TNF-α and RPLP0 drive the apoptosis of endothelial cells and increase susceptibility to high-altitude pulmonary edema.

High-altitude pulmonary edema (HAPE) is a fatal threat for sojourners who ascend rapidly without sufficient acclimatization. Acclimatized sojourners and adapted natives are both insensitive to HAPE but have different physiological traits and molecular bases. In this study, based on GSE52209, the gene expression profiles of HAPE patients were compared with those of acclimatized sojourners and adapted natives, with the common and divergent differentially expressed genes (DEGs) and their hub genes identified, respectively. Bioinformatic methodologies for functional enrichment analysis, immune infiltration, diagnostic model construction, competing endogenous RNA (ceRNA) analysis and drug prediction were performed to detect potential biological functions and molecular mechanisms. Next, an array of in vivo experiments in a HAPE rat model and in vitro experiments in HUVECs were conducted to verify the results of the bioinformatic analysis. The enriched pathways of DEGs and immune landscapes for HAPE were significantly different between sojourners and natives, and the common DEGs were enriched mainly in the pathways of development and immunity. Nomograms revealed that the upregulation of TNF-α and downregulation of RPLP0 exhibited high diagnostic efficiency for HAPE in both sojourners and natives, which was further validated in the HAPE rat model. The addition of TNF-α and RPLP0 knockdown activated apoptosis signaling in endothelial cells (ECs) and enhanced endothelial permeability. In conclusion, TNF-α and RPLP0 are shared biomarkers and molecular bases for HAPE susceptibility during the acclimatization/adaptation/maladaptation processes in sojourners and natives, inspiring new ideas for predicting and treating HAPE.

P-phenylenediamine antioxidants and their quinone derivatives: A review of their environmental occurrence, accessibility, potential toxicity, and human exposure.

Substituted p-phenylenediamines (PPDs), a class of antioxidants, have been widely used to extend the lifespan of rubber products, such as tires and pipes. During use, PPDs will generate their quinone derivatives (PPD-Qs). In recent years, PPDs and PPD-Qs have been detected in the global environment. Among them, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q), the oxidation product of N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), has been identified as highly toxic to coho salmon, with the lethal concentration of 50 % (LC50) being 95 ng/L, highlighting it as an emerging pollutant of great concern. This review summarizes the physicochemical properties, global environmental distribution, bioaccessibility, potential toxicity, human exposure risk, and green measures of PPDs and PPD-Qs. These chemicals exhibit lipophilicity, bioaccumulation potential, and poor aqueous stability. They have been found in water, air, dust, soil, and sediment worldwide, indicating their significance as emerging pollutants. Notably, current studies have identified electronic waste (e-waste), such as discarded wires and cables, as a non-negligible source of PPDs and PPD-Qs, in addition to tire wear. PPDs and PPD-Qs exhibit strong bioaccumulation in aquatic organisms and mammals, with a tendency for biomagnification within the food web, posing health threats to humans. Available toxicity data indicate that PPDs and PPD-Qs have negative effects on aquatic organisms, mammals, and invertebrates. Acute exposure leads to death and acute damage, and long-term exposure can cause a series of adverse effects, including growth and development toxicity, reproductive toxicity, neurotoxicity, intestinal toxicity, and multi-organ damage. This paper discusses current research gaps and offers recommendations to understand better the occurrence, behavior, toxicity, and environmental exposure risks of PPDs and PPD-Qs.

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

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

Organoids and organoids-on-a-chip as the new testing strategies for environmental toxicology-applications & advantages.

An increasing number of harmful environmental factors are causing serious impacts on human health, and there is an urgent need to accurately identify the toxic effects and mechanisms of these harmful environmental factors. However, traditional toxicity test methods (e.g., animal models and cell lines) often fail to provide accurate results. Fortunately, organoids differentiated from stem cells can more accurately, sensitively and specifically reflect the effects of harmful environmental factors on the human body. They are also suitable for specific studies and are frequently used in environmental toxicology nowadays. As a combination of organoids and organ-on-a-chip technology, organoids-on-a-chip has great potential in environmental toxicology. It is more controllable to the physicochemical microenvironment and is not easy to be contaminated. It has higher homogeneity in the size and shape of organoids. In addition, it can achieve vascularization and exchange the nutrients and metabolic wastes in time. Multi-organoids-chip can also simulate the interactions of different organs. These advantages can facilitate better function and maturity of organoids, which can also make up for the shortcomings of common organoids to a certain extent. This review firstly discussed the limitations of traditional toxicology testing platforms, leading to the introduction of new platforms: organoids and organoids-on-a-chip. Next, the applications of different organoids and organoids-on-a-chip in environmental toxicology were summarized and prospected. Since the advantages of the new platforms have not been sufficiently considered in previous literature, we particularly emphasized them. Finally, this review also summarized the opportunities and challenges faced by organoids and organoids-on-a-chip, with the expectation that readers will gain a deeper understanding of their value in the field of environmental toxicology.

Ferroptosis participated in inhaled polystyrene nanoplastics-induced liver injury and fibrosis.

The emerging contaminant nanoplastics (NPs) have received considerable attention. Due to their tiny size and unique colloidal properties, NPs could more easily enter the body and cross biological barriers with inhalation exposure. While NPs-induced hepatotoxicity has been reported, the hepatic impact of inhaled NPs was still unknown. To close this gap, a 40 nm polystyrene NPs (PS-NPs) inhalation exposure mice model was developed to explore the hepatotoxicity during acute (1 week), subacute (4 weeks), and subchronic period (12 weeks), with four exposure doses (0, 16, 40, and 100 µg/day). Results showed that inhaled PS-NPs caused a remarkable increase of ALT, AST, and ALP with a decrease of CHE, indicating liver dysfunction. Various histological abnormalities and significantly higher levels of inflammation in a dose- and time-dependent manner were observed. Moreover, after 4 weeks and 12 weeks of exposure, Masson staining and upregulated expression of TGF-ß, α-SMA, and Col1a1 identified that inhaled PS-NPs exposure triggered the progression of liver fibrosis with the exposure time prolonged. From the mechanistic perspective, transcriptome analysis revealed that ferroptosis was involved in PS-NPs-induced liver hepatotoxicity, and key features of ferroptosis were detected, including persistent oxidative stress, iron overload, increased LPO, mitochondria damage, and the expression changes of GPX4, TFRC, and Ferritin. And in vitro and in vivo recovery tests showed that ferroptosis inhibitor Fer-1 treatment alleviated liver injury and fibrosis. The above results confirmed the critical role of ferroptosis in PS-NPs-induced hepatotoxicity. Furthermore, to better conclude our findings and understand the mechanistic causality within it, an adverse outcome pathway (AOP) framework was established. In total, this present study conducted the first experimental assessment of inhalation exposure to PS-NPs on the liver, identified that continuous inhaled PS-NPs could cause liver injury and fibrosis, and PS-NPs- ferroptosis provided a novel mechanistic explanation.

Long-term MNNG exposure promotes gastric carcinogenesis by activating METTL3/m6A/miR1184 axis-mediated epithelial-mesenchymal transition.

As the representative item of environmental chemical carcinogen, MNNG was closely associated with the onset of Gastric cancer (GC), while the underlying mechanisms remain largely unknown. Here, we comprehensively analyzed the potential clinical significance of METTL3 in multiple GC patient cohorts. Additionally, we demonstrated that long-term exposure to MNNG elevated METTL3 and EMT marker expression by in vitro and in vivo models. Furthermore, the depletion of METTL3 impacted the proliferation, migration, invasion, and tumorigenesis of MNNG malignant transformation cells and GC cells. By me-RIP sequencing, we identified a panel of vital miRNAs potentially regulated by METTL3 that aberrantly expressed in MNNG-induced GC cells. Mechanistically, we showed that METTL3 meditated miR-1184/TRPM2 axis by regulating the process of miRNA-118. Our results provide novel insights into critical epigenetic molecular events vital to MNNG-induced gastric carcinogenesis. These findings suggest the potential therapeutic targets of METTL3 for GC treatment.