Oxidative Stress Induces E-Selectin Expression through Repression of Endothelial Transcription Factor ERG.

Oxidative stress induces a prothrombotic state through enhancement of adhesion properties of the endothelium. E-selectin, an endothelial cell adhesion molecule, becomes a therapeutic target for venous thrombosis, whereas the regulatory mechanisms of its expression have not been fully understood. In the present study, we report that H2O2 treatment increases expression of E-selectin but decreases expression of the endothelial transcription factor ETS-related gene (ERG) in HUVECs in a dose- and time-dependent manner. In BALB/c mice treated with hypochlorous acid, E-selectin expression is increased and ERG expression is decreased in endothelial cells of the brain and lung. RNA interference of ERG upregulates E-selectin expression, whereas transfection of ERG-expressing plasmid downregulates E-selectin expression in HUVECs. Knockdown or overexpression of ERG comprises H2O2-induced E-selectin expression in HUVECs. Deletion of the Erg gene in mice results in embryonic lethality at embryonic days 10.5-12.5, and E-selectin expression is increased in the Erg-/- embryos. No chromatin loop was found on the E-selectin gene or its promoter region by capture high-throughput chromosome conformation capture. Chromatin immunoprecipitation and luciferase reporter assay determined that the -127 ERG binding motif mediates ERG-repressed E-selectin promoter activity. In addition, ERG decreases H2O2-induced monocyte adhesion. Together, ERG represses the E-selectin gene transcription and inhibits oxidative stress-induced endothelial cell adhesion.

The leading role of adsorbed lead in PM2.5-induced hippocampal neuronal apoptosis and synaptic damage.

Neurodegenerative diseases may be caused by air pollution, such as PM2.5. However, particles still need to be elucidated the mechanism of synergistic neurotoxicity induced by pollutant-loading PM2.5. In this study, we used a reductionist approach to study leading role of lead (Pb) in PM2.5-induced hippocampal neuronal apoptosis and synaptic damage both in vivo and in vitro. Pb in PM2.5 caused neurotoxicity: 1) by increasing ROS levels and thus causing apoptosis in neuronal cells and 2) by decreasing the expression of PSD95 via interfering with the calcium signaling pathway through cAMP/CREB/pCREB/BDNF/PSD95 pathway and reducing the synapse length by 50%. This study clarifies a key factor in PM2.5-induced neurotoxicity and provides the experimental basis for reducing PM2.5-induced neurotoxicity.

Altered gut microbiome accompanying with placenta barrier dysfunction programs pregnant complications in mice caused by graphene oxide.

The wide use of graphene oxide (GO) has raised increasing concerns about the potential risks to environmental and human health. Recent studies have shown the vital role of gut microbiome in various pathological status or even exogenous exposure, but more detailed understanding about the effects of possible gut microbiome alterations under GO exposure on reproductive toxicology evaluations in pregnant mammals remained elusive. Here we found that orally administrated GO daily during gestational day (GD) 7-16 caused dose-dependent pregnant complications of mice on the endpoint (GD19), including decreased weight of dam and live fetus, high rate of resorbed embryos and dead fetus, and skeletal development retardation. Meanwhile in placenta tissues of pregnant mice exposed to GO at dose over 10 mg/kg, the expression levels of tight junctions (Claudin1 and Occludin) and vascular endothelial growth factor (VEGFA) decreased approximately by 30%-80%, meaning impaired placenta barrier. According to the data of fecal 16s RNA sequencing in 40 mg/kg dose group and the control group, gut microbiome showed dramatically decreased α- and ß-diversity, and upregulated Firmicutes/Bacteroidetes ratio owing to GO exposure. What's more, significantly differentiated abundance of Euryarchaeota is expected to be a special biomarker for failed pregnancy caused by GO. Notably, the result of Spearman correlation analysis suggested that there was a strong link (correlation coefficient>0.6) between perturbed gut microbiome with both abnormally expressed factors of placenta barrier and adverse pregnant outcomes. In summary, the damages of GO exposure to placenta barrier and pregnancy were dose-dependent. And GO exposure was responsible for gut microbiome dysbiosis in mice with pregnant complications. These findings could provide referable evidence to evaluate reproductive risk of GO to mammals.

Breakthrough of ZrO2 nanoparticles into fetal brains depends on developmental stage of maternal placental barrier and fetal blood-brain-barrier.

Ingestion of nanoparticles may cause various damages to human body. However, how such ingestion by pregnant mother influences fetal development is not known because, presumably, ingested nanoparticles have to cross multiple biological barriers (such as intestinal and placental) to reach fetus. To answer this crucial question, here we investigated how a relatively biocompatible zirconia nanoparticles (ZrO2 NPs, 16 nm) were translocated to fetal brains in three exposure models of pregnant mice: Model 1, oral exposure of nanoparticles before maternal blood-placental barrier (BPB) was fully developed; Model 2, exposures after BPB was developed, but before fetal blood-brain-barrier (BBB) was fully developed; Model 3, exposures after both maternal BPB and fetal BBB were fully developed. Our experimental results showed that translocation of ZrO2 NPs into fetal brains was 55 % higher in Model 2 and 96 % higher in Model 1 compared with that in Model 3 after nanoparticles (50 mg/kg) were orally exposed to pregnant mice. Therefore, nanoparticles are able to cross multiple biological barriers and nanotoxicity to fetus is highly dependent on stages of pregnancy and fetal development or the maturity of multiple biological barriers. Oral exposures to nanoparticles during pregnancy are dangerous to fetal brain development, especially in early pregnancy.

Oral intake of ZrO2 nanoparticles by pregnant mice results in nanoparticles' deposition in fetal brains.

Nanotoxicity to fetal brains after maternal oral exposures during pregnancy is often in question because nanoparticles have to cross multiple biological barriers such as intestinal barrier, maternal blood placental barrier (BPB) and fetal blood brain barrier (BBB). Here, we investigated this seemingly impossible passage for ZrO2 nanoparticles (ZrO2 NPs) from maternal body to fetal brains using a pregnant mouse model. After three oral exposures to pregnant mice at late pregnancy (GD16, 17, 18), ZrO2 NPs were able to accumulate in fetal brains at GD19 via crossing the well-developed maternal BPB and fetal BBB. Moreover, ZrO2 NPs crossed the mature biological barriers with increasing the expression levels of caveolae, clathrin and arf6 proteins as well as decreasing the expression levels of the tight junction proteins claudin-5, occludin and ZO-1 in placenta and fetal brain. From this investigation, we speculated that the main mechanisms for such translocation were receptor-mediated endocytosis transcellular pathway and breakthrough of tight junctions paracellular pathway in mature maternal BPB and fetal BBB. These findings have important implications for other nanoparticles exposures during pregnancy and provide crucial information to safeguard fetal development from contamination of widely used nanoproducts.

Nanoparticles induced embryo-fetal toxicity.

Applications of nanomaterials cause a general concern on their toxicity when they intentionally (such as in medicine) or unintentionally (environment exposure) enter into the human body. As a special subpopulation, pregnant women are more susceptible to nanoparticle (NP)-induced toxicity. More importantly, prenatal exposures may affect the entire life of the fetus. Through blood circulation, NPs may cross placental barriers and enter into fetus. A cascade of events, such as damage in placental barriers, generation of oxidative stress, inflammation, and altered gene expression, may induce delayed or abnormal fetal development. The physicochemical properties of NPs, exposure time, and other factors directly affect nanotoxicity in pregnant populations. Even though results from animal studies cannot directly extrapolate to humans, compelling evidence has already shown that, for pregnant women, caution must be taken when dealing with nanomedicines or NP pollutants.

Crossing Biological Barriers by Engineered Nanoparticles.

Engineered nanoparticles (ENPs) may cause toxicity if they cross various biological barriers and are accumulated in vital organs. Which factors affect barrier crossing efficiency of ENPs are crucial to understand. Here, we present strong data showing that various nanoparticles crossed biological barriers to enter vital animal organs and cause toxicity. We also point out that physicochemical properties of ENPs, modifications of ENPs in biofluid, and physiological and pathological conditions of the body all affect barrier crossing efficiency. We also summarized our limited understanding of the related mechanisms. On the basis of this summary, major research gaps and direction of further efforts are then discussed.

The reproductive and developmental toxicity of nanoparticles: A bibliometric analysis.

Because of the advantages of nanoparticles (NPs) in a variety of industrial, biomedical, and consumer applications, they are intentionally (such as in medicine) or unintentionally (environment exposure) introduced into the human body. However, to date, the detrimental effects of NPs are still unclear, especially in reproductive and developmental toxicity. In this study, we researched 266 articles related to the reproductive and developmental toxicity of NPs from 2006 to December 2016 based on the database of the Web of Science. According to the bibliometric analysis, we found that China and the United States were the leading countries in this field and the major research trends might focus on the pathogenesis of NPs, such as oxidative stress, inflammation, and DNA damage. By this analysis, we provide new insights into the research trends and characteristics of the field.

Chronic exposure to aluminum and risk of Alzheimer's disease: A meta-analysis.

A meta-analysis was performed to investigate whether chronic exposure to aluminum (Al) is associated with increased risk of Alzheimer's disease (AD). Eight cohort and case-control studies (with a total of 10567 individuals) that met inclusion criteria for the meta-analysis were selected after a thorough literature review of PubMed, Web of Knowledge, Elsevier ScienceDirect and Springer databases up to June, 2015. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of included studies. Q test and I(2) statistic were used to examine heterogeneity between selected studies. The overall odds ratio (OR) was calculated using a fixed-effect model because no significant heterogeneity between studies was found. No publication bias was observed based on a funnel plot and Egger's test. Results showed that individuals chronically exposed to Al were 71% more likely to develop AD (OR: 1.71, 95% confidence interval (CI), 1.35-2.18). The finding suggests that chronic Al exposure is associated with increased risk of AD.