Stressor: 319

Title

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Acrolein

Stressor Overview

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. More help

AOPs Including This Stressor

This table is automatically generated and lists the AOPs associated with this Stressor. More help

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

This table is automatically generated and lists the Key Events associated with this Stressor. More help

Event Name
Protein Adduct Formation
Cystic Fibrosis Transmembrane Regulator Function, Decreased
Cilia Beat Frequency, Decreased
Activation, EGFR
Occurrence, Hyperplasia of goblet cells
Increase, Proliferation of goblet cells
Increase, Mucin production
Occurrence, Metaplasia of goblet cells

Chemical Table

The Chemical Table lists chemicals associated with a stressor. This table contains information about the User’s term for a chemical, the DTXID, Preferred name, CAS number, JChem InChIKey, and Indigo InChIKey.To add a chemical associated with a particular stressor, next to the Chemical Table click ‘Add chemical.’ This will redirect you to a page entitled “New Stressor Chemical.’ The dialog box can be used to search for chemical by name, CAS number, JChem InChIKey, and Indigo InChIKey. Searching by these fields will bring forward a drop down list of existing stressor chemicals formatted as Preferred name, “CAS- preferred name,” “JChem InChIKey – preferred name,” or “Indigo InChIKey- preferred name,” depending on by which field you perform the search. It may take several moments for the drop down list to display. Select an entity from the drop down list and click ‘Add chemical.’ This will return you to the Stressor Page, where the new record should be in the ‘Chemical Table’ on the page.To remove a chemical associated with a particular stressor, in the Chemical Table next to the chemical you wish to delete, click ‘Remove’ and then click 'OK.' The chemical should no longer be visible in the Chemical table. More help

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

This table is automatically generated and includes the AOPs with this associated stressor as well as the evidence term and evidence text from this AOP Stressor. More help

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

This table is automatically generated and includes the Events with this associated stressor as well as the evidence text from this Event Stressor. More help

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

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

Text sections under this subheading include the Chemical/Category Description and Characterization of Exposure. More help

Chemical/Category Description

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Characterization of Exposure

To edit the “Characterization of Exposure” section, on a Stressor page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.” Scroll down to the “Characterization of Exposure” section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page. The new text should appear under the “Characterization of Exposure” section on the page. More help

References

List of the literature that was cited for this Stressor description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015).To edit the “References” section, on a Stressor page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.” Scroll down to the “References” section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page. The new text should appear under the “References” section on the page. More help

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.