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Few studies have reported the accumulation of non-observable acute effect (NOAE) of PM

Amorphous silica nanoparticles (SiNPs) have been widely used and mass-producted due to its unique properties. With the life cycle of SiNPs-based products, SiNPs are further released into the air, soil, surface water and sediment, resulting in an increasing risk to humans. SiNPs could enter into the human body through vein, respiratory tract, digestive tract or skin. Moreover, recent evidences have showed that, regardless of exposure pathways, SiNPs could even be traced in liver, which is gradually considered as one of the main organs that SiNPs accumulate. Increasing evidences supported the link between SiNPs exposure and adverse liver effects. However, the research models are diverse and the molecular mechanisms have not been well integrated. In this review, the liver-related studies of SiNPs in vivo and in vitro were screened from the PubMed database by systematic retrieval method. We explored the interaction between SiNPs and the liver, and especially proposed a framework of SiNPs-caused liver toxicity, considering AOP Wiki and existing studies. We identified increased reactive oxygen species (ROS) as a molecular initiating event (MIE), oxidative stress, endoplasmic reticulum stress, lysosome disruption and mitochondrial dysfunction as subsequent key events (KEs), which gradually led to adverse outcomes (AOs) containing liver dysfunction and liver fibrosis through a series of key events about cell inflammation and death such as hepatocyte apoptosis/pyroptosis, hepatocyte autophagy dysfuncton and hepatic macrophages pyroptosis. To our best knowledge, this is the first AOP proposed on SiNPs-related liver toxicity. In the future, more epidemiological studies need to be performed and more biomarkers need to be explored to improve the AOP framework for SiNPs-associated liver toxicity.

Fine particulate matter (PM

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.

Air pollution, especially PM

Short-term PM2.5 exposure is related to vascular remodeling and stiffness. Mitochondria-targeted antioxidant MitoQ is reported to improve the occurrence and development of mitochondrial redox-related diseases. At present, there is limited data on whether MitoQ can alleviate the vascular damage caused by PM2.5. Therefore, the current study was aimed to evaluate the protective role of MitoQ on aortic fibrosis induced by PM2.5 exposure. Vascular Doppler ultrasound manifested PM2.5 damaged both vascular function and structure in C57BL/6J mice. Histopathological analysis found that PM2.5 induced aortic fibrosis and disordered elastic fibers, accompanied by collagen I/III deposition and synthetic phenotype remodeling of vascular smooth muscle cells; while these alterations were partially alleviated following MitoQ treatment. We further demonstrated that mitochondrial dysfunction, including mitochondrial reactive oxygen species (ROS) overproduction and activated superoxide dismutase 2 (SOD2) expression, decreased mitochondrial membrane potential (MMP), oxygen consumption rate (OCR), ATP and increased intracellular Ca2+, as well as mitochondrial fragmentation caused by increased Drp1 expression and decreased Mfn2 expression, occurred in PM2.5-exposed aorta or human aortic vascular smooth muscle cells (HAVSMCs), which were reversed by MitoQ. Moreover, the enhanced expressions of LC3II/I, p62, PINK1 and Parkin regulated mitophagy in PM2.5-exposed aorta and HAVSMCs were weakened by MitoQ. Transfection with PINK1 siRNA in PM2.5-exposed HAVSMCs further improved the effects of MitoQ on HAVSMCs synthetic phenotype remodeling, mitochondrial fragmentation and mitophagy. In summary, our data demonstrated that MitoQ treatment had a protective role in aortic fibrosis after PM2.5 exposure through mitochondrial quality control, which regulated by mitochondrial ROS/PINK1/Parkin-mediated mitophagy. Our study provides a possible targeted therapy for PM2.5-induced arterial stiffness., Graphical abstract Image 1

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.

As the main components of fine particulate matter (PM2.5), silica nanoparticles (SiNPs) and benzo[a]pyrene (B[a]P) have attracted increasing attention recently. However, co-exposure to SiNPs and B[a]P causes pulmonary injury by aggravating toxicity via an unknown mechanism. This study aimed at investigating the toxicity caused due to long-term co-exposure to SiNPs and B[a]P on pulmonary systems at low dose using human bronchial epithelial (BEAS-2B) cells. The characterizations of SiNPs and B[a]P were done by transmission electron microscopy (TEM) and zeta potential granulometry. Cytotoxicity is evaluated using cell counting kit-8 (CCK-8) assay and lactate dehydrogenase (LDH) activity; oxidative stress, cell cycle and apoptosis were assessed by flow cytometry, and inflammatory factors were detected using a Luminex xMAP system. Results show an obvious inhibition of cell proliferation and a marked increase in the LDH expression in the BEAS-2B cells after long-term co-exposure. Furthermore, long-term co-exposure is the most potent in generating intracellular ROS, thus causing inflammation. Cellular apoptotic rate is enhanced in the co-exposed group at low dose. Moreover, the long-term co-exposure induces significant cell cycle arrest, increasing the proportion of cells at the G2/M phase, while decreasing those at the G0/G1 phase. This study is the first attempt to reveal the severe synergistic and additive toxic effects induced by SiNPs and B[a]P co-exposure for long-term in BEAS-2B cells even at low dose.

Silica nanoparticles (SiNPs) are found in the environmental particulate matter and have been proved to pose an adverse effect on fertility. However, the relationship between miRNA and apoptosis induced by SiNPs in spermatogenesis and its underlying mechanism remains confusing. Therefore, the present study was designed to investigate the toxic effects of SiNPs on spermatogenic cells mediated through miRNAs. Spermatocyte cells were divided into 0 μg/mL and 5 μg/mL SiNPs groups, and the cells were collected and analyzed after passaging for 1, 10, 20, and 30 generations. miRNA profile and mRNA profile of spermatocyte cells were measured after exposure to SiNPs for 30 generations. Further, mimics and inhibitors of miRNA were used to verify the relationship between miRNA and their predicted target genes in the 30th-generation cells. The results showed that the degree of cell apoptosis in the SiNPs group significantly increased in the 30th generation. After exposure to SiNPs for 30 generations, the expression of 15 miRNAs was altered, including 5 upregulated miRNAs and 10 downregulated miRNAs. Of the 15 miRNAs, miR-138 and miR-2861 were related to the death receptor pathway. The miR-2861 mimic could target to regulate the mRNA expression of fas/fasl/ripk1 and increase the protein expression of Fas/FasL/RIPK1/FADD/caspase-8/caspase-3 of spermatogenic cells in the 30th generation, while the miR-138 inhibitor could not. In conclusion, SiNPs could cause apoptosis of spermatocyte cells by inhibiting the expression of miRNA-2861, thereby resulting in the upregulation of mRNA expression of fas/fasl/ripk1 and activating the death receptor pathway of spermatocyte cells. miRNA-2861 could be considered a biomarker of the toxic effect of SiNPs on spermatocyte cells. The main finding: Silica nanoparticles induce apoptosis in spermatocyte cells through microRNA-2861 inhibition, thereby upregulating mRNA expression of fas/fasl/ripk1 and activating the death receptor pathway of spermatocyte cells.

Background: Long-term exposure to fine particulate matter (PM2.5) can causally contribute to progression of atherosclerosis, risk of ischemic heart disease and death, but the underlying mechanism is little known. Since DNA methylation impacts the process of heart disease, it might be useful in exploring potential mechanistic pathways linking PM2.5 exposure and heart disease. Objectives: Here, we investigated the PM2.5-induced ADRB2 hypermethylation and the involving epigenetic mechanism of PM2.5-induced cardiomyocytes apoptosis and cardiac dysfunction. Methods and results: In vitro, PM2.5 markedly augmented cardiotoxicity including oxidative damage and apoptosis in cardiomyocytes AC16 as well as epigenetic alteration. DNA methylation profiling revealed a significant gene-ADRB2 was involved in the cardiac relative GO and KEGG pathways. Methylation chip and Bisulfite Sequencing PCR (BSP) both identified the hypermethylation status of ADRB2 which encodes β2-Adrenergic receptor (β2AR). Mechanistic study showed ADRB2 hypermethylation-induced down-regulation of β2AR inhibited PI3K/Akt and then activated Bcl-2/BAX and p53 pathway in AC16. The transgenic cell lines showed over-expression of ADRB2 weakened the PM2.5-induced cardiomyocytes apoptosis in opposite way, but was augmented by PI3K inhibitor (LY294002). In vivo, echocardiography showed the heart contractile function was decreased after SD rats intratracheal instillation of PM2.5 for 30 days. The myocardial interstitial edema, myocardial gap expansion and myofibril disorder in PM2.5 treated group were observed in rats heart tissue. What's more, basal expression of β2AR and VEGFR2 decreased in heart tissue as the dosage of PM2.5 increasing, meanwhile PM2.5 markedly attenuated PI3K/Akt pathway followed by augmented Bcl-2/BAX and p53 pathway, thus caused a greater number of TUNEL positive cardiomyocytes resulted in cardiac dysfunction in vivo. Conclusions: PM2.5 exposure could cause the myocardial ADRB2 hypermethylation and activate the β2AR/PI3K/Akt pathway, resulted in PM2.5-induced cardiomyocytes apoptosis and cardiac dysfunction. Our study suggested that the ADRB2 demethylation or ADRB2/β2AR activation may serve as a potential pathway to prevent cardiac dysfunction induced by PM2.5 exposure. Keywords: PM2.5, ADRB2 hypermethylation, β2AR, Apoptosis, Cardiomyocytes, PI3K/Akt, Cardiac dysfunction

Epidemiological evidence showed that the particulate matter exposure is associated with atherosclerotic plaque progression, which may be related to foam cell formation, but the mechanism is still unknown. The study was aimed to investigate the toxic effects and possible mechanism of PM2.5 on the formation of macrophage foam cells induced by oxidized low density lipoprotein (ox-LDL). Results showed that PM2.5 induced cytotoxicity by decreasing the cell viability and increasing the LDH level in macrophage foam cells. PM2.5 aggravated the lipid accumulation in ox-LDL-stimulated macrophage RAW264.7 within markedly increasing level of intracellular lipid by Oil red O staining. The level of ROS increased obivously after co-exposure to PM2.5 and ox-LDL than single exposure group. In addition, serious mitochondrial damage such as the mitochondrial swelling, cristae rupturing and disappearance were observed in macrophage foam cells. The loss of the mitochondrial membrane potential (MMP) further exacerbated the mitochondrial damage in PM2.5-induced macrophage foam cells. The apoptotic rate increased more severely via up-regulated protein level of Bax, Cyt C, Caspase-9, Caspase-3, and down-regulated that of Bcl-2, indicating that PM2.5 activated the mitochondrial-mediated apoptosis pathway. In summary, our results demonstrated that PM2.5 aggravated the lipid accumulation, mitochondrial damage and apoptosis in macrophage foam cells, suggesting that PM2.5 was a risk factor of atherosclerosis progression.

The mechanisms of systemic pulmonary inflammation and toxicity of fine particulate matter (PM2.5) exposure remains unclear. The current study investigated the inflammatory response and lung toxicity of PM2.5 in rats following intratracheal instillation of PM2.5. After repeated (treated every 3 days for 30 days) PM2.5 exposure, total protein (TP), lactate dehydrogenase (LDH) activity and inflammatory cytokines including interleukin 6 (IL-6), interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) levels in bronchoalveolar lavage fluid (BALF) were markedly elevated. The expression levels of IL-6, IL-1β, TNF-α and NF-κB in rat lung tissue and BEAS-2B cells were significantly upregulated after PM2.5 exposure. Histopathological evaluation suggested that the major pathological changes were alveolar wall thickening and inflammatory cell infiltration of the lungs. Genome wide DNA methylation and RNA-transcription analysis was performed on human bronchial epithelial cells (BEAS-2B) to explore the potential mechanisms in vitro. PM2.5 induced genome wide DNA methylation and transcription changes. Differentially methylated CpGs were located in gene promoter region linked with CpG islands. Integrated analysis with DNA methylation and transcription data indicated a clear bias toward transcriptional alteration by differential methylation. Disease ontology of differentially methylated and expressed genes addressed their prominent role in respiratory disease. Functional enrichment revealed their involvement in inflammation or immune response, cellular community, cellular motility, cell growth, development and differentiation, signal transduction and responses to exogenous stimuli. Gene expression validation of ACTN4, CXCL1, MARK2, ABR, PSEN1, PSMA3, PSMD1 verified their functional participation in critical biological processes and supported the microarray bioinformatics analysis. Collectively, our data shows that PM2.5 induced genome wide methylome and transcriptome alterations that could be involved in pulmonary toxicity and pathological process of respiratory disease, providing new insight into the toxicity mechanisms of PM2.5.

Ambient air pollution is a leading cause of non-communicable disease in the world. PM

Environmental exposure to nanoplastics is inevitable as the application of nanoplastics in our daily life is more and more extensively. So, the adverse effects of nanoplastics on human health are also gaining greater concerns. However, the subsequent toxicological response to nanoplastics, especially on cardiovascular damage was still largely unknown. In this regard, the evaluation of cardiovascular effects of nanoplastics was performed in zebrafish embryos. The results indicated that the no observed adverse effect level (NOAEL) of nanoplastics is 50 μg/mL. The pericardial toxicity and hemodynamic changes were assessed by Albino (melanin allele) mutant zebrafish line. Severe pericardial edema was observed in zebrafish embryos after exposure to nanoplastics. At the concentration higher than NOAEL, nanoplastics significantly decreased the cardiac output (CO) and blood flow velocity. The fluorescence images manifested that the nanoplastics could inhibit the subintestinal angiogenesis of transgenic zebrafish embryos line Tg (fli-1: EGFP), which might disturb the cardiovascular formation and development. The resulting vascular endothelial dysfunction and hypercoagulable state of circulating blood further accelerated thrombosis. Reactive oxidative stress (ROS) and systemic inflammation were also found in Wild AB and Tg (mpo: GFP) zebrafish embryos, respectively. We also found many neutrophils recruiting in the tail vein where the zebrafish embryo thrombosis occurred. Our data suggested that nanoplastics could trigger the cardiovascular toxicity in zebrafish embryos, which could provide an essential clue for the safety assessment of nanoplastics.

The in-utero environmental exposure to fine particulate matter (PM

Fine particle matter (PM

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.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.26 studies were included in this meta-analysis. 19 studies have shown that PMExposure to PM

Quantities of researches have demonstrated silica nanoparticles (SiNPs) exposure inevitably induced damage to respiratory system, nonetheless, knowledge of its toxicological behavior and metabolic interactions with the cellular machinery that determines the potentially deleterious outcomes are limited and poorly elucidated. Here, the metabolic responses of lung bronchial epithelial cells (BEAS-2B) under SiNPs exposure were investigated using ultra performance liquid chromatography-mass spectrum (UPLC-MS)-based metabolomics research. Results revealed that even with low cytotoxicity, SiNPs disturbed global metabolism. Five metabolic pathways were significantly perturbed, in particular, oxidative stress- and mitochondrial dysfunction-related GSH metabolism and pantothenate and coenzyme A (CoA) biosynthesis, where the identified metabolites glutathione (GSH), glycine, beta-alanine, cysteine, cysteinyl-glycine and pantothenic acid were included. In support of the metabolomics profiling, SiNPs caused abnormality in mitochondrial structure and mitochondrial dysfunction, as evidenced by the inhibition of cellular respiration and ATP production. Moreover, SiNPs triggered oxidative stress as confirmed by the dose-dependent ROS generation, down-regulated nuclear factor erythroid 2-related factor 2 (NRF2) signaling, together with GSH depletion in SiNPs-treated BEAS-2B cells. Oxidative DNA damage and cell membrane dis-integrity were also detected in response to SiNPs exposure, which was correspondingly in agreed with the elevated 8-hydroxyguanosine (8-OHdG) and decreased phospholipids screened through metabolic analysis. Thereby, we successfully used the metabolomics approaches to manifest SiNPs-elicited toxicity through oxidative stress, mitochondrial dysfunction, DNA damage and rupture of membrane integrity in BEAS-2B cells. Overall, our study provided novel insights into the mechanism underlying SiNPs-induced pulmonary toxicity.

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.

Many studies have linked airborne fine particulate matter (PM2.5) exposure to cardiovascular diseases. We performed a time-series analysis to investigate whether the disruption of lipid metabolism recovered or lasted after acute PM2.5 exposure in mice. Targeted lipidomic analysis showed that four major plasma membrane phospholipids along with cholesterol esters (CE) were significantly altered on 7th post-exposure day (PED7), and the alteration reached a peak on PED14. On PED21, the phosphatidylcholine (PC) decrease was more marked than on PED14, and its resurgence was indirectly linked to triglyceride (TG) increase. Homocysteine (HCY), lactate dehydrogenase (LDH), and α-hydroxybutyrate dehydrogenase (α-HBDH) levels increased but glucose levels decreased markedly in a dose- and time-dependent manner throughout the experimental period. Network analysis showed that the lasting lipid deregulation on PED21 correlated to myocardial markers and glucose interruption, during which high-density lipoprotein cholesterol (HDL-C) decreased. The present data implied that the constructional membrane lipids were initially interrupted by PM2.5, and the subsequent rehabilitation resulted in the deregulation of storage lipids; the parallel myocardial and glucose effects may be enhanced by the lasting HDL-C lipid deregulation on PED21. These myocardial and lipidomic events were early indicators of cardiovascular risk, resulting from subsequent exposure to and accumulation of PM2.5.

Exposure to fine particulate matter (PM

Background: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fracture compared with those without T2DM. Some oral glucose-lowering agents may increase the incidence of fracture. Whether sodium-glucose co-transporter 2 inhibitors (SGLT2is) are associated with increased risk of fracture remains unclear. Methods: We retrieved articles from PubMed, Embase, Cochrane Library database, and other sources up to 24 October 2019. We included randomized controlled trials (RCTs) that reported fractures and analyzed the fracture incidence of SGLT2i, canagliflozin, dapagliflozin, and empagliflozin. Subgroup analysis was also performed based on baseline characteristics. Results: A total of 78 RCTs with 85,122 patients were included in our analysis. The overall SGLT2i fracture incidence was 2.56% versus 2.77% in the control group [odds ratio (OR), 1.03; 95% confidence interval (CI) (0.95, 1.12); p = 0.49]. Compared with the control treatment, treatment with canagliflozin led to a higher rate of fractures [OR, 1.17; 95% CI (1.00, 1.37); p = 0.05], but no significant difference was observed when compared with dapagliflozin [OR, 1.02; 95% CI (0.90, 1.15); p = 0.79] or empagliflozin [OR, 0.89; 95% CI (0.73, 1.10); p = 0.30]. Subgroup analysis showed that, in a follow-up of less than 52 weeks, SGLT2i decreased the incidence of fracture by 29% [OR, 0.71; 95% CI (0.55, 0.93); p = 0.01], but this benefit was lost when the follow-up extended to more than 52 weeks [OR, 1.08; 95% CI (0.98, 1.18); p = 0.12]. Conclusion: Canagliflozin seems to increase the risk of fracture, while other SGLT2is do not result in a higher incidence of fracture.

With the increasing production and application of engineered amorphous silica nanoparticles (aSiNPs), people have more opportunities to be exposed to aSiNPs. However, the knowledge of its adverse health effects and related mechanisms is still limited, compared with the well-studied crystalline micron-sized silica. Since small differences in the physical–chemical properties of nanoparticles could cause significant differences in the toxic effect, it is important to distinguish how these variations influence the outcoming toxicity. Notably, particle size, as one of the essential characterizations of aSiNPs, is relevant to its biological activities. Thus, the aim of this systematic review was to summarize the relationship between the particle size of aSiNPs and its adverse biological effects. In order to avoid the influence of complicated in vivo experimental conditions on the toxic outcome, only in vitro toxicity studies which reported on the cytotoxic effect of different sizes aSiNPs were included. After the systematic literature retrieval, selection, and quality assessment process, 76 eligible scientific papers were finally included in this review. There were 76% of the studies that concluded a size-dependent cytotoxicity of aSiNPs, in which smaller-sized aSiNPs possessed greater toxicity. However, this trend could be modified by certain influence factors, such as the synthetic method of aSiNPs, particle aggregation state in cell culture medium, toxicity endpoint detection method, and some other experimental conditions. The effects of these influence factors on the size-dependent cytotoxicity of aSiNPs were also discussed in detail in the present review.

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.

Among various air pollutants, particulate matter (PM) is the most harmful and representative pollutant. At the same time, allergic rhinitis (AR) is getting more and more attention, so we explore the relationship between PM and the prevalence of AR among children. Then, PubMed, Web of Science, Google Scholar was used to search for relevant studies up to January 2020. Literature quality assessment was processed using the Newcastle-Ottawa Scale (NOS) evaluation scale. Adjusted odds ratio (OR) with corresponding 95% confidence interval (CI) was retrieved from individual studies and pooled to generate a summary effect via STATA software. Besides, we test the result stability by Egger’s test and funnel plot, and using the trim-and-fill method to modify the possible asymmetric funnel graph. 21 studies were included in the meta-analysis. 9 articles reported about PM2.5 on childhood AR (1.09, 95%CI: 1.01, 1.17, per 10 μg/m3 increase). 15 articles reported about PM10 on childhood AR (1.06, 95%CI: 1.02,1.11, per 10 μg/m3 increase), PM2.5 exposure has a bigger effect on children AR than PM10. In addition, a series of subgroup analysis was performed, and we found that PM2.5 and PM10 have different performances in different subgroups. In addition to this, we analyzed the sources of heterogeneity of the study. Apart from the results we got all have good stability without publication bias. Therefore, it can be concluded that exposure to PM may increase the prevalence of AR among children.

Ambient air pollution is recognized as a major threat to those with cardiovascular disease (CVD), especially among old adults within this high risk group. Heart rate variability (HRV) is a marker of cardiac autonomic system, which links air pollution and CVD. However, the relationship between PM and HRV has been inconsistently reported. To investigate the associations of PM

Objective Silica nanoparticles (SiO2 NPs) have been extensively employed in biomedical field. SiO2 NPs are primarily designed to enter the circulatory system; however, little information is available on potential adverse effects of SiO2 NPs on the nervous system. Methods The neurotoxicity of SiO2 NPs at different concentrations (3, 6, 12 ng/nL) on zebrafish embryos was determined using immunofluorescence and microarray techniques, and subsequently confirmed by qRT-PCR. Results SiO2 NPs disrupt the axonal integrity and decrease the length of axons in Tg (NBT: EGFP) transgenic lines. The number of apoptotic cells in the brain and central nervous system of zebrafish embryos was increased in the presence of 12 ng/nL of SiO2 NPs, but the difference did not reach statistical significance. Screening for changes in the expression of genes involved in the neuroactive ligand–receptor interaction pathway was performed by microarray and confirmed by qRT-PCR. These analyses demonstrated that SiO2 NPs markedly downregulated genes associated with neural function (grm6a, drd1b, chrnb3b, adrb2a, grin2ab, npffr2.1, npy8br, gabrd, chrma3, gabrg3, gria3a, grm1a, adra2b, and glra3). Conclusion The obtained results documented that SiO2 NPs can induce developmental neurotoxicity by affecting the neuroactive ligand–receptor interaction signaling pathway. This new evidence may help to clarify the mechanism of SiO2 NPs-mediated neurotoxicity.

Ambient fine particulate matter (PMTo explore the influence of short-term PMBy using a combination of computer and manual retrieval, a systematic literature retrieval was conducted on PubMed, Cochrane Library, Web of Science, Embase and Scopus databases up to October 2019. The heterogeneity among studies was tested by Stata 12.0, and the pooled %-change (percentage change per 10 μg/m12 articles were included in this meta-analysis. Short-term PMShort-term PM

Nowadays, the great majority of toxicological studies have focused on immediate cardiovascular effects of simultaneous exposure to long-term or short-term PM

Background Large-scale production and application of amorphous silica nanoparticles (SiNPs) have enhanced the risk of human exposure to SiNPs. However, the toxic effects and the underlying biological mechanisms of SiNPs on Caenorhabditis elegans remain largely unclear. Purpose This study was to investigate the genome-wide transcriptional alteration of SiNPs on C. elegans. Methods and Results In this study, a total number of 3105 differentially expressed genes were identified in C. elegans. Among them, 1398 genes were significantly upregulated and 1707 genes were notably downregulated in C. elegans. Gene ontology analysis revealed that the significant change of gene functional categories triggered by SiNPs was focused on locomotion, determination of adult lifespan, reproduction, body morphogenesis, multicellular organism development, endoplasmic reticulum unfolded protein response, oocyte development, and nematode larval development. Meanwhile, we explored the regulated effects between microRNA and genes or signaling pathways. Pathway enrichment analysis and miRNA-gene-pathway-network displayed that 23 differential expression microRNA including cel-miR-85-3p, cel-miR-793, cel-miR-241-5p, and cel-miR-5549-5p could regulate the longevity-related pathways and inflammation signaling pathways, etc. Additionally, our data confirmed that SiNPs could disrupt the locomotion behavior and reduce the longevity by activating ins-7, daf-16, ftt-2, fat-5, and rho-1 genes in C. elegans. Conclusion Our study showed that SiNPs induced the change of the whole transcriptome in C. elegans, and triggered negative effects on longevity, development, reproduction, and body morphogenesis. These data provide abundant clues to understand the molecular mechanisms of SiNPs in C. elegans.

Intense ultraviolet irradiation is an important environmental factor affecting the service performance of asphalt mixtures in high-altitude areas, and the asphalt mortar is the main factor affecting the durability of asphalt mixtures. It is of great theoretical significance and engineering value to study the performance of the asphalt mortar at medium and low temperatures under ultraviolet irradiation. Therefore, this paper focuses on the evolution of the effect of the filler content on the rheological properties of different asphalt materials at low and medium temperatures under quantitative UV irradiation. Taking the average amount of UV irradiation observed annually in Northwest China as the indoor aging condition, the matrix asphalt mortar and modified asphalt mortar with different mass ratios of asphalt mortar are selected for indoor aging tests. Physical property tests, low-temperature performance tests, and dynamic shear rheological tests are carried out. The effects of the UV irradiation intensity and mineral powder content on the low temperature performance of the asphalt mortar are studied by variance analysis method, and the reasonable mass ratio range of the asphalt mortar under UV irradiation is proposed based on the standard residual square sum (STRSS) method. The results show that the temperature sensibility and low-temperature deformation energy significantly decrease with the increase in the filler content, while the values of the softening point, fatigue factor (G*sin &delta, ), and creep stiffness modulus of the asphalt mortar increase. In addition, the variance analysis of the creep stiffness modulus aging index (SAI) shows that the ultraviolet radiation intensity has a significant impact on the performance of the asphalt mortar. When the mineral powder content is less than 40%. When the filler content is greater than 40%, the filler content effects the performance of the asphalt mortar. According to the standard residual square sum (STRSS) method, the best mass ratio of the base asphalt mortar is 1.096, and the best mass ratio of the modified asphalt mortar is 0.9091.

PM2.5 exposure is strongly linked to cardiac disease. Subtle epigenetic or transcriptional alterations induced by PM2.5 might contribute to pathogenesis and disease susceptibility of cardiac disease. It is still a major challenge to identify biological targets in human genetics. Human cardiomyocytes AC16 was chosen as cell model. Epigenetic effect of PM2.5 in AC16 was analyzed using Illumina HumanMethylation 450 K BeadChip. Meanwhile the transcriptomic profiling was performed by Affymetrix® microarray. PM2.5 induced genome wide variation of DNA methylation pattern, including differentially methylated CpGs in promoter region. Then gene ontology analysis demonstrated differentially methylated genes were significantly clustered in pathways in regulation of apoptotic process, cell death and metabolic pathways, or associated with ion binding and shuttling. Correlation of the methylome and transcriptome revealed a clear bias toward transcriptional suppression by hypermethylation or activation by hypomethylation. Identified 386 genes which exhibited both differential methylation and expression were functionally associated with pathways including cardiovascular system development, regulation of blood vessel size, vasculature development, p53 pathway, AC-modulating/inhibiting GPCRs pathway and cellular response to metal ion/inorganic substance. Disease ontology demonstrated their prominent role in cardiac diseases and identified 14 cardiac-specific genes (ANK2, AQP1 et al.). PPI network analysis revealed 6 novel genes (POLR2I, LEP, BRIX1, ADCY6, INSL3, RARS). Those genes were then verified by qRT-PCR. Thus, in AC16, PM2.5 alters the methylome and transcriptome of genes might be relevant for PM2.5-/heart-associated diseases. Result gives additional insight in PM2.5 relative cardiac diseases/associated genes and the potential mechanisms that contribute to PM2.5 related cardiac disease.

Although the strongly causal associations were between fine particulate matter (PM2.5) and cardiovascular disease, the toxic effect and potential mechanism of PM2.5 on heart was poorly understood. Thus, the aim of this study was to evaluate the cardiac toxicity of PM2.5 exposure on human cardiomyocytes (AC16). The cell viability was decreased while the LDH release was increased in a dose-dependent way after AC16 exposed to PM2.5. The reactive oxygen species (ROS) generation and production of malondialdehyde (MDA) were increased followed by the decreasing in superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). The damage of mitochondria was observed by ultra-structural analysis and MMP measurement. The apoptotic rate of AC16 were markedly elevated which was triggered by PM2.5. In addition, the proteins involved in mitochondria- mediated apoptosis pathway were measured. The protein levels of Caspase-3, Caspase-9 and Bax were up-regulated while the anti-apoptotic protein, Bcl-2 was down-regulated after AC16 exposed to PM2.5. In summary, our results demonstrated that mitochondria-mediated apoptosis pathway played a critical role in PM2.5-induced myocardial cytotoxicity in AC16, which suggested that PM2.5 may contribute to cardiac dysfunction.

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.

Fine particulate matter (PM2.5) has been listed as an important environmental risk factor for human health. However, the systemic biological effects on metabolic responses induced by PM2.5 and its components were poorly understood. This study was aimed to evaluate the toxicity of different components of PM2.5 at molecular level via metabolomics approach. In the present study, we adopted a 1H NMR-based metabolomics approach to evaluate metabolic profiles in mice after acute exposure to Total-PM2.5, water soluble components of PM2.5 (WS-PM2.5) and water insoluble components of PM2.5 (WIS-PM2.5). First, we characterized the morphological features and chemical composition of PM2.5. Then, the metabolites changes of serum and urine in mice were systematically analyzed using 800 MHz 1H NMR techniques in combination with multivariate statistical analysis. Total-PM2.5 exposure affected metabolites mainly involved in amino acid metabolism, protein biosynthesis, energy metabolism and metabolism of cofactors and vitamins. WS-PM2.5 exposure influenced lipid metabolism and carbohydrate metabolism. WIS-PM2.5 exposure mainly perturbed amino acid metabolism and energy metabolism. The results suggested that acute exposure to the Total-PM2.5, WS-PM2.5 and WIS-PM2.5 in mice exhibited marked systemic metabolic changes. In addition, the insoluble fraction of PM2.5 contributed greatly to the toxicity of PM2.5.

Recent years, air pollution has been a serious problem, and PM2.5 is the main air particulate pollutant. Studies have investigated that PM2.5 is a risky factor to the deterioration of semen quality in males. But, the related mechanism is still unclear. To explore the effect of PM2.5, Sprague Dawley (SD) rats were exposed to PM2.5 (0, 1.8, 5.4 and 16.2mg/kg.bw.) through intratracheal instillation. The exposure was performed once every 3days and continued for 30days. In vitro, GC-2spd cells were treated using 0, 50, 100, 200μg/mL PM2.5 for 24h. The data showed that sperm relative motility rates and density were remarkably decreased, while sperm malformation rates were significantly increased with exposure to the PM2.5. The expression of Fas/FasL/RIPK1/FADD/Caspase-8/Caspase-3 and the level of 8-OHdG expression in testes were significantly increased after exposure to PM2.5. Additionally, in vitro the results showed that PM2.5 inhibited cell viability, increased the release of lactate dehydrogenase (LDH) by increasing reactive oxygen species (ROS) level. And ROS induced-DNA damage led to cell cycle arrest at G0/G1 phases and proliferation inhibition. Similar to the vivo study, the expressions of Fas/FasL/RIPK1/FADD/Caspase-8/Caspase-3 in GC-2spd cells were significantly increased after exposure to PM2.5 for 24-h. In addition, PM2.5 decreased the levels of ATP by impairing mitochondria structures, which led to energy metabolism obstruction resulted in the decrease of sperm motility. The above three aspects together resulted in the decrease in sperm quantity and quality.

The released nanoparticles into environment can potentially interact with pre-existing pollution, maybe causing higher toxicity. As such, assessment of their joint toxic effects is necessary. This study was to investigate the co-exposure cardiac toxicity of silica nanoparticles (SiNPs) and methylmercury (MeHg). Factorial design was used to determine the potential joint action type. In vitro study, human cardiomyocytes (AC16) were exposed to SiNPs and MeHg alone or the combination. Higher toxicity was observed on cell viability, cell membrane damage in co-exposure compared with single exposure and control. The co-exposure enhanced the ROS, MDA generation and reduced the activity of SOD and GSH-Px. In addition, the co-exposure induced much higher cellular apoptotic rate in AC16. In vivo study, after SD rats exposed to SiNPs and MeHg and their mixture by intratracheal instillation for 30days, pathological changes (myocardial interstitial edema) of heart were occurred in co-exposure compared with single exposure and control. Moreover obvious ultra-structural changes, including myofibril disorder, myocardial gap expansion, and mitochondrial damage were observed in co-exposure group. The activity of myocardial enzymes, including CK-MB, ANP, BNP and cTnT, were significantly elevated in co-exposure group of rat serum. Meanwhile, the cardiac injury-linked proteins expression showed an increase in SERCA2 and decreased levels of cTnT, ANP and BNP in co-exposure group. Factorial design analysis demonstrated that additive and synergistic interactions were responsible for the co-exposure cardiac toxicity in vitro and vivo. In summary, our results showed severe cardiac toxicity induced by co-exposure of SiNPs and MeHg in both cardiomycytes and heart. It will help to clarify the potential cardiovascular toxicity in regards to combined exposure pollutions.

As silica nanoparticles (SiNPs) pervade the global economy, however, the followed emissions during the manufacturing, use, and disposal stages inevitably bring an environmental release, potentially result in harmful impacts. Endothelial dysfunction precedes cardiovascular disease, and is often accompanied by mitochondrial impairment and dysfunction. We had reported endothelial dysfunction induced by SiNPs, however, the related mechanisms by which SiNPs interact with mitochondria are not well understood. In the present study, we examined SiNPs-induced mitochondrial dysfunction, and further demonstrated their adverse effects on mitochondrial dynamics and biogenesis in endothelial cells (HUVECs). Consequently, SiNPs entered mitochondria, caused mitochondrial swelling, cristae disruption and even disappearance. Further analyses revealed SiNPs increased the intracellular level of mitochondrial reactive oxygen species, eventually resulting in the collapse of mitochondrial membrane potential, impairments in ATP synthesis, cellular respiration and the activities of three ATP-dependent enzymes (including Na+/K+-ATPase, Ca2+-ATPase and Ca2+/Mg2+-ATPase), as well as an elevated intracellular calcium level. Furthermore, mitochondria in SiNPs-treated HUVECs displayed a fission phenotype. Accordingly, dysregulation of the key gene expressions (FIS1, DRP1, OPA1, Mfn1 and Mfn2) involved in fission/fusion event further certified the SiNPs-induced perturbation of mitochondrial dynamics. Meanwhile, SiNPs-treated HUVECs displayed declined levels of mitochondrial DNA copy number, PGC-1α, NRF1 and also TFAM, indicating an inhibition of mitochondrial biogenesis triggered by SiNPs via PGC-1α-NRF1-TFAM signaling. Overall, SiNPs triggered endothelial toxicity through mitochondria as target, including the induction of mitochondrial dysfunction, as well as the perturbations of their dynamics and biogenesis.

Currently, the potential applications of polydopamine (PDA) nanoparticles in the biomedical field are being extensively studied, such as cell internalization, biocompatible surface modification, biological imaging, nano-drug delivery, cancer diagnosis, and treatment. However, the subsequent toxicological response to PDA nanoparticles, especially on nervous system damage was still largely unknown. In this regard, the evaluation of the neurotoxicity of PDA nanoparticles was performed in the developing zebrafish larvae. Results of the transmission electron microscope (TEM), diameter analysis, 1H NMR, and thermogravimetric analysis (TGA) indicated that PDA nanoparticles had high stability without any depolymerization; the maximum non-lethal dose (MNLD) and LD10 of PDA nanoparticles for zebrafish were determined to be 0.5 mg/mL and 4 mg/mL. Pericardial edema and uninflated swim bladders were observed in zebrafish larvae after exposure to PDA nanoparticles. At a concentration higher than MNLD, the fluorescence images manifested that the PDA nanoparticles could inhibit the axonal growth of peripheral motor neurons in zebrafish, which might affect the movement distances and speed, disturb the movement trace, finally resulting in impaired motor function. However, in further investigating the mechanism of PDA nanoparticles-induced neurotoxicity in zebrafish larvae, we did not find apoptosis of central neurocytes. Our data suggested that PDA nanoparticles might trigger neurotoxicity in zebrafish, which could provide an essential clue for the safety assessment of PDA nanoparticles.

The in-utero environmental exposure to fine particulate matter (PM2.5) might lead to adverse birth outcomes, such as low birth weight (LBW) and preterm birth (PTB), thereby increasing susceptibility to diseases in later life. However, no studies have examined the underlying mechanism through cross-omics of lipidome and adipokines profiling, as well as the possible effect modification by maternal hyperlipidemia. In total, 203 mother-newborn pairs were recruited in the birth cohort study ongoing since February 2017 in Beijing, China. Individual-level of PM2.5 exposure was estimated using a satellite data based random forest model. Cord blood lipidome and adipokines were assessed through the lipidomic approaches and antibody-based array. Multivariable logistic/linear regression models and moderation analysis were employed in this study. We observed a significantly increased risk of PTB associated with PM2.5 exposure during the second trimester, especially in pregnant women with pre-existing hyperlipidemia. 9 lipid classes and 21 adipokines were associated with PM2.5 exposure independently or significantly influenced by the interaction of maternal PM2.5 exposure and hyperlipidemia. In addition, 4 adipokines (ANGPTL4, IGFBP-2, IL-12p40, and TNF-RII) and 3 lipid classes [phosphatidylcholines (PCs), phosphatidylinositols (PIs), and triglycerides (TGs)] were related to the increased risk of PTB, indicating that inflammation, IGF/IGFBP axis, and lipolysis induced lipid homeostasis disorder of PCs, TGs, and PIs might be the possible mediators for the PM2.5-induced adverse birth outcomes. Our results substantiated the need for reducing exposure in susceptible populations.

Silica nanoparticles (SiNPs) have been found to pass through biological barriers and get distributed in the human body. They induce cell apoptosis via various mechanisms in body organs. To understand these mechanisms, we carried out systematic review of in vitro studies on SiNPs-induced cell apoptosis. Office of Health Assessment and Translation approach for Systematic Review and Evidence Integration was used to identify 14 studies dating from the year 2000 to current. Four studies showed an increase in DNA damage, cell cycle arrest, proapoptotic factors and decrease in antiapoptotic factors resulting to apoptosis. Eight studies showed induction of mitochondrial dysfunction, Bax upregulation, Bcl-2 downregulation, and caspase-3, −7, −9 activities increase. Increase in FADD, TNFR1 and Bid proteins was observed in one study, while the other NO production and caspase-3 activity was increased. These studies found the potency of SiNPs to induce cell apoptosis through DNA damage, mitochondrial, tumor necrosis factor, and nitric oxide related pathways.

Air pollution has been shown to increase cardiovascular diseases. However, little attention has been paid to the combined effects of PM and air pollutants on the cardiovascular system. To explore this, a high-throughput sequencing technology was used to determine combined effects of silica nanoparticles (SiNPs) and MeHg in zebrafish. Our study demonstrated that SiNPs and MeHg co-exposure could cause significant changes in mRNA and miRNA expression patterns in zebrafish. The differentially expressed (DE) genes in profiles 17 and 26 of STC analysis suggest that SiNPs and MeHg co-exposure had more proinflammatory and cardiovascular toxicity in zebrafish than single exposure. Major gene functions associated with cardiovascular system in the co-exposed zebrafish were discerned from the dynamic-gene-network, including stxbp1a, celf4, ahr1b and bai2. In addition, the prominently expressed pathway of cardiac muscle contraction was targeted by 3 DE miRNAs identified by the miRNA-pathway-network (dre-miR-7147, dre-miR-26a and dre-miR-375), which included 23 DE genes. This study presents a global view of the combined SiNPs and MeHg toxicity on the dynamic expression of both mRNAs and miRNAs in zebrafish, and could serve as fundamental research clues for future studies, especially on cardiovascular system toxicity.

The co-exposure toxicity mechanism of ultrafine particles and pollutants on human cardiovascular system are still unclear. In this study, the combined effects of silica nanoparticles (SiNPs) and/or carbon black nanoparticles (CBNPs) with Pb(AC)2 compared with particulate matter (PM)2.5 were investigated in human myocardial cells (AC16). Our study detected three different combinations of SiNPs and Pb(AC)2, CBNPs and Pb(AC)2, and SiNPs and CBNPs compared with PM2.5 at low-dose exposure. Using PM2.5 as positive control, our results suggested that the combination of SiNPs and Pb(AC)2/CBNPs could increase the production of reactive oxygen species (ROS), lactate dehydrogenase leakage (LDH), and malondialdehyde (MDA) and decrease the activities of superoxide dismutase (SOD) and glutathione (GSH); induce inflammation by the upregulation of protein CRP and TNF-α, and apoptosis by the upregulation of protein caspase-3, caspase-9, and Bax while the downregulation of protein Bcl-2; and trigger G2/M phase arrest by the upregulation of protein Chk2 and downregulation of protein Cdc2 and cyclin B1. In addition, the combination of CBNPs and Pb(AC)2 induced a significant increase in MDA and reduced the activities of ROS, LDH, SOD, and GSH, with G1/S phase arrest via upregulation of Chk1 and downregulation of CDK6 and cyclin D1. Our data suggested that the additive interaction and synergistic interaction are the major interaction in co-exposure system, and PM2.5 could trigger more severe oxidative stress, G2/M arrest, and apoptosis than either co-exposure or single exposure.

With rapid development of nanotechnology and growing environmental pollution, the combined toxic effects of SiNPs and pollutants of heavy metals like lead have received global attentions. The aim of this study was to explore the cardiovascular effects of the co-exposure of SiNPs and lead acetate (PbAc) in zebrafish using microarray and bioinformatics analysis. Although there was no other obvious cardiovascular malformation except bleeding phenotype, bradycardia, angiogenesis inhibition and declined cardiac output in zebrafish co-exposed of SiNPs and PbAc at NOAEL level, significant changes were observed in mRNA and microRNA (miRNA) expression patterns. STC-GO analysis indicated that the co-exposure might have more toxic effects on cardiovascular system than that exposure alone. Key differentially expressed genes were discerned out based on the Dynamic-gene-network, including stxbp1a, ndfip2, celf4 and gsk3b. Furthermore, several miRNAs obtained from the miRNA-Gene-Network might play crucial roles in cardiovascular disease, such as dre-miR-93, dre-miR-34a, dre-miR-181c, dre-miR-7145, dre-miR-730, dre-miR-129-5p, dre-miR-19d, dre-miR-218b, dre-miR-221. Besides, the analysis of miRNA-pathway-network indicated that the zebrafish were stimulated by the co-exposure of SiNPs and PbAc, which might cause the disturbance of calcium homeostasis and endoplasmic reticulum stress. As a result, cardiac muscle contraction might be deteriorated. In general, our data provide abundant fundamental research clues to the combined toxicity of environmental pollutants and further in-depth verifications are needed.

Cardiovascular system is demonstrated the main target of PM2.5 and the objective of this study was to explore the toxic effect and molecular mechanisms caused by PM2.5 in primary human umbilical vein endothelial cells (HUVECs) using microarray and bioinformatics analysis. The results showed that 591 genes were differentially expressed triggered by PM2.5, of which 174 genes were down-regulated, while 417 genes were up-regulated. Gene ontology analysis revealed that PM2.5 caused significant changes in gene expression patterns, including response to stimuli, immune response, and cellular processes. Pathway analysis and Signal-net analysis suggested that endocytosis, chemokine signaling pathway, RNA transport, protein processing in endoplasmic reticulum (ER) and autophagy regulation were the most critical pathways in PM2.5-induced toxicity in HUVECs. Moreover, gene expression confirmation of LIF, BCL2L1, CSF3, HMOX1, RPS6, PFKFB, CAPN1, HSPBP1, MOGS, PREB, TUBB2A, GABARAP by qRT-PCR indicated that endocytosis might be involved in the cellular uptake of PM2.5 by forming phagosomes, and subsequently inflammation, hypoxia and ER stress was occurred, which finally activated autophagy after PM2.5 exposure in HUVECs. In summary, our data can serve as fundamental research clues for further studies of PM2.5-induced toxicity in HUVECs.

The fine particulate matter (PM2.5) in air pollution is a major public health concern and now known to contribute to severe diseases, therefore, a comprehensive understanding of PM2.5-induced adverse effects in living organisms is needed urgently. This study was aimed to evaluate the toxicity of PM2.5 on multi-organ systems in a zebrafish (Danio rerio) model. The embryonic toxicity induced by PM2.5 was demonstrated by an increase in mortality and inhibition of hatching rate, in a dose- and time-dependent manner. PM2.5 caused the pericardial edema, as well as reducing heart rate and cardiac output. The area of sub-intestinal vessels (SIVs) was significant reduced in Tg(fli-1:EGFP) transgenic zebrafish lines. Morphological defects and yolk sac retention were associated with hepatocyte injury. In addition, PM2.5 disrupted the axonal integrity, altering of axon length and pattern in Tg(NBT:EGFP) transgenic lines. Genes involved in cardiac function (spaw, supt6h, cmlc1), angiogenesis (vegfr2a, vegfr2b), and neural function (gabrd, chrna3, npy8br) were markedly down-regulated; while genes linked to hepatic metabolism (cyp1a, cyp1b1, cyp1c1) were significantly up-regulated by PM2.5. In summary, our data showed that PM2.5 induced the cardiovascular toxicity, hepatotoxicity and neurotoxicity in zebrafish, suggested that PM2.5 could cause multi-organ toxicity in aquatic organism.

PM2.5 is a major public health concern and some severe diseases have been attributed to exposure to PM2.5. However, a comprehensive understanding of gene and microRNA expression patterns induced by PM2.5 is missing. The objective of this study was to evaluate the toxicity of PM2.5 via genome-wide transcriptional analysis in the model teleost fish, zebrafish (Danio rerio). Gene ontology analysis revealed that the most impact gene functional categories induced by PM2.5 included oxidation-reduction process, transport, response to xenobiotic stimulus, response to chemical stimulus and metabolic process. Pathway and Signal-net analysis showed that the critical pathway involved in the response to exposure to PM2.5 was the metabolism of xenobiotics by cytochrome P450. Results from verification experiments also demonstrated that the key genes with degree higher than 10 induced by PM2.5 were related to metabolism of xenobiotics by cytochrome P450, including cyp3a65, mgst2, gstp1, gsto2, gsto1, cyp1a, ehx1, gstal and aldh3b1. The differential expression of 8 microRNAs corresponding to those in the human genome, revealed that PM2.5 could up-regulate let-7b, miR-153b-3p, miR-122, miR-24 and down-regulate let-7i, miR-19a-3p, miR-19b-3p and miR-7a, which suggested PM2.5 had multiple means through which it induced toxicity in living organisms, such as suppression of adaptive immune responses, autophagy, deregulation of metabolism, impaired vasorelaxation, progression of cancers, as well as hypertension, atherosclerosis and myocardial infarction.