Comprehensive pulmonary metabolic responses to silica nanoparticles exposure in Fisher 344 rats.

Silica nanoparticles (SiNPs) could induce adverse pulmonary effects, but the mechanism was not clear enough. Metabolomics is a sensitive and high-throughput approach that could investigate the intrinsic causes of adverse health effects caused by SiNPs. The current investigation represented the first in vivo metabolomics study examining the chronic pulmonary toxicity of SiNPs at a low dosage, mimicking real human exposure situation. The recovery process after the cessation of exposure was also taken into consideration. Fisher 344 rats were treated with either saline or SiNPs for 6 months. Half of the animals in each group received an additional six-month period for recovery. The findings indicated that chronic low-level exposure to SiNPs resulted in notable alterations in pulmonary metabolism of amino acids, lipids, carbohydrates, and nucleotides. SiNPs exerted an impact on various metabolites and metabolic pathways which are linked to oxidative stress, inflammation and tumorigenesis. These included but were not limited to L-carnitine, spermidine, taurine, xanthine, and glutathione metabolism. The metabolic alterations caused by SiNPs exhibited a degree of reversibility. However, the interference of SiNPs on two metabolic pathways related to tumorigenesis was observed to persist after a recovery period. The two metabolic pathways are glycerophospholipid metabolism as well as phenylalanine, tyrosine and tryptophan biosynthesis. This study elucidated the metabolic alterations induced by chronic low-level exposure to SiNPs and presented novel evidence of the chronic pulmonary toxicity and carcinogenicity of SiNPs, from a metabolomic perspective.

Ferritinophagy was involved in long-term SiNPs exposure induced ferroptosis and liver fibrosis.

SiNPs could induce liver fibrosisinvivo, but the mechanism was not completely clear. This study focused on exploring whether long-term SiNPs exposure at human-related exposure dosage could lead to ferritinophagy-mediated ferroptosis and liver fibrosis. In vivo, long-term SiNPs exposure induced liver fibrosis inrats accompanied by ferritinophagy and ferroptosis in hepatocytes. Interestingly, the progression of liver fibrosis was alleviated after exposure cessation and recovery, meanwhile ferritinophagy and ferroptosis were not further activated. In vitro, after long-term SiNPs exposure, the mitochondrial membrane ruptured, lipid peroxidation intensified, the level of redox active iron increased and the repair protein of lipid peroxidation were consumed in L-02 cells, demonstrating ferroptosis occurrence. Notably, NCOA4 knockdown inhibited ferritin degradation, alleviated the increase of intracellular ferrous iron level, reduced lipid peroxidation and the depletion of glutathione peroxidase 4 (GPX4). In conclusion, ferritinophagy mediated by NCOA4 was responsible for long-term SiNPs exposure induced hepatocytes ferroptosis and liver fibrosis, which provided a scientific basis for toxicological assessment of SiNPs and would be benefited for the safety design of SiNPs-based products.

Adverse effects and underlying mechanism of amorphous silica nanoparticles in liver.

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.

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.

Silica nanoparticles induce pyroptosis and cardiac hypertrophy via ROS/NLRP3/Caspase-1 pathway.

Growing literatures suggest that silica nanoparticles (SiNPs) exposure is correlated with adverse cardiovascular effects. Cardiac hypertrophy is one of the most common risk factors for heart failure. However, whether SiNPs involved in cardiac hypertrophy and the underlying mechanisms was remained unexploited. Our study aimed to investigate the molecular mechanisms of SiNPs on pyroptosis and cardiac hypertrophy. The in vivo results found that SiNPs induced ultrastructural change and histopathological damage, accompanied by oxidative damage occurred and increased levels of inflammatory factors (IL-18 and IL-1ß) in heart tissue. In addition, SiNPs could upregulate the expressions of cardiac hypertrophy-related special marker including ANP, BNP, ß-MHC, it also elevated the pyroptosis-related protein, such as NLRP3, Cleaved-Caspase-1, GSDMD, IL-18 and Cleaved-IL-1ß in vivo. For in vitro study, SiNPs increased the intracellular ROS generation and activated the NLRP3/Caspase-1/GSDMD signaling pathway in cardiomyocytes. Whereas, the NADPH oxidase (NOX) inhibitor VAS2870 had effectively inhibited the ROS level and suppressed the expression of NLRP3, ASC, Pro-Caspase-1, Cleaved-Caspase-1, N-GSDMD, IL-18, Cleaved-IL-1ß, ANP, BNP and ß-MHC. Moreover, transfected with si-NLRP3 or adopted with Caspase-1 inhibitor VX-765 in cardiomyocytes showed an inhibitory effect on SiNPs-induced pyroptosis and cardiac hypertrophy. In summary, our results demonstrated that SiNPs could trigger pyroptosis and cardiac hypertrophy via ROS/NLRP3/Caspase-1 signaling pathway.

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.

The relationship between exposure to PM2.5 and atrial fibrillation in older adults: A systematic review and meta-analysis.

Fine particle matter (PM2.5) is recognized as atrial fibrillation (AF) risk factor, especially for older adults. However, studies on the relationship between PM2.5 and AF were inconsistent. Herein, we present a systematic review to further assess the correlation between PM2.5 and AF in older adults (average age > 50 years old). A comprehensive search was conducted with the keywords in PubMed (675 records), Web of Science (1130 records), Embase (82 records), and the Cochrane Library (42 records). Using Stata12.0 software to test the heterogeneity between studies, and select the corresponding model to calculate the comprehensive effect value, odds ratio (OR, odds ratio), the pooled %-change (percentage change) and its 95% confidence interval (CL, confidence interval). A total of 16 observational studies were included, involving 10,580,394 participants, the results showed that PM2.5 had an adverse effects on AF in older adults. An association was found between exposure to PM2.5 (per 10 µg/m3 increase) and AF in older adults, with the corresponding pooled OR (1.11, 95% CI: 1.03-1.19) and pooled %-change (1.01%, 95% CI: 0.14%-1.88%). Our study indicated that PM2.5 exposure was significantly related to increased incidence of AF in older adults. Both the pooled OR and %-change value were higher in areas with higher levels of PM2.5(≥25 µg/m3).

Effect of particulate matter exposure on the prevalence of allergic rhinitis in children: A systematic review and meta-analysis.

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.

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'.

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.

Short-term PM2.5 exposure and circulating von Willebrand factor level: a meta-analysis.

BACKGROUND: Ambient fine particulate matter (PM2.5) is a major threat to cardiovascular health. Endothelial dysfunction is the initiating event associated with the PM2.5-induced cardiovascular disease (CVD). A sensitive marker of endothelial function-circulating von Willebrand factor (vWF), is an independent predictor of adverse clinical outcome in CVD patients. PM2.5 exposure may cause CVD, but the reports of relationship between short-term PM2.5 exposure and circulating vWF are inconsistent. OBJECTIVE: To explore the influence of short-term PM2.5 exposure on circulating vWF. METHODS: By 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/m3 increase in PM2.5) and its 95% confidence interval (95%CI) were calculated by using random effect model. Sensitivity analysis and publication bias detection were also carried out. RESULTS: 12 articles were included in this meta-analysis. Short-term PM2.5 exposure (per 10 µg/m3 increase) was associated with the increased vWF (%-change = 0.41, 95%CI: 0.11-0.71). The pooled effect estimates of subgroup with PM2.5 exposure level < 25 µg/m3 was higher (%-change = 8.26; 95%CI: 1.99-14.53) than that with PM2.5 exposure level ≥ 25 µg/m3 (%-change = 0.36; 95%CI: 0.09-0.63). CONCLUSION: Short-term PM2.5 exposure is associated with the increased circulating vWF. It suggests that short-term PM2.5 exposure causes endothelial dysfunction.

The relationship between exposure to PM2.5 and heart rate variability in older adults: A systematic review and meta-analysis.

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 PM2.5 and HRV in old adults whose average age was 55 years old or above, we conducted a meta-analysis of nineteen longitudinal studies including nine short-term and ten long-term studies. In the short-term exposure group, per 10 µg/m3 increase of PM2.5 was associated with decreases in the time-domain measurements, for SDNN -0.39% (95% CI: -0.72%, -0.06%) and for RMSSD -1.20% (95% CI: -2.17%, -0.23%) and in frequency-domain measurements, for LF -2.31% (95% CI: -3.85%, -0.77%) and for HF -1.87% (95% CI: -3.45%, -0.29%); In the long-term exposure group, per 10 µg/m3 increase of PM2.5 was associated with decreases in the time-domain measurements, for SDNN -0.92% (95% CI: -2.14%, 0.31%) and for RMSSD -1.96% (95% CI: -3.48%, -0.44%) and in frequency-domain measurements, for LF -2.78% (95% CI: -4.02%, -1.55%) and for HF -1.61% (95% CI: -4.02%, 0.80%). Exposure to PM2.5 is associated with decreased indicators of HRV in older adults suggesting an affected cardiac autonomic system upon exposure, which may explain the association between PM2.5 and risk of CVD in older adults. Long-term exposure to PM2.5 was more strongly associated with indicators of HRV than short-term exposure.

Estrogen therapy before hysteroscopic adhesiolysis improves the fertility outcome in patients with intrauterine adhesions.

PURPOSES: To describe the fertility outcomes after hysteroscopic adhesiolysis combined with preoperative hormone treatment in women with intrauterine adhesion (IUA). METHODS: This study is a retrospective cohort study. A total of 230 patients with IUA underwent hysteroscopic adhesiolysis combined with hormone treatment from Jan 2012 to Jun 2018. 148 patients who received preoperative estrogen treatment were enrolled into group A and 82 patients without preoperative estrogen treatment were enrolled into group B. All the patients underwent hysteroscopic adhesiolysis and received postoperative estrogen therapy, intrauterine indwelling device. Second or third look was performed after 2-3 months. RESULTS: 90.87% (209/230) patients complete the study. The AFS scores at baseline were higher in the group A than group B. After the preoperative E2 treatment, group A achieved the comparable AFS score to group B before the surgery. The cumulative fertility rate in group A was comparable in group B, both in the ITT analysis (49.32% vs. 52.44%, p = 0.651) and the PP analysis (54.07% vs.58.10%, p = 0.575).The mean conception time was also similar in group A and group B (8.30 ± 6.47 vs. 8.54 ± 5.68 months, p = 0.837). Besides, the surgery times in group A were less than group B. There was no difference in the rate of adverse events between two groups. CONCLUSIONS: Hysteroscopic adhesiolysis combined with preoperative oestrogen could reduce the preoperative AFS scores and the times of surgery which yield a similar conception rate in women with less severe intrauterine adhesions.