Stressor: 319
Title
Acrolein
Stressor Overview
AOPs Including This Stressor
AOP Name | Evidence |
---|---|
Oxidative stress Leading to Decreased Lung Function | Moderate |
Oxidative stress Leading to Decreased Lung Function via CFTR dysfunction | Moderate |
Events Including This Stressor
Chemical Table
User term | DTXID | Preferred name | Casrn | jchem_inchi_key | indigo_inchi_key |
---|---|---|---|---|---|
Acrolein | DTXSID5020023 | Acrolein | 107-02-8 | HGINCPLSRVDWNT-UHFFFAOYSA-N | HGINCPLSRVDWNT-UHFFFAOYSA-N |
AOP Evidence
Oxidative stress Leading to Decreased Lung Function
Acrolein, a ubiquitous environmental pollutant, is a highly reactive unsaturated aldehyde that exerts toxicity through several mechanism, including oxidative stress (Moghe et al., 2015). Acrolein exposure decreased CFTR-mediated Cl− transport in primary murine nasal septal epithelia, in human bronchial epithelial cells grown in monolayers and in human Calu-3 lung cancer cells (Alexander et al., 2012; Raju et al., 2013), transiently reduced CBF at low concentrations (0.5‒1 mM) and induced ciliostasis at high concentrations (> 1 mM) in rabbit tracheal epithelial cells (Romet et al., 1990), and significantly increased mucin production in rats (Chen et al., 2013; Liu et al., 2009; Borchers et al., 1998; Wang et al., 2009). In addition, exposure of Fischer rats to acrolein caused a left shift in the quasi-static compliance curves and increased lung volumes, indicative of airway obstruction (Costa et al., 1986).
Oxidative stress Leading to Decreased Lung Function via CFTR dysfunction
Acrolein, a ubiquitous environmental pollutant, is a highly reactive unsaturated aldehyde that exerts toxicity through several mechanism, including oxidative stress (Moghe et al., 2015). Acrolein exposure decreased CFTR-mediated Cl− transport in primary murine nasal septal epithelia, in human bronchial epithelial cells grown in monolayers and in human Calu-3 lung cancer cells (Alexander et al., 2012; Raju et al., 2013), transiently reduced CBF at low concentrations (0.5‒1 mM) and induced ciliostasis at high concentrations (> 1 mM) in rabbit tracheal epithelial cells (Romet et al., 1990). In addition, exposure of Fischer rats to acrolein caused a left shift in the quasi-static compliance curves and increased lung volumes, indicative of airway obstruction (Costa et al., 1986).
Event Evidence
Protein Adduct Formation
LoPachin, R. M. & DeCaprio, A. P. Protein adduct formation as a molecular mechanism in neurotoxicity. Toxicological Sciences 86, 214–225 (2005).
Cystic Fibrosis Transmembrane Regulator Function, Decreased
Acrolein exhibited a complex dose-dependent response with respect to CFTR-mediated Cl− transport in primary murine nasal septal epithelia: At 100 µM acrolein, Cl− currents increased, whereas 300 µM acrolein reduced forskolin-induced total apical Cl− secretion and 300 µM acrolein abolished all Cl− transport. These effects were independent of cAMP, suggesting that channel activation was not PKA/cAMP phosphorylation-dependent (Alexander et al., 2012). Acrolein decreased cAMP-mediated CFTR ion transport in human bronchial epithelial cells grown in monolayers and in human Calu-3 lung cancer cells, where the response was dose-dependent. Repeated, low-level exposure of human bronchial epithelial cells to acrolein (2.5 – 10 ng/mL for 7 days) had a similar effect on CFTR function and was shown to be unrelated to modulation of CFTR expression. Pretreatment with the antioxidant N-acetylcysteine could prevent acrolein-induced CFTR inhibition (Raju et al., 2013). Similar effects on CFTR function (as measured by nasal and intestinal transepithelial potential difference) were elicited by subcutaneous administration of 1 mg/kg acrolein for 4 weeks, and these could also be counteracted by co-treatment with NAC (Raju et al., 2013).
Cilia Beat Frequency, Decreased
Acrolein, an aldehyde in the gas phase of cigarette smoke, induced ciliostasis at high concentrations (> 1 mM), after 5 min of treatment, and cellular necrosis after 3 hr. However, at lower concentrations (from 0.5‒1 mM), acrolein transiently reduced the CBF to 4 Hz (Romet et al., 1990).
Activation, EGFR
EGFR activation was seen in human NCI-H292 lung cancer cells following treatment with 0.03 µM acrolein for 1 h (Deshmukh et al., 2005; Deshmukh et al., 2008).
Treatment of human normal oral keratinocytes with 5 µM acrolein for 3 h also increased EGFR phosphorylation (Tsou et al., 2021).
Occurrence, Hyperplasia of goblet cells
Treatment of primary human bronchial epithelial cells differentiated at the air-liquid interface with up to 1 µM acrolein induced a concentration dependent increase in the percentage of MUC5A-positive cells (Haswell et al., 2010).
Increase, Proliferation of goblet cells
Treatment of primary human bronchial epithelial cells differentiated at the air-liquid interface with up to 1 µM acrolein induced a concentration dependent increase in the percentage of MUC5A-positive cells (Haswell et al., 2010).
Exposure of Kunming mice to 4 ppm acrolein (nebulized) for 6 h per day, for up to 21 days caused a significant increase in the area of AB-PAS positive staining in the small airways (Liu et al., 2009).
Increase, Mucin production
Exposure of Sprague-Dawley rats to 3 ppm acrolein for 6 h a day, for 12 days significantly increased lung Muc5ac gene and protein expression (Chen et al., 2013).
Bronchoalveolar lavage fluid mucin content as well as Muc5ac gene and protein expression were significantly increased in the lungs of Sprague-Dawley rats that were exposed to 3 ppm of acrolein for 6 h a day, 7 days a week, for up to 2 weeks (Liu et al., 2009).
Exposure of Sprague Dawley rats to 3 ppm acrolein for 6 h a day, 5 days a week, for up to 12 days significantly increased Muc5ac gene expression in trachea and lung (Borchers et al., 1998).
Exposure of Sprague Dawley rats to 3 ppm acrolein for 3 h a day, 7 days a week, for up to 4 days significantly increased Muc5ac gene and protein expression in the lungs (Wang et al., 2009).
Occurrence, Metaplasia of goblet cells
Exposure of Kunming mice to 4 ppm acrolein (nebulized) for 6 h per day, for up to 21 days caused goblet cell metaplasia and a significant increase in the area of AB-PAS positive staining in the small airways (Liu et al., 2009).
Exposure of Sprague–Dawley rats to 3 ppm acrolein for 3 h a day, 7 days a week, for 2 or 4 weeks caused goblet cell metaplasia and a time-dependent increase in the ratio of AB/PAS-positively staining area to total epithelial area in the airways (Wang et al., 2009).
Stressor Info
Chemical/Category Description
Characterization of Exposure
References
Alexander, N.S., Blount, A., Zhang, S., Skinner, D., Hicks, S.B., Chestnut, M., et al. (2012). Cystic fibrosis transmembrane conductance regulator modulation by the tobacco smoke toxin acrolein. Laryngoscope 122(6), 1193-1197.
Borchers, M.T., Wesselkamper, S., Wert, S.E., Shapiro, S.D., and Leikauf, G.D. (1999). Monocyte inflammation augments acrolein-induced Muc5ac expression in mouse lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 277(3), L489-L497.
Chen, P., Deng, Z., Wang, T., Chen, L., Li, J., Feng, Y., et al. (2013). The potential interaction of MARCKS-related peptide and diltiazem on acrolin-induced airway mucus hypersecretion in rats. Intl. Immunopharmacol. 17(3), 625-632.
Costa, D.L., Kutzman, R.S., Lehmann, J.R., and Drew, R.T. (1986). Altered Lung Function and Structure in the Rat after Subchronic Exposure to Acrolein. Am. Rev. Respir. Dis. 133(2), 286-291.
Liu, D.-S., Wang, T., Han, S.-X., Dong, J.-J., Liao, Z.-L., He, G.-M., et al. (2009). p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog. Intl. Immunopharmacol. 9(10), 1228-1235.
Moghe, A., Ghare, S., Lamoreau, B., Mohammad, M., Barve, S., McClain, C., et al. (2015). Molecular mechanisms of acrolein toxicity: relevance to human disease. Toxicol. Sci. 143(2), 242-255.
Raju, S.V., Jackson, P.L., Courville, C.A., McNicholas, C.M., Sloane, P.A., Sabbatini, G., et al. (2013). Cigarette smoke induces systemic defects in cystic fibrosis transmembrane conductance regulator function. Am. J. Respir. Crit. Care Med. 188(11), 1321-1330.
Romet, S., Dubreuil, A., Baeza, A., Moreau, A., Schoevaert, D., and Marano, F. (1990). Respiratory tract epithelium in primary culture: Effects of ciliotoxic compounds. Toxicol. in vitro 4(4-5), 399-402.
Wang, T., Liu, Y., Chen, L., Wang, X., Hu, X.-R., Feng, Y.-L., et al. (2009). Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats. Eur. Respir. J. 33(5), 1122-1132.