Dissecting contributions of representative heavy metal components in PM2.5 to its cytotoxicity.

PM2.5 is a complex pollutant that is a pervasive threat to human health. The health risks and toxicity mechanisms of PM2.5 components must be identified to alleviate the corresponding risks. In this study, a reductionism approach based on model PM2.5 particles was used to investigate the contributions of the most harmful components in PM2.5 to its toxicity. Human liver and kidney cells were used as models. The results showed that Cr(VI) was the most critical toxic component among other components (Pb, As, and benzo[a]pyrene) in human liver and kidney cells. PM2.5-Cr(VI) induced oxidative stress, which led to cytotoxicity by inducing cell cycle arrest in the S-phase in HepG2 and HEK293 cells. The presented findings can provide valuable insights into the toxicity levels of PM2.5 components, which can help clarify the potential health risks from PM2.5 exposure.

Zn2+ loading as a critical contributor to the circ_0008553-mediated oxidative stress and inflammation in response to PM2.5 exposures.

Inflammation is a major adverse outcome induced by inhaled particulate matter with a diameter of ≤ 2.5 µm (PM2.5), and a critical trigger of most PM2.5 exposure-associated diseases. However, the key molecular events regulating the PM2.5-induced airway inflammation are yet to be elucidated. Considering the critical role of circular RNAs (circRNAs) in regulating inflammation, we predicted 11 circRNAs that may be involved in the PM2.5-induced airway inflammation using three previously reported miRNAs through the starBase website. A novel circRNA circ_0008553 was identified to be responsible for the PM2.5-activated inflammatory response in human bronchial epithelial cells (16HBE) via inducing oxidative stress. Using a combinatorial model PM2.5 library, we found that the synergistic effect of the insoluble core and loaded Zn2+ ions at environmentally relevant concentrations was the major contributor to the upregulation of circ_0008553 and subsequent induction of oxidative stress and inflammation in response to PM2.5 exposures. Our findings provided new insight into the intervention of PM2.5-induced adverse outcomes.

Biosafety-inspired structural optimization of triazolium ionic liquids based on structure-toxicity relationships.

Ionic liquids (ILs), owing to their low vapor pressure and excellent solvating ability, are being increasingly applied in various industries to replace highly toxic organic solvents. They mainly pollute aquatic environment and soils, directly endangering eco-environment and human health. Therefore, it is critical to understand and optimize structural motifs of ILs with reduced toxicity. Considering human oral exposure is the major route, our investigations employed a human cell panel (modeling oral exposures) including human stomach (GES-1), intestinal (FHC), liver (HepG2) and kidney (HEK293) cells using a series of experimental and computational approaches to explore the cytotoxicity and molecular mechanism of ILs. We discovered that the cytotoxicity of triazolium and imidazolium ILs was human cell line-dependent with cytotoxicity in an order of FHC > GES-1 > HepG2 > HEK293. For this reason, a toxicity assay using a single cell line was highly inappropriate. Compared to anions (Br-, OTs-, OTMBS-) we tested, the cation of ILs played a major role in causing cytotoxicity. Ionic liquids with cations having longer hydrophobic sidechains (IL09 vs. IL01) readily insert into cell membranes with enhanced membrane and lipidomic perturbations, induce cytotoxicity by triggering cell cycle arrest and apoptosis. Reducing sidechain length and incorporating three nitrogen atoms (triazolium) instead of two (imidazolium) in the cation core alleviated cytotoxicity by reducing cell membrane perturbations and cell function interference. These findings provide important guiding principles for the design of the next-generation of "green" and safe ILs.

Emerging impacts of ionic liquids on eco-environmental safety and human health.

Owing to their unique physicochemical properties, ionic liquids (ILs) have been rapidly applied in diverse areas, such as organic synthesis, electrochemistry, analytical chemistry, functional materials, pharmaceutics, and biomedicine. The increase in the production and application of ILs has resulted in their release into aquatic and terrestrial environments. Because of their low vapor pressure, ILs cause very little pollution in the atmosphere compared to organic solvents. However, ILs are highly persistent in aquatic and terrestrial environments due to their stability, and therefore, potentially threaten the safety of eco-environments and human health. Specifically, the environmental translocation and retention of ILs, or their accumulation in organisms, are all related to their physiochemical properties, such as hydrophobicity. Based on results of ecotoxicity, cytotoxicity, and toxicity in mammalian models, the mechanisms involved in IL-induced toxicity include damage of cell membranes and induction of oxidative stress. Recently, artificial intelligence and machine learning techniques have been used in mining and modeling toxicity data to make meaningful predictions. Major future challenges are also discussed. This review will accelerate our understanding of the safety issues of ILs and serve as a guideline for the design of the next generation of ILs.

Synergistic effects of carbon nanoparticle-Cr-Pb in PM2.5 cause cell cycle arrest via upregulating a novel lncRNA NONHSAT074301.2 in human bronchial epithelial cells.

Inhalation of carcinogenic PM2.5 particles is a severe threat to all the people in both developing and developed nations. However, which components of PM2.5 and how they perturb human cells to cause various diseases are still not understood. Here, employing a reductionism approach, we revealed that one of the crucial toxic and pathogenic mechanisms of PM2.5 was the blocking of human bronchial cell cycle through upregulation of a novel long non-coding RNA NONHSAT074301.2 by carbon particles with payloads of Cr(VI) and Pb2+. We also discovered that NONHSAT074301.2 is a key regulatory molecule controlling cell cycle arrest at G2/M phase. This work highlights cellular function and molecular signaling events investigations using a 16-membered combinational model PM2.5 library which contain carbon particles carrying four toxic pollutants in all possible combinations at environmental relevant concentrations. This work demonstrates a very powerful methodology to elucidate mechanisms at molecular level and help unlock the "black box" of PM2.5-induced toxicities.

Analysis of model PM2.5-induced inflammation and cytotoxicity by the combination of a virtual carbon nanoparticle library and computational modeling.

Health risks induced by PM2.5 have become one of the major concerns among living populations, especially in regions facing serious pollution such as China and India. Furthermore, the composition of PM2.5 is complex and it also varies with time and locations. To facilitate our understanding of PM2.5-induced toxicity, a predictive modeling framework was developed in the present study. The core of this study was 1) to construct a virtual carbon nanoparticle library based on the experimental data to simulate the PM2.5 structures; 2) to quantify the nanoparticle structures by novel nanodescriptors; and 3) to perform computational modeling for critical toxicity endpoints. The virtual carbon nanoparticle library was developed to represent the nanostructures of 20 carbon nanoparticles, which were synthesized to simulate PM2.5 structures and tested for potential health risks. Based on the calculated nanodescriptors from virtual carbon nanoparticles, quantitative nanostructure-activity relationship (QNAR) models were developed to predict cytotoxicity and four different inflammatory responses induced by model PM2.5. The high predictability (R2 > 0.65 for leave-one-out validations) of the resulted consensus models indicated that this approach could be a universal tool to predict and analyze the potential toxicity of model PM2.5, ultimately understanding and evaluating the ambient PM2.5-induced toxicity.

CircRNA104250 and lncRNAuc001.dgp.1 promote the PM2.5-induced inflammatory response by co-targeting miR-3607-5p in BEAS-2B cells.

Long-term exposure to particulate matter 2.5 (PM2.5) is closely related to the occurrence and development of airway inflammation. Exploration of the role of PM2.5 in inflammation is the first step towards clarifying the harmful effects of particulate pollution. However, the molecular mechanisms underlying PM2.5-induced airway inflammation are yet to be fully established. In this study, we focused on the specific roles of non-coding RNAs (ncRNAs) in PM2.5-induced airway inflammation. In a human bronchial epithelial cell line, BEAS-2B, PM2.5 at a concentration of 75 µg/mL induced the inflammatory response. Microarray and quantitative real-time polymerase chain reaction (qRT-PCR) analyses revealed significant upregulation of circRNA104250 and lncRNAuc001.dgp.1 during the PM2.5-induced inflammatory response in this cell line. Data from functional analyses further showed that both molecules promote an inflammatory response. CircRNA104250 and lncRNAuc001.dgp.1 target miR-3607-5p and affect expression of interleukin 1 receptor 1 (IL1R1), which influences the nuclear factor κB (NF-κB) signaling pathway. In summary, we have uncovered an underlying mechanism of airway inflammation by PM2.5 involving regulation of ncRNA for the first time, which provides further insights into the toxicological effects of PM2.5.

Induction of Inflammatory Responses in Human Bronchial Epithelial Cells by Pb2+-Containing Model PM2.5 Particles via Downregulation of a Novel Long Noncoding RNA lnc-PCK1-2:1.

Airborne particular matter (PM2.5) contains complex mixtures of pollutants, and their compositions also vary with time and location. Inhalation of PM2.5 may cause a number of diseases, such as bronchial and lung inflammation and lung cancer. So far, how different components of PM2.5 contribute to inflammation and toxicity is still not known. To identify key PM2.5 components that are responsible for inflammation, here we took a reductionism approach and synthesized a model PM2.5 library containing 20 carbon nanoparticle based members with loadings of As(III), Pb2+, Cr(VI), and BaP individually or in combination at environment relevant concentrations. We discovered that only carbon nanoparticle-Pb2+ adducts, not other pollutants or adducts, induced inflammation in human bronchial cells by suppressing the expression of a novel long noncoding RNA lnc-PCK1-2:1, while lnc-PCK1-2:1 routinely plays a regulatory role in inhibiting inflammation. This finding was further substantiated by varying Pb2+ loadings on carbon nanoparticles and overexpressing lnc-PCK1-2:1. The success of this approach opens an avenue for further elucidation of molecular mechanisms of PM2.5-induced inflammation and toxicity.