declining trend in liver tissue. The orthogonal partial least squares discriminant analysis (OPLS-DA) scores plots revealed different metabolic profiles between control and high-dose group (Q2 =0.495, R2Y=0.802, p = 0.037), and a total of 11 differential metabolites. Pathway analysis indicated that SiNPs treatment mainly affected 10 metabolic pathways including purine metabolism, glucose-alanine cycle and metabolism of various amino acids such as glutamate, cysteine and aspartate (impact value>0.1, false discovery rate (FDR)< 0.05). The result indicated that exposure to SiNPs caused liver lipid metabolism disorder in rats, the biochemical criterions related to lipid metabolism changed significantly. The obviously changed metabolomics in SiNPs-treated rats mostly occurred in amino acids, organic acids and nucleosides.

The critical role of endothelial function in fine particulate matter-induced atherosclerosis.

Ambient and indoor air pollution contributes annually to approximately seven million premature deaths. Air pollution is a complex mixture of gaseous and particulate materials. In particular, fine particulate matter (PM2.5) plays a major mortality risk factor particularly on cardiovascular diseases through mechanisms of atherosclerosis, thrombosis and inflammation. A review on the PM2.5-induced atherosclerosis is needed to better understand the involved mechanisms. In this review, we summarized epidemiology and animal studies of PM2.5-induced atherosclerosis. Vascular endothelial injury is a critical early predictor of atherosclerosis. The evidence of mechanisms of PM2.5-induced atherosclerosis supports effects on vascular function. Thus, we summarized the main mechanisms of PM2.5-triggered vascular endothelial injury, which mainly involved three aspects, including vascular endothelial permeability, vasomotor function and vascular reparative capacity. Then we reviewed the relationship between PM2.5-induced endothelial injury and atherosclerosis. PM2.5-induced endothelial injury associated with inflammation, pro-coagulation and lipid deposition. Although the evidence of PM2.5-induced atherosclerosis is undergoing continual refinement, the mechanisms of PM2.5-triggered atherosclerosis are still limited, especially indoor PM2.5. Subsequent efforts of researchers are needed to improve the understanding of PM2.5 and atherosclerosis. Preventing or avoiding PM2.5-induced endothelial damage may greatly reduce the occurrence and development of atherosclerosis.

Particulate matter exposure and biomarkers associated with blood coagulation: A meta-analysis.

OBJECTIVE: Find the correlation between particulate matter (PM) and biomarkers related to blood coagulation, offer medical evidence to sensitive indicators and carry out early diagnosis of cardiovascular diseases. METHOD: A combination of computer and manual retrieval was used to search for the keywords in PubMed (584 records), Cochrane Library (28 records), Web of Science (162 records) and Embase (163 records). Finally, a total of 25 articles were included in this meta-analysis. Stata 13.0 was applied to examine the heterogeneity among the studies and to calculate the combined effect estimates, percent variation (%) and 95% CI by selecting corresponding models. Additionally, sensitivity analysis and publication bias test were also conducted. RESULTS: Meta-analysis indicated that there was an association between PM2.5 exposure (per 10 µg/m3 increase) and fibrinogen. With the increase of PM2.5 exposure (per 10 µg/m3 increase), the content of fibrinogen revealed a high level (2.26%; 95% CI: 1.08-3.44%); and the increase of UFPs exposure (per 5000/cm3 increase) was correlated with some biomarkers such as cell surface antigen and protein ligand including ICAM-1, sCD40L, P-selectin, E-selectin and PAI-1 that indirectly related to blood coagulation, yielding a percent variation of 10.83% (95% CI: 3.49%-18.17%). CONCLUSION: This meta-analysis expounded that PM-related biomarkers were associated with blood coagulation, and the relationship with fibrinogen was much stronger.

Silica nanoparticles trigger the vascular endothelial dysfunction and prethrombotic state via miR-451 directly regulating the IL6R signaling pathway.

BACKGROUND: Safety evaluation is a prerequisite for nanomaterials in a wide range of fields, including chemical industries, medicine or food sciences. Previously, we had demonstrated that SiNPs could trigger the thrombotic effects in vivo, but the underlying mechanisms remain unknown. This study was aimed to explore and verify the role of miR-451a on SiNPs-induced vascular endothelial dysfunction and pre-thrombotic state. RESULTS: The color doppler ultrasound results showed that SiNPs had the inhibitory effects on aorta velocity and cardiac output. The histological and ultrastructural analysis manifested that SiNPs could induce the vascular endothelial damage. In addition, the expression level of MDA was elevated while the activity of SOD and GSH-Px were decreased in aortic arch triggered by SiNPs, accompanied with the release of iNOS and decline of eNOS in blood serum. The immunohistochemistry results showed that the positive staining of TF and PECAM-1 were elevated in a dose-dependent manner induced by SiNPs. The activation of coagulation function occurred via shortened TT, PT and APTT while the FIB was elevated markedly induced by SiNPs. Coagulant factors (TF, FXa and vWF) and PLT numbers were increased whereas the levels of anticoagulant factors (ATIII, TFPI and t-PA) were decreased. Microarray analysis showed that the down-regulated miR-451a could target the gene expression of IL6R, which further activated the JAK/STAT signaling pathway triggered by SiNPs. Dual-luciferase reporter gene assay confirmed the directly target relationship between miR-451a and IL6R. Additionally, the chemical mimics of miR-451a led to attenuate the expression of IL6R/STAT/TF signaling pathway in vitro and in vivo induced by SiNPs, while the inhibitor of miR-451a enhanced the activation of IL6R/STAT/TF signaling pathway. CONCLUSIONS: In summary, SiNPs could accelerate the vascular endothelial dysfunction and prethrombotic state via miR-451a negative regulating the IL6R/STAT/TF signaling pathway.

Fine particulate matters induce apoptosis via the ATM/P53/CDK2 and mitochondria apoptosis pathway triggered by oxidative stress in rat and GC-2spd cell.

Fine particulate matters (PM2.5) have been associated with male reproductive toxicity because it can penetrate into the lung's gas-exchange region, and spread to the whole body via circulatory system. Previous studies have shown that PM2.5 could induce DNA damage and apoptosis by reactive oxygen species (ROS). The aim of the present study is to determine the exact mechanism and role of apoptosis induced by PM2.5 in spermatocyte cells. Male Sprague-Dawley (SD) rats were treated with normal saline (control group) or PM2.5 with the doses of 1.8, 5.4 and 16.2 mg/kg bw. via intratracheal instillation every 3 days for 30 days. Mouse spermatocyte-derived cells (GC-2spd cells) were treated with various concentrations (0, 50, 100, 200 µg/mL) of PM2.5 for 24 h. The results showed that exposure to PM2.5 resulted in injury of testicular tissue and impaired mitochondria integrity in GC-2spd cells. Moreover, PM2.5 induced DNA damage and apoptosis in GC-2spad cells via ROS generation, and the ATM/P53/CDK2 and mitochondria apoptosis pathway autophagy signal pathway were activated. N-Acetyl-L-cysteine (NAC), a well-known antioxidant, ameliorated DNA damage, and inhibited apoptosis. These findings demonstrated PM2.5 might induce apoptosis via the mitochondrial apoptosis pathway through causing DNA damage resulting from oxidative stress, and finally caused spermatogenesis disorder.

DNA methylation: A critical epigenetic mechanism underlying the detrimental effects of airborne particulate matter.

Exposure to airborne particulate matter (PM) does great harm to the health of human beings. To date, PM exposure has been closely associated with respiratory and cardiovascular diseases, as well as some types of cancer. As the associations of PM with the adverse health effects are well documented in literatures, the underlying mechanisms have not been completely clarified. With the field of epigenetics rising in recent years, PM-associated epigenetic alterations have gradually turned into the hot research topic. DNA methylation is one of the earliest-discovered and best-studied epigenetic mechanisms, of which the alteration can influence the transcription initiation of genes. A number of studies have been published to demonstrate that PM exposure is linked with DNA methylation patterns in the human genome. DNA methylation is the potential regulator of the biological effects of PM exposure. In the present review, DNA methylation related to PM exposure was elaborated on genome-wide and gene-specific methylation. In particular, genome-wide DNA methylation was composed of the alterations in global methylation content and genome-wide methylation profile; gene-specific methylation included the methylation changes in mechanism-related and disease-specific genes. Representative epidemiological and experimental studies were cited to elucidate the viewpoints, focusing on both PM-related methylation changes and the mediating effects of DNA methylation between PM and the health impacts. This review will provide advantageous clues for subsequent studies on the DNA methylation in relation to PM exposure.

Gene profiles to characterize the combined toxicity induced by low level co-exposure of silica nanoparticles and benzo[a]pyrene using whole genome microarrays in zebrafish embryos.

Several studies have suggested that air pollutants combine exposure have greater adverse effects. However, limited studies were available on the combined toxicity of silica nanoparticles (SiNPs) and benzo[a]pyrene (B[a]P). The study was to evaluate the toxic effect and mechanisms of low-dose exposure of SiNPs, B[a]P and co-exposure in zebrafish embryos. In this study, zebrafish embryos received intravenous microinjection of SiNPs and B[a]P, and then was used to select differentially expressed genes by microarray analysis. Multiple bioinformatics analyses and STC analysis were done to identify key genes, pathways and biological processes and the expression trend of genes in each group. 1) 3065 differentially expressed genes were identified in zebrafish embryos. 2) These differentially expressed genes were involved in multiple biological processes and cellular processes such as immunity, response to stimuli, cell proliferation, adhesion, signaling transduction, and embryonic development. 3) Dynamic Gene Network analysis was used to identify a subgroup of 26 core genes that involved in multiple biological processes and cellular processes. 4) Pathway analysis and Signal-net analysis indicated that the MAPK signaling pathway, calcium signaling pathway, p53 signaling pathway, PI3k/Akt signaling pathway, and several pathways associated with immune response were the most prominent significant pathways induced by co-exposure of SiNPs and B[a]P in zebrafish embryos. Our study demonstrated that the molecular actions of co-treated with SiNPs and B[a]P on the immune system, inflammatory process and cardiovascular development had more severe toxicity than single exposure.