Evaluating the Sub-Acute Toxicity of Formaldehyde Fumes in an In Vitro Human Airway Epithelial Tissue Model

Ren, Baiping; Wu, Qiangen; Muskhelishvili, Levan; Davis, Kelly J.; Wang, Yiying; Rua, Diego; Cao, Xuefei

doi:10.3390/ijms23052593

Cited by 13 publications

(11 citation statements)

References 58 publications

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“…In this study, we showed that repeated exposure to glutaraldehyde (GA) aerosols induced a panel of temporal changes in tissue responses in the ALI cultures. In general, the toxicity responses to GA exposure in the ALI airway cultures are consistent with observations on other aldehydes, i.e., ortho-phthalaldehyde (OPA), formaldehyde, and acrolein, as reported in our previous studies [ 11 , 12 , 13 ].…”

Section: Discussionsupporting

confidence: 90%

“…Morphological changes caused by GA aerosols were evaluated at T5 and PT7. Sample preparation and histopathology staining were performed as described previously [ 12 , 13 ]. Hematoxylin and eosin (H&E) staining was conducted using a Leica Autostainer (Buffalo Grove, IL, USA); histopathologic changes were evaluated and scored by a board-certified pathologist.…”

Section: Methodsmentioning

confidence: 99%

“…Secretion and expression of MUC5AC, MUC5B, and club-cell secretory protein (CCSP) were assessed in apical washes (50 µL) and cell lysates (5 µg), respectively, using a mucin ELISA method described previously [ 13 ].…”

Section: Methodsmentioning

confidence: 99%

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Subacute Pulmonary Toxicity of Glutaraldehyde Aerosols in a Human In Vitro Airway Tissue Model

Wang

Ren

et al. 2022

IJMS

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Glutaraldehyde (GA) has been cleared by the Center for Devices and Radiological Health (CDRH) of the Food and Drug Administration (FDA) as a high-level disinfectant for disinfecting heat-sensitive medical equipment in hospitals and healthcare facilities. Inhalation exposure to GA is known to cause respiratory irritation and sensitization in animals and humans. To reproduce some of the known in vivo effects elicited by GA, we used a liquid aerosol exposure system and evaluated the tissue responses in a human in vitro airway epithelial tissue model. The cultures were treated at the air interface with various concentrations of GA aerosols on five consecutive days and changes in tissue function and structure were evaluated at select timepoints during the treatment phase and after a 7-day recovery period. Exposure to GA aerosols caused oxidative stress, inhibition of ciliary beating frequency, aberrant mucin production, and disturbance of cytokine and matrix metalloproteinase secretion, as well as morphological transformation. Some effects, such as those on goblet cells and ciliated cells, persisted following the 7-day recovery period. Of note, the functional and structural disturbances observed in GA-treated cultures resemble those found in ortho-phthaldehyde (OPA)-treated cultures. Furthermore, our in vitro findings on GA toxicity partially and qualitatively mimicked those reported in the animal and human survey studies. Taken together, observations from this study demonstrate that the human air-liquid-interface (ALI) airway tissue model, integrated with an in vitro exposure system that simulates human inhalation exposure, could be used for in vitro-based human hazard identification and the risk characterization of aerosolized chemicals.

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Section: Discussionsupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

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Subacute Pulmonary Toxicity of Glutaraldehyde Aerosols in a Human In Vitro Airway Tissue Model

Wang

Ren

et al. 2022

IJMS

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“…In the FDA’s recommendations, various in vitro samples were declared as qualified alternative methods that incorporate the 3Rs, such as but not limited to organs-on-a-chip. For example, lung microphysiological systems were used to evaluate the toxicity induced by subacute exposures to formaldehyde fumes at different concentrations . In another example, liver microphysiological systems were used to study drugs with high liver toxicity to demonstrate effectiveness and to suggest reduced risk .…”

Section: Introductionmentioning

confidence: 99%

Quantification of Irinotecan in Single Spheroids Using Internal Standards by MALDI Mass Spectrometry Imaging

Wang

Hummon

2023

Anal. Chem.

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Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has been used to visualize molecular distributions in various biological samples. While it has succeeded in localizing molecules ranging from metabolites to peptides, quantitative MSI (qMSI) has remained challenging, especially in small biological samples like spheroids. Spheroids are a three-dimensional cellular model system that replicate the chemical microenvironments of tumors. This cellular model has played an important role in evaluating the penetration of drugs to better understand the efficacy of clinical chemotherapy. Therefore, we aim to optimize a method to quantify the distribution of therapeutics in a single spheroid using MALDI-MSI. Studies were performed with the therapeutic irinotecan (IR). The calibration curve showed a linear relationship with a limit of detection (LOD) of 0.058 ng/mm2 and R 2 value at 0.9643. Spheroids treated with IR for different lengths of time were imaged using the optimized method to quantify the drug concentration during the penetration process. With a dosing concentration of 20.6 μM, the concentration of IR at 48 h of treatment was 16.90 μM within a single spheroid. Furthermore, spheroids were divided into different layers by spatial segmentation to be quantified separately. This MALDI-qMSI method is amenable to a wide range of drugs as well as their metabolites. The quantification results show great potential to extend this method to other small biological samples such as organoids for patient derived therapies.

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“…Formaldehyde (FA), with the chemical formula CH 2 O, is a colorless, strongly irritating gas that is widely found in nature, industrial production and consumer products [7,8]. FA is classi ed as a Group 1 carcinogen by International Agency for Research on Cancer (IARC) and a known carcinogen by NTP [9,10]. It has been reported that long-term exposure to FA exceeding the national standard concentration has a variety of toxic effects on the nasopharynx, lung, brain, skin, as well as on the hematopoietic organs bone marrow (BM) and spleen [11], even leading to cancer [12,13].…”

Section: Introductionmentioning

confidence: 99%

Formaldehyde-induced toxicity causes senescence and apoptosis in BMSCs via PI3K/P53 signaling pathways

She

Yang

Zhu

et al. 2023

Preprint

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Background Formaldehyde (FA) has been classified as a human carcinogen by the International Agency for Research on Cancer (IARC) and has toxic effects on various tissues and cells. It is reported that FA can accelerate cellular senescence in mice HT22 cells and induce the apoptosis of BALB/c mice BMSCs. Our previous study has confirmed that FA has genotoxic effects on BMSCs by the formation of DNA-protein crosslinks (DPC), sister chromatid exchange (SCE) and micronucleus (MN). However, whether FA causes apoptosis and senescence effects on human BMSCs has not been fully investigated. The aim of this study is to explore the toxic effects and mechanisms of FA on BMSCs based on senescence and apoptosis. Method In this study, Human BMSCs were cultured in vitro and randomly divided into a blank group, a control group and five groups of cells treated with different concentrations (60, 90, 120, 150 and 180 umol/L) of FA. And the cell groups were cultured for 6, 12 and 24 hours. The effect of different concentrations of FA on the viability of human BMSCs was investigated using the MTT assay. Based on the results of MTT assay, we selected the cell group with 120 µmol/L FA for 24 hours for the following experiments. Changes of FA on the morphology of BMSCs were analyzed using the phase-contrast microscope and phalloidin/hoechst33258 staining. We performed bioinformatic analysis on the RNA-Seq data, including differential expression analysis, GO and KEGG analysis in order to further understand the mechanisms of toxicity of FA on BMSCs. The changes in the mRNA and protein expression levels of PIK3CA, Caspase3, Bcl2, P53 and P21 of BMSCs following exposure to FA were detected using qRT-PCR and western blotting. Result When FA concentration reached 90 umol/L, the inhibition of proliferation activity of human BMSCs began to appear, and increased with the increase of FA concentration and time. By morphological detection, we observed that BMSCs treated with 120 µmol/L FA became smaller and rounder, of which the cytoskeleton was disordered and the nuclei were pyknotic, dense stained and fragmented, even with apoptotic bodies formed. The results of the bioinformatics analysis showed that 249 differentially expressed mRNAs (DE mRNAs) were identified in the RNA-seq samples, which included 158 upregulated and 91 downregulated mRNAs. And functional enrichment analysis revealed the pathway of accumulation to cellular senescence and apoptosis. Further assays were performed on factors of the PI3K/P53 pathway, which was a pathway related to senescence and apoptosis. The mRNA and protein expression levels of Caspase3, P53 and P21 in the 120 µmol/L FA-treated group were significantly higher than those in the control group, while the mRNA expression levels of PIK3CA and Bcl2 were significantly lower than those in the control group. Treatment with 120 µmol/L FA reduced the protein expression levels of PIK3CA. Conclusion FA had toxic effects on human BMSCs and the mechanism might be related to the regulation of PI3K/P53 signaling pathway to promote cellular senescence and apoptosis.

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Evaluating the Sub-Acute Toxicity of Formaldehyde Fumes in an In Vitro Human Airway Epithelial Tissue Model

Cited by 13 publications

References 58 publications

Subacute Pulmonary Toxicity of Glutaraldehyde Aerosols in a Human In Vitro Airway Tissue Model

Subacute Pulmonary Toxicity of Glutaraldehyde Aerosols in a Human In Vitro Airway Tissue Model

Quantification of Irinotecan in Single Spheroids Using Internal Standards by MALDI Mass Spectrometry Imaging

Formaldehyde-induced toxicity causes senescence and apoptosis in BMSCs via PI3K/P53 signaling pathways

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