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Typically used household chemicals comprise numerous compounds. Determining mixture toxicity, as observed when using household chemicals containing multiple substances, is of considerable importance from a regulatory perspective. Upon examining the toxic effects of household chemical mixtures, we observed that hydramethylnon combined with tetramethrin resulted in synergistic toxicity. To determine the unknown toxicity mechanism of hydramethylnon, which carries the risk of inhalation exposure when using household chemicals, we conducted a further investigation using BEAS-2B cells, a human bronchial epithelial cell line. Hydramethylnon-induced cytotoxicity was determined following 24 and 48 h of exposure using the water-soluble tetrazolium 1 and lactate dehydrogenase assays. To elucidate the toxicity mechanism, we utilized flow cytometry and measured the levels of apoptosis-related proteins and caspase activities. Given that hydramethylnon, as an insecticide, disrupts the mitochondrial electron transfer chain, we analyzed the relevant mechanisms, including mitochondrial superoxide levels as well as the mitochondrial membrane potential (MMP). Hydramethylnon dose-dependently induced BEAS-2B cell apoptosis via the intrinsic pathway. Furthermore, it significantly increased mitochondrial superoxide levels and disrupted the MMP. Pre-treatment with a caspase inhibitor (Z -DEVD-FMK) confirmed that hydramethylnon induced caspase-dependent apoptosis. Apoptosis, a key event in the toxicological process of chemicals, can lead to lung diseases, including fibrosis and cancer. The results of the present study suggest a mechanism of toxicity of hydramethrylnon, an organofluorine biocide whose toxicity has been little studied, to the lung epithelium. Considering the potential risks associated with inhalation exposure, these results highlight the need for careful management and regulation of hydramethylnon. • Hydramethylnon can cause lung toxicity by inducing apoptosis of lung epithelial cells. • Hydramethylnon induces mitochondrial superoxide levels and membrane potential loss. • Oxidative stress causes subsequent cellular damage in lung epithelial cells. • Hydramethylnon-induced apoptosis occurs via intrinsic pathway; is caspase-dependent. [ABSTRACT FROM AUTHOR]

Pollution from fine particulate matter (PM2.5) has become a major threat to public health and has been related to lung toxicity. One of the key regulators of the Hippo signaling system, Yes-associated protein 1 (YAP1), is speculated to play a role in ferroptosis development. Here, we focused on investigating the function of YAP1 in pyroptosis and ferroptosis, aiming to explore its therapeutic potential in PM2.5-induced lung toxicity. PM2.5-induced lung toxicity was induced in Wild-type WT and conditional YAP1-knockout mice, and lung epithelial cells were stimulatd by PM2.5 in vitro. We used western blot, transmission electron microscopy, and fluorescence microscopy to investigate pyroptosis- and ferroptosis-related characteristics. We found that PM2.5 leads to lung toxicity using mechanisms involving pyroptosis and ferroptosis. YAP1 knockdown impeded pyroptosis, ferroptosis, and PM2.5-induced lung damage, as shown by increased histopathology, higher levels of proinflammatory cytokines, GSDMD protein, lipid peroxidation, and iron accumulation, as well as increased NLRP3 inflammasome activation and decreased SLC7A11 expression. YAP1 silencing consistently promoted NLRP3 inflammasome activation and reduced SLC7A11 levels, aggravating PM2.5-induced cellular damage. In contrast, YAP1-overexpressing cells inhibited NLRP3 inflammasome activation and increased SLC7A11 levels, preventing pyroptosis and ferroptosis. Overall, our data suggest that YAP1 ameliorates PM2.5-induced lung injury by inhibiting NLRP3-mediated pyroptosis and SL7A11-dependent ferroptosis. [Display omitted] • Pyroptosis and ferroptosis are major contributors to PM2.5-induced lung toxicity. • YAP1 deficiency aggravated, but YAP1 overexpression alleviated, PM2.5-induced lung toxicity. • YAP1's protective function in PM2.5-induced toxicity was linked to suppression of pyroptosis and ferroptosis. [ABSTRACT FROM AUTHOR]

Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis; this is associated with a sequential accumulation of pro- and anti-inflammatory macrophages in the lung which have been implicated in NM toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating lipid homeostasis and inflammation. In these studies, we analyzed the role of FXR in inflammatory macrophage activation, lung injury and oxidative stress following NM exposure. Wild-type (WT) and FXR−/− mice were treated intratracheally with PBS (control) or NM (0.08 mg/kg). Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 3, 14 and 28 d later. NM caused progressive histopathologic alterations in the lung including inflammatory cell infiltration and alveolar wall thickening and increases in protein and cells in BAL; oxidative stress was also noted, as reflected by upregulation of heme oxygenase-1. These changes were more prominent in male FXR−/− mice. Flow cytometric analysis revealed that loss of FXR resulted in increases in proinflammatory macrophages at 3 d post NM; this correlated with upregulation of COX-2 and ARL11, markers of macrophage activation. Markers of anti-inflammatory macrophage activation, CD163 and STAT6, were also upregulated after NM; this response was exacerbated in FXR−/− mice at 14 d post-NM. These findings demonstrate that FXR plays a role in limiting macrophage inflammatory responses important in lung injury and oxidative stress. Maintaining or enhancing FXR function may represent a useful strategy in the development of countermeasures to treat mustard lung toxicity. • Nitrogen mustard (NM) exposure causes inflammatory macrophage activation. • NM-induced lung injury, oxidative stress and inflammation are exacerbated in male FXR−/− mice. • FXR regulates pro- and anti-inflammatory macrophage activation following NM-induced lung injury. [ABSTRACT FROM AUTHOR]

While the evidence for the health adverse effects of air pollution Particulate Matter (PM) has been growing, there is still uncertainty as to which constituents within PM are most harmful. Hence, to contribute to fulfill this gap of knowledge, some physicochemical characteristics and toxicological endpoints ( i.e. cytotoxicity, oxidative damage, cytokine secretion) of PM 2.5–0.3 samples produced during two different seasons ( i.e. spring/summer or autumn/winter) in three different surroundings ( i.e. rural, urban, or industrial) were studied, thereby expecting to differentiate their respective adverse effects in human bronchial epithelial cells (BEAS-2B). Physicochemical characteristics were closely related to respective origins and seasons of the six PM 2.5–0.3 samples, highlighting the respective contributions of industrial and heavy motor vehicle traffic sources. Space- and season-dependent differences in cytotoxicity of the six PM 2.5–0.3 samples could only be supported by considering both the physicochemical properties and the variance in air PM concentrations. Whatever spaces and seasons, dose- and even time-dependent increases in oxidative damage and cytokine secretion were reported in PM 2.5–0.3 -exposed BEAS-2B cells. However, the relationship between the chemical composition of each of the six PM 2.5–0.3 samples and their oxidative or inflammatory potentials seemed to be very complex. These results supported the role of inorganic, ionic and organic components as exogenous source of Reactive Oxygen Species and, thereafter, cytokine secretion. Nevertheless, one of the most striking observation was that some inorganic, ionic and organic chemical components were preferentially associated with early oxidative events whereas others in the later oxidative damage and/or cytokine secretion. Taken together, these results indicated that PM mass concentration alone might not be able to explain the health outcomes, because PM is chemically nonspecific, and supported growing evidence that PM-size, composition and emission source, together with sampling season, interact in a complex manner to produce PM 2.5–0.3 -induced human adverse health effects. [ABSTRACT FROM AUTHOR]

To study the regulatory relationship between ozone-induced mitophagy and pyroptosis in lung epithelial cells. First, type I primary alveolar epithelial cells and male Wistar rats were treated with ozone at different dosages. The ATP content and mitochondrial membrane potential significantly decreased in type I primary alveolar epithelial cells. The mitophagy-related markers and PINK1/Parkin pathway-related proteins, and the co-localization of LC3, Parkin, and mitochondria in type I alveolar epithelial cells indicated that ozone exposure triggered mitophagy. On the other hand, the reactive oxygen species (ROS) inhibitor NAC could significantly alleviate mitophagy in epithelial cells. After treatment with the mitophagy inhibitor MDIVI-1, the levels of the NLRP3 inflammasome, cleaved caspase-1, and N-gasdermin D (N-GSDMD) significantly decreased in the cells. Altogether, these results indicated that mitophagy can be triggered by ozone exposure, and subsequently induces cell death mediated by the NLRP3 inflammasome. Finally, the overexpression and knockdown of NLRP3 confirmed this conclusion. Ozone exposure induced oxidative damage, leading to mitochondrial structural and functional damage. Ozone-induced ROS triggered mitophagy through the activation of the PINK1/Parkin signaling pathway, then pyroptosis through activation of the NLRP3 inflammasome. • Ozone exposure can lead to pulmonary mitochondrial dysfunction in vivo and in vitro. • Ozone exposure can lead to mitophagy in lung, and ROS is involved in this process. • ROS induce mitophagy through the activation of the PINK1/Parkin signaling pathway. • Mitophagy induced by ozone can induce pyroptosis through the activation of NLRP3 inflammasome in lung. [ABSTRACT FROM AUTHOR]

The massive increase in emissions of air pollutants due to economic and industrial growth in developing countries has made air quality a crucial health problem in this continent. Hence, it is somewhat critical to have a better knowledge on the air pollution in Sub-Saharan Africa countries. Three air pollution PM2.5 samples were also collected in two urban sites (i.e. Fann and Faidherbe) in Dakar (Senegal) and in a rural site near Dakar (i.e. Ngaparu). The two urban sites mainly differ in the type of used vehicles: in Fann, most of the traffic is made of buses, which are absent, in Faidherbe. The physicochemical characteristics of the three PM2.5 samples revealed their high heterogeneities and complexities, related to the multiple natural and anthropogenic emission sources. Results from 5-bromodeoxyuridine incorporation into DNA, mitochondrial dehydrogenase activity, and extracellular lactate dehydrogenase activity in PM2.5-exposed BEAS-2B cells suggested the exposure conditions (i.e. 3 and 12μg PM/cm² during 24, 48, and 72h) to further consider. The organic fractions (i.e. mainly PAHs) of the PM2.5 samples were able to induce a time and/or concentration-dependent gene expression of CYP1A1 and CYP1B1, and, to a lesser extent, NQO1. There was a time and/or dose-dependent increase of both the gene expression and/or protein secretion of inflammatory mediators (i.e. TNF-α, IL-1β, IL-6, and/or IL-8) in PM2.5-exposed BEAS-2B cells. In agreement with the physicochemical characterization, urban PM2.5 samples caused greater biological responses in BEAS-2B cells than the rural one. Variable concentrations of transition metals (i.e. Fe, Al, Pb, Mn, Zn) and organic compounds (i.e. PAHs) founded in the three PM2.5 samples might be firmly involved in a time- and/or dose-dependent toxicity, relying on inflammatory processes. [Copyright &y& Elsevier]

Abstract: Bleomycin is an antibiotic drug with anticancer properties produced by Streptomyces verticillus [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians&Wilkins; 2001. p. 452–459]. It was isolated in 1966 by Umezawa et al. and its mechanism of action is breaking the DNA double helix by the production of free radicals, which is oxygen and iron dependent [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians&Wilkins; 2001. p. 452–459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81–94]. Bleomycin may be inactivated by bleomycin hidrolase presents in normal and tumoral cells [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians&Wilkins; 2001. p. 452–459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81–94; Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clinics Chest Med 1990;11:1–20]. The complex bleomycin-Fe has been the most studied because bleomycin joins the DNA and Fe at the same time, and release of free radicals happens in the presence of molecular oxygen [Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81–94]. Bleomycin has a renal metabolism with 50% of dose eliminated in 4h after its administration and 70% in the next 24h. Its half-life (T½) is not altered, although the creatinine clearance drops to 25–35ml/min [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians&Wilkins; 2001. p. 452–459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81–94]. This drug has been used as cytostatic treatment of many malignant tumors, such as germ cell tumors, lymphomas, head and neck, and Kaposi''s sarcomas [Chen XL, Li WB, Zhou AM et al. Role of endogenous peroxynitrite in pulmonary injury and fibrosis induced by bleomycin A5 in rats. Acta Pharmacol Sin 2003;24:697–702]. Minor important adverse effects are myelossupression, nauseas, vomiting, allergic reactions, mucositis, alopecia, erythema, hyperkeratosis, hypopigmentation, skin ulceration, and acute arthritis [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians&Wilkins; 2001. p. 452–459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81–94]. Fever is reported in 20–50% of patients and some of them present hyperthermia [Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81–94]. [Copyright &y& Elsevier]

Abstract: Carbon nanotubes focus the attention of many scientists because of their huge potential of industrial applications, but there is a paucity of information on the toxicological properties of this material. The aim of this experimental study was to characterize the biological reactivity of purified multi-wall carbon nanotubes in the rat lung and in vitro. Multi-wall carbon nanotubes (CNT) or ground CNT were administered intratracheally (0.5, 2 or 5 mg) to Sprague–Dawley rats and we estimated lung persistence, inflammation and fibrosis biochemically and histologically. CNT and ground CNT were still present in the lung after 60 days (80% and 40% of the lowest dose) and both induced inflammatory and fibrotic reactions. At 2 months, pulmonary lesions induced by CNT were characterized by the formation of collagen-rich granulomas protruding in the bronchial lumen, in association with alveolitis in the surrounding tissues. These lesions were caused by the accumulation of large CNT agglomerates in the airways. Ground CNT were better dispersed in the lung parenchyma and also induced inflammatory and fibrotic responses. Both CNT and ground CNT stimulated the production of TNF-α in the lung of treated animals. In vitro, ground CNT induced the overproduction of TNF-α by macrophages. These results suggest that carbon nanotubes are potentially toxic to humans and that strict industrial hygiene measures should to be taken to limit exposure during their manipulation. [Copyright &y& Elsevier]

Abstract: The cytochrome P450 enzymes are highly expressed in the liver and are involved in the metabolism of xenobiotics. Because of the initiatives associated with the Human Genome Project, a great progress has recently been seen in the identification and characterization of novel extrahepatic P450s, including CYP2S1, CYP2R1, CYP2U1 and CYP2W1. Like the hepatic enzymes, these P450s may play a role in the tissue-specific metabolism of foreign compounds, but they may also have important endogenous functions. CYP2S1 has been shown to metabolize all-trans retinoic acid and CYP2R1 is a major vitamin D 25-hydroxylase. Regarding their metabolism of xenobiotics, much remains to be established, but CYP2S1 metabolizes naphthalene and it is likely that these P450s are responsible for metabolic activation of several different kinds of xenobiotic chemicals and contribute to extrahepatic toxicity and carcinogenesis. [Copyright &y& Elsevier]

Sulfur mustard (SM) is a bifunctional alkylating agent that causes severe injury to the respiratory tract. This is accompanied by an accumulation of macrophages in the lung and the release of the proinflammatory cytokine, tumor necrosis factor (TNF)α. In these studies, we analyzed the effects of blocking TNFα on lung injury, inflammation and oxidative stress induced by inhaled SM. Rats were treated with SM vapor (0.4 mg/kg) or air control by intratracheal inhalation. This was followed 15–30 min later by anti-TNFα antibody (15 mg/kg, i.v.) or PBS control. Animals were euthanized 3 days later. Anti-TNFα antibody was found to blunt SM-induced peribronchial edema, perivascular inflammation and alveolar plasma protein and inflammatory cell accumulation in the lung; this was associated with reduced expression of PCNA in histologic sections and decreases in BAL levels of fibrinogen. SM-induced increases in inflammatory proteins including soluble receptor for glycation end products, its ligand, high mobility group box-1, and matrix metalloproteinase-9 were also reduced by anti-TNFα antibody administration, along with increases in numbers of lung macrophages expressing TNFα, cyclooxygenase-2 and inducible nitric oxide synthase. This was correlated with reduced oxidative stress as measured by expression of heme oxygenase-1 and Ym-1. Together, these data suggest that inhibiting TNFα may represent an efficacious approach to mitigating acute lung injury, inflammatory macrophage activation, and oxidative stress induced by inhaled sulfur mustard. • Acute inhalation of SM causes pulmonary oxidative stress, injury and inflammation. • Anti-TNFα antibody attenuates SM lung injury and oxidative stress. • Inflammation induced by SM is suppressed by anti-TNFα antibody. [ABSTRACT FROM AUTHOR]

Exposure to ambient air-borne fine particulate matter (PM 2.5) increases respiratory morbidity and mortality. The mechanisms underlying PM 2.5 -induced adverse effects remain unclear. This study aimed to uncover the molecular mechanisms of PM 2.5 -induced lung toxicity using a mouse model. Scanning electron microscopy and inductively coupled plasma mass spectrometry were used to examine and analyze PM 2.5 morphology and element compositions, respectively. Twenty four male mice were randomly divided into three groups: control (PBS), PM 2.5 (4.0 mg/kg b.w.), and PM 2.5 + Z-YVAD-FMK. In the latter group, the pan-caspase inhibitor (Z-YVAD-FMK) was intraperitoneally injected into mice at a dose of 12.5 mg/kg body weight prior to intratracheal instillation of PM 2.5 (4.0 mg/kg b.w.) every other day for a total of 3 times (n = 8 in each group). Bronchoalveolar lavage fluids (BALFs) were collected 24 h after the last instillation of PM 2.5. Levels of total proteins (TP), lactate dehydrogenase (LDH), IL-1β and IL-18 were analyzed for biomarkers of cell injury and inflammation. Additionally, histological alterations of lung tissues were assessed by hematoxylin-eosin staining. mRNA and protein expression of Caspase1, NLRP3 and GSDMD were examined by real-time fluorescent quantitative PCR and immunohistochemical staining. Exposure to PM 2.5 increased levels of TP, LDH, IL-1β, IL-18 and inflammatory cell counts in lung. The mRNA and protein expression of Caspase1, NLRP3 and GSDMD were increased. Inhibition of the NALRP3/Caspase-1 signaling pathway ameliorated PM 2.5 -induced lung injury and inflammation, partially through suppressing pyroptosis in lung. PM 2.5 exposure induces lung injury and inflammation, which is mediated by the NALRP3/Caspase-1 signaling pathway. • PM 2.5 exposure caused lung injury and inflammation in mice. • Inhibition of NALRP3/Caspase-1 signaling pathway can amelioration PM 2.5 -induced lung toxicity. • PM 2.5 exposure induced lung toxicity is related to NALRP3 inflammasome mediated macrophage pyroptosis. [ABSTRACT FROM AUTHOR]

Epidemiological studies have shown that particulate matter with an aerodynamic diameter less than 2.5 μm (PM 2.5) is closely associated with human health issues, especially pulmonary diseases such as chronic obstructive pulmonary disease (COPD), asthma and lung cancer. In this study, particles were characterized by scanning electron microscopy (SEM), microbeam energy-dispersive X-ray spectroscopy (EDS), inductively coupled plasma mass spectrometry (ICP-MS) and high-performance liquid chromatography (HPLC). A rat model of PM 2.5 exposure was established by nonsurgical intratracheal instillation, and the effects of biochanin A (BCA) treatment were examined. BCA showed a protective effect; it reduced PM 2.5 -induced apoptosis and the production of proinflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), interleukin-6 (IL-6), and the chemokine interleukin-8 (IL-8), as measured using ELISA. These effects were accompanied by increases in the levels of antioxidant enzymes and decreases in the levels of malondialdehyde (MDA), lactate dehydrogenase (LDH) and alkaline phosphatase (AKP). Furthermore, isobaric tag for relative and absolute quantitation (iTRAQ)-based analytical techniques and bioinformatics tools were used to identify putative biomarkers, including XRCC1, MP2K5, IGJ, and F1LQ12, and the results were verified by Western blot analysis. In conclusion, our findings have scientific significance for the application of flavonoids in preventive and therapeutic strategies for PM 2.5 -associated pulmonary diseases and for the promotion of human health. Image 1 • PM 2.5 can induce oxidative stress, inflammatory response and immune regulation. • PM 2.5 induces 35 abnormal proteins expression and 4 differently expressed proteins. • Biochanin A can alleviate the PM 2.5 -induced lung toxicity in rats. [ABSTRACT FROM AUTHOR]