Genome-Wide Transcriptional Responses to Acrolein

Colin Thompson, Philip Burcham

    Research output: Contribution to journalArticle

    52 Citations (Scopus)

    Abstract

    The lipid peroxidation product and environmental pollutant acrolein participates in many diseases. Because of its formation during tobacco combustion, its role in various smoking-related respiratory conditions including lung cancer has received increasing attention. As a reactive electrophile, acrolein seems likely to disrupt many biochemical pathways, but these are poorly characterized on a genome-wide basis. This study used microarrays to study short-term transcriptional responses of A549 human lung cells to acrolein, with cells exposed to 100 mu M acrolein for 1, 2, or 4 h prior to RNA extraction and transcription profiling. Major pathways dysregulated by acrolein included those involved in apoptosis, cell cycle control, transcription, cell signaling, and protein biosynthesis. Although HMOX1 is a widely used marker of transcriptional responses to acrolein, this gene was the sole upregulated member of the Nrf2-driven family of antioxidant response genes. Transcript levels of several members of the metallothionein class of cytoprotective metal-chelating proteins decreased strongly in response to acrolein. Other novel findings included strong and persistent upregulation of several members of the early growth response (EGR) class of zinc finger transcription factors. Real-time PCR and Western blotting confirmed strong upregulation of a key member of this family (EGR-2), the DNA damage response gene GADD45 beta, the heat shock response participant Hsp70, and also HMOX1. Consistent with changes in Nur77 mRNA levels during the microarray study, Western blotting confirmed strong Nur77 induction at the protein level, raising the possibility that this death-inducing protein contributes to the loss of cell viability during acrolein exposure. Collectively, the transcriptional response to acrolein is complex and dynamic, with future work needed to determine whether acrolein-responsive genes identified in this study contribute to cell and tissue injury in the smoke-exposed lung.
    Original languageEnglish
    Pages (from-to)2245-2256
    JournalChemical Research in Toxicology
    Volume21
    Issue number12
    DOIs
    Publication statusPublished - 2008

    Fingerprint

    Acrolein
    Genes
    Genome
    Transcription
    Microarrays
    Proteins
    Up-Regulation
    Western Blotting
    Cells
    Cell signaling
    Heat-Shock Response
    Environmental Pollutants
    Lung
    Tobacco
    Metallothionein
    Biosynthesis
    Zinc Fingers
    Protein Biosynthesis
    Growth
    Chelation

    Cite this

    @article{310ae20979f94dcf8164f4776bba94ed,
    title = "Genome-Wide Transcriptional Responses to Acrolein",
    abstract = "The lipid peroxidation product and environmental pollutant acrolein participates in many diseases. Because of its formation during tobacco combustion, its role in various smoking-related respiratory conditions including lung cancer has received increasing attention. As a reactive electrophile, acrolein seems likely to disrupt many biochemical pathways, but these are poorly characterized on a genome-wide basis. This study used microarrays to study short-term transcriptional responses of A549 human lung cells to acrolein, with cells exposed to 100 mu M acrolein for 1, 2, or 4 h prior to RNA extraction and transcription profiling. Major pathways dysregulated by acrolein included those involved in apoptosis, cell cycle control, transcription, cell signaling, and protein biosynthesis. Although HMOX1 is a widely used marker of transcriptional responses to acrolein, this gene was the sole upregulated member of the Nrf2-driven family of antioxidant response genes. Transcript levels of several members of the metallothionein class of cytoprotective metal-chelating proteins decreased strongly in response to acrolein. Other novel findings included strong and persistent upregulation of several members of the early growth response (EGR) class of zinc finger transcription factors. Real-time PCR and Western blotting confirmed strong upregulation of a key member of this family (EGR-2), the DNA damage response gene GADD45 beta, the heat shock response participant Hsp70, and also HMOX1. Consistent with changes in Nur77 mRNA levels during the microarray study, Western blotting confirmed strong Nur77 induction at the protein level, raising the possibility that this death-inducing protein contributes to the loss of cell viability during acrolein exposure. Collectively, the transcriptional response to acrolein is complex and dynamic, with future work needed to determine whether acrolein-responsive genes identified in this study contribute to cell and tissue injury in the smoke-exposed lung.",
    author = "Colin Thompson and Philip Burcham",
    year = "2008",
    doi = "10.1021/tx8001934",
    language = "English",
    volume = "21",
    pages = "2245--2256",
    journal = "Chemical Research in Toxicology",
    issn = "0893-228X",
    publisher = "American Chemical Society",
    number = "12",

    }

    Genome-Wide Transcriptional Responses to Acrolein. / Thompson, Colin; Burcham, Philip.

    In: Chemical Research in Toxicology, Vol. 21, No. 12, 2008, p. 2245-2256.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Genome-Wide Transcriptional Responses to Acrolein

    AU - Thompson, Colin

    AU - Burcham, Philip

    PY - 2008

    Y1 - 2008

    N2 - The lipid peroxidation product and environmental pollutant acrolein participates in many diseases. Because of its formation during tobacco combustion, its role in various smoking-related respiratory conditions including lung cancer has received increasing attention. As a reactive electrophile, acrolein seems likely to disrupt many biochemical pathways, but these are poorly characterized on a genome-wide basis. This study used microarrays to study short-term transcriptional responses of A549 human lung cells to acrolein, with cells exposed to 100 mu M acrolein for 1, 2, or 4 h prior to RNA extraction and transcription profiling. Major pathways dysregulated by acrolein included those involved in apoptosis, cell cycle control, transcription, cell signaling, and protein biosynthesis. Although HMOX1 is a widely used marker of transcriptional responses to acrolein, this gene was the sole upregulated member of the Nrf2-driven family of antioxidant response genes. Transcript levels of several members of the metallothionein class of cytoprotective metal-chelating proteins decreased strongly in response to acrolein. Other novel findings included strong and persistent upregulation of several members of the early growth response (EGR) class of zinc finger transcription factors. Real-time PCR and Western blotting confirmed strong upregulation of a key member of this family (EGR-2), the DNA damage response gene GADD45 beta, the heat shock response participant Hsp70, and also HMOX1. Consistent with changes in Nur77 mRNA levels during the microarray study, Western blotting confirmed strong Nur77 induction at the protein level, raising the possibility that this death-inducing protein contributes to the loss of cell viability during acrolein exposure. Collectively, the transcriptional response to acrolein is complex and dynamic, with future work needed to determine whether acrolein-responsive genes identified in this study contribute to cell and tissue injury in the smoke-exposed lung.

    AB - The lipid peroxidation product and environmental pollutant acrolein participates in many diseases. Because of its formation during tobacco combustion, its role in various smoking-related respiratory conditions including lung cancer has received increasing attention. As a reactive electrophile, acrolein seems likely to disrupt many biochemical pathways, but these are poorly characterized on a genome-wide basis. This study used microarrays to study short-term transcriptional responses of A549 human lung cells to acrolein, with cells exposed to 100 mu M acrolein for 1, 2, or 4 h prior to RNA extraction and transcription profiling. Major pathways dysregulated by acrolein included those involved in apoptosis, cell cycle control, transcription, cell signaling, and protein biosynthesis. Although HMOX1 is a widely used marker of transcriptional responses to acrolein, this gene was the sole upregulated member of the Nrf2-driven family of antioxidant response genes. Transcript levels of several members of the metallothionein class of cytoprotective metal-chelating proteins decreased strongly in response to acrolein. Other novel findings included strong and persistent upregulation of several members of the early growth response (EGR) class of zinc finger transcription factors. Real-time PCR and Western blotting confirmed strong upregulation of a key member of this family (EGR-2), the DNA damage response gene GADD45 beta, the heat shock response participant Hsp70, and also HMOX1. Consistent with changes in Nur77 mRNA levels during the microarray study, Western blotting confirmed strong Nur77 induction at the protein level, raising the possibility that this death-inducing protein contributes to the loss of cell viability during acrolein exposure. Collectively, the transcriptional response to acrolein is complex and dynamic, with future work needed to determine whether acrolein-responsive genes identified in this study contribute to cell and tissue injury in the smoke-exposed lung.

    U2 - 10.1021/tx8001934

    DO - 10.1021/tx8001934

    M3 - Article

    VL - 21

    SP - 2245

    EP - 2256

    JO - Chemical Research in Toxicology

    JF - Chemical Research in Toxicology

    SN - 0893-228X

    IS - 12

    ER -