Alkylphenol xenoestrogens with varying carbon chain lengths differentially and potently activate signaling and functional responses in GH3/B6/F10 somatomammotropes

Mikhail Y. Kochukov, Yow Jiun Jeng, Cheryl S. Watson

    Research output: Contribution to journalArticle

    61 Citations (Scopus)

    Abstract

    Background: Alkylphenols varying in their side-chain lengths [ethyl-, propyl-, octyl-, and nonylphenol (EP, PP, OP, and NP, respectively)] and bisphenol A (BPA) represent a large group of structurally related xenoestrogens that have endocrine-disruptive effects. Their rapid nongenomic effects that depend on structure for cell signaling and resulting functions are unknown. Objectives: We compared nongenomic estrogenic activities of alkylphenols with BPA and 17β-estradiol (E2) in membrane estrogen receptor-α-enriched GH3/B6/F10 pituitary tumor cells. These actions included calcium (Ca) signaling, prolactin (PRL) release, extracellular-regulated kinase (ERK) phosphorylation, and cell proliferation. Methods: We imaged Ca using fura-2, measured PRL release via radioimmunoassay, detected ERK phosphorylation by fixed cell immunoassay, and estimated cell number using the crystal violet assay. Results: All compounds caused increases in Ca oscillation frequency and intracellular Ca volume at 100 fM to 1 nM concentrations, although long-chain alkylphenols were most effective. All estrogens caused rapid PRL release at concentrations as low as 1 fM to 10 pM; the potency of EP, PP, and NP exceeded that of E2. All compounds at 1 nM produced similar increases in ERK phosphorylation, causing rapid peaks at 2.5-5 min, followed by inactivation and additional 60-min peaks (except for BPA). Dose-response patterns of ERK activation at 5 min were similar for E2, BPA, and PP, whereas EP caused larger effects. Only E2 and NP increased cell number. Some rapid estrogenic responses showed correlations with the hydrophobicity of estrogenic molecules; the more hydrophobic OP and NP were superior at Ca and cell proliferation responses, whereas the less hydrophobic EP and PP were better at ERK activations. Conclusions: Alkylphenols are potent estrogens in evoking these nongenomic responses contributing to complex functions; their hydrophobicity can largely predict these behaviors.

    Original languageEnglish (US)
    Pages (from-to)723-730
    Number of pages8
    JournalEnvironmental Health Perspectives
    Volume117
    Issue number5
    DOIs
    StatePublished - 2009

    Fingerprint

    Phosphotransferases
    Carbon
    Prolactin
    Calcium Signaling
    Phosphorylation
    Calcium
    Hydrophobic and Hydrophilic Interactions
    Estrogens
    Cell Count
    Cell Proliferation
    Gentian Violet
    Fura-2
    Pituitary Neoplasms
    Immunoassay
    Estrogen Receptors
    Radioimmunoassay
    Estradiol
    Membranes
    bisphenol A

    Keywords

    • Bisphenol A
    • Calcium oscillation
    • ERK activation
    • Estradiol
    • Hydrophobicity
    • Non-genomic response
    • Prolactin release

    ASJC Scopus subject areas

    • Health, Toxicology and Mutagenesis
    • Public Health, Environmental and Occupational Health

    Cite this

    Alkylphenol xenoestrogens with varying carbon chain lengths differentially and potently activate signaling and functional responses in GH3/B6/F10 somatomammotropes. / Kochukov, Mikhail Y.; Jeng, Yow Jiun; Watson, Cheryl S.

    In: Environmental Health Perspectives, Vol. 117, No. 5, 2009, p. 723-730.

    Research output: Contribution to journalArticle

    @article{ffba4d97f8574d45b017fc001dacfc93,
    title = "Alkylphenol xenoestrogens with varying carbon chain lengths differentially and potently activate signaling and functional responses in GH3/B6/F10 somatomammotropes",
    abstract = "Background: Alkylphenols varying in their side-chain lengths [ethyl-, propyl-, octyl-, and nonylphenol (EP, PP, OP, and NP, respectively)] and bisphenol A (BPA) represent a large group of structurally related xenoestrogens that have endocrine-disruptive effects. Their rapid nongenomic effects that depend on structure for cell signaling and resulting functions are unknown. Objectives: We compared nongenomic estrogenic activities of alkylphenols with BPA and 17β-estradiol (E2) in membrane estrogen receptor-α-enriched GH3/B6/F10 pituitary tumor cells. These actions included calcium (Ca) signaling, prolactin (PRL) release, extracellular-regulated kinase (ERK) phosphorylation, and cell proliferation. Methods: We imaged Ca using fura-2, measured PRL release via radioimmunoassay, detected ERK phosphorylation by fixed cell immunoassay, and estimated cell number using the crystal violet assay. Results: All compounds caused increases in Ca oscillation frequency and intracellular Ca volume at 100 fM to 1 nM concentrations, although long-chain alkylphenols were most effective. All estrogens caused rapid PRL release at concentrations as low as 1 fM to 10 pM; the potency of EP, PP, and NP exceeded that of E2. All compounds at 1 nM produced similar increases in ERK phosphorylation, causing rapid peaks at 2.5-5 min, followed by inactivation and additional 60-min peaks (except for BPA). Dose-response patterns of ERK activation at 5 min were similar for E2, BPA, and PP, whereas EP caused larger effects. Only E2 and NP increased cell number. Some rapid estrogenic responses showed correlations with the hydrophobicity of estrogenic molecules; the more hydrophobic OP and NP were superior at Ca and cell proliferation responses, whereas the less hydrophobic EP and PP were better at ERK activations. Conclusions: Alkylphenols are potent estrogens in evoking these nongenomic responses contributing to complex functions; their hydrophobicity can largely predict these behaviors.",
    keywords = "Bisphenol A, Calcium oscillation, ERK activation, Estradiol, Hydrophobicity, Non-genomic response, Prolactin release",
    author = "Kochukov, {Mikhail Y.} and Jeng, {Yow Jiun} and Watson, {Cheryl S.}",
    year = "2009",
    doi = "10.1289/ehp.0800182",
    language = "English (US)",
    volume = "117",
    pages = "723--730",
    journal = "Environmental Health Perspectives",
    issn = "0091-6765",
    publisher = "Public Health Services, US Dept of Health and Human Services",
    number = "5",

    }

    TY - JOUR

    T1 - Alkylphenol xenoestrogens with varying carbon chain lengths differentially and potently activate signaling and functional responses in GH3/B6/F10 somatomammotropes

    AU - Kochukov, Mikhail Y.

    AU - Jeng, Yow Jiun

    AU - Watson, Cheryl S.

    PY - 2009

    Y1 - 2009

    N2 - Background: Alkylphenols varying in their side-chain lengths [ethyl-, propyl-, octyl-, and nonylphenol (EP, PP, OP, and NP, respectively)] and bisphenol A (BPA) represent a large group of structurally related xenoestrogens that have endocrine-disruptive effects. Their rapid nongenomic effects that depend on structure for cell signaling and resulting functions are unknown. Objectives: We compared nongenomic estrogenic activities of alkylphenols with BPA and 17β-estradiol (E2) in membrane estrogen receptor-α-enriched GH3/B6/F10 pituitary tumor cells. These actions included calcium (Ca) signaling, prolactin (PRL) release, extracellular-regulated kinase (ERK) phosphorylation, and cell proliferation. Methods: We imaged Ca using fura-2, measured PRL release via radioimmunoassay, detected ERK phosphorylation by fixed cell immunoassay, and estimated cell number using the crystal violet assay. Results: All compounds caused increases in Ca oscillation frequency and intracellular Ca volume at 100 fM to 1 nM concentrations, although long-chain alkylphenols were most effective. All estrogens caused rapid PRL release at concentrations as low as 1 fM to 10 pM; the potency of EP, PP, and NP exceeded that of E2. All compounds at 1 nM produced similar increases in ERK phosphorylation, causing rapid peaks at 2.5-5 min, followed by inactivation and additional 60-min peaks (except for BPA). Dose-response patterns of ERK activation at 5 min were similar for E2, BPA, and PP, whereas EP caused larger effects. Only E2 and NP increased cell number. Some rapid estrogenic responses showed correlations with the hydrophobicity of estrogenic molecules; the more hydrophobic OP and NP were superior at Ca and cell proliferation responses, whereas the less hydrophobic EP and PP were better at ERK activations. Conclusions: Alkylphenols are potent estrogens in evoking these nongenomic responses contributing to complex functions; their hydrophobicity can largely predict these behaviors.

    AB - Background: Alkylphenols varying in their side-chain lengths [ethyl-, propyl-, octyl-, and nonylphenol (EP, PP, OP, and NP, respectively)] and bisphenol A (BPA) represent a large group of structurally related xenoestrogens that have endocrine-disruptive effects. Their rapid nongenomic effects that depend on structure for cell signaling and resulting functions are unknown. Objectives: We compared nongenomic estrogenic activities of alkylphenols with BPA and 17β-estradiol (E2) in membrane estrogen receptor-α-enriched GH3/B6/F10 pituitary tumor cells. These actions included calcium (Ca) signaling, prolactin (PRL) release, extracellular-regulated kinase (ERK) phosphorylation, and cell proliferation. Methods: We imaged Ca using fura-2, measured PRL release via radioimmunoassay, detected ERK phosphorylation by fixed cell immunoassay, and estimated cell number using the crystal violet assay. Results: All compounds caused increases in Ca oscillation frequency and intracellular Ca volume at 100 fM to 1 nM concentrations, although long-chain alkylphenols were most effective. All estrogens caused rapid PRL release at concentrations as low as 1 fM to 10 pM; the potency of EP, PP, and NP exceeded that of E2. All compounds at 1 nM produced similar increases in ERK phosphorylation, causing rapid peaks at 2.5-5 min, followed by inactivation and additional 60-min peaks (except for BPA). Dose-response patterns of ERK activation at 5 min were similar for E2, BPA, and PP, whereas EP caused larger effects. Only E2 and NP increased cell number. Some rapid estrogenic responses showed correlations with the hydrophobicity of estrogenic molecules; the more hydrophobic OP and NP were superior at Ca and cell proliferation responses, whereas the less hydrophobic EP and PP were better at ERK activations. Conclusions: Alkylphenols are potent estrogens in evoking these nongenomic responses contributing to complex functions; their hydrophobicity can largely predict these behaviors.

    KW - Bisphenol A

    KW - Calcium oscillation

    KW - ERK activation

    KW - Estradiol

    KW - Hydrophobicity

    KW - Non-genomic response

    KW - Prolactin release

    UR - http://www.scopus.com/inward/record.url?scp=66349127920&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=66349127920&partnerID=8YFLogxK

    U2 - 10.1289/ehp.0800182

    DO - 10.1289/ehp.0800182

    M3 - Article

    C2 - 19479013

    AN - SCOPUS:66349127920

    VL - 117

    SP - 723

    EP - 730

    JO - Environmental Health Perspectives

    JF - Environmental Health Perspectives

    SN - 0091-6765

    IS - 5

    ER -