Bisphenol S disrupts estradiol-induced nongenomic signaling in a rat pituitary cell line: Effects on cell functions

René Viñas, Cheryl S. Watson

    Research output: Contribution to journalArticle

    116 Citations (Scopus)

    Abstract

    Background: Bisphenol A (BPA) is a well-known endocrine disruptor that imperfectly mimics the effects of physiologic estrogens via membrane-bound estrogen receptors (mERα, mERβ, and GPER/GPR30), thereby initiating nongenomic signaling. Bisphenol S (BPS) is an alternative to BPA in plastic consumer products and thermal paper. Objective: To characterize the nongenomic activities of BPS, we examined signaling pathways it evoked in GH3/B6/F10 rat pituitary cells alone and together with the physiologic estrogen estradiol (E2). Extracellular signal-regulated kinase (ERK)- and c-Jun-N-terminal kinase (JNK)-specific phosphorylations were examined for their correlation to three functional responses: proliferation, caspase activation, and prolactin (PRL) release. Methods: We detected ERK and JNK phosphorylations by fixed-cell immunoassays, identified the predominant mER initiating the signaling with selective inhibitors, estimated cell numbers by crystal violet assays, measured caspase activity by cleavage of fluorescent caspase substrates, and measured PRL release by radioimmunoassay. Results: BPS phosphoactivated ERK within 2.5 min in a nonmonotonic dose-dependent manner (10-15 to 10-7 M). When combined with 10-9 M E2, the physiologic estrogen's ERK response was attenuated. BPS could not activate JNK, but it greatly enhanced E2-induced JNK activity. BPS induced cell proliferation at low concentrations (femtomolar to nanomolar), similar to E2. Combinations of both estrogens reduced cell numbers below those of the vehicle control and also activated caspases. Earlier activation of caspase 8 versus caspase 9 demonstrated that BPS initiates apoptosis via the extrinsic pathway, consistent with activation via a membrane receptor. BPS also inhibited rapid (≤ 1 min) E2-induced PRL release. Conclusion: BPS, once considered a safe substitute for BPA, disrupts membrane-initiated E2-induced cell signaling, leading to altered cell proliferation, cell death, and PRL release.

    Original languageEnglish (US)
    Pages (from-to)352-358
    Number of pages7
    JournalEnvironmental Health Perspectives
    Volume121
    Issue number3
    DOIs
    StatePublished - 2013

    Fingerprint

    Estradiol
    Cell Line
    JNK Mitogen-Activated Protein Kinases
    Extracellular Signal-Regulated MAP Kinases
    Caspases
    Prolactin
    Estrogens
    Membranes
    Cell Count
    Phosphorylation
    Cell Proliferation
    Gentian Violet
    Endocrine Disruptors
    bis(4-hydroxyphenyl)sulfone
    Caspase 9
    Caspase 8
    Immunoassay
    Estrogen Receptors
    Plastics
    Radioimmunoassay

    Keywords

    • Bisphenol S
    • ERα
    • ERK activation
    • JNK activation
    • Membrane estrogen receptors
    • Nongenomic effects
    • Prolactinoma cell line
    • Xenoestrogens

    ASJC Scopus subject areas

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

    Cite this

    Bisphenol S disrupts estradiol-induced nongenomic signaling in a rat pituitary cell line : Effects on cell functions. / Viñas, René; Watson, Cheryl S.

    In: Environmental Health Perspectives, Vol. 121, No. 3, 2013, p. 352-358.

    Research output: Contribution to journalArticle

    @article{4841a45c977849a19287011dda06486f,
    title = "Bisphenol S disrupts estradiol-induced nongenomic signaling in a rat pituitary cell line: Effects on cell functions",
    abstract = "Background: Bisphenol A (BPA) is a well-known endocrine disruptor that imperfectly mimics the effects of physiologic estrogens via membrane-bound estrogen receptors (mERα, mERβ, and GPER/GPR30), thereby initiating nongenomic signaling. Bisphenol S (BPS) is an alternative to BPA in plastic consumer products and thermal paper. Objective: To characterize the nongenomic activities of BPS, we examined signaling pathways it evoked in GH3/B6/F10 rat pituitary cells alone and together with the physiologic estrogen estradiol (E2). Extracellular signal-regulated kinase (ERK)- and c-Jun-N-terminal kinase (JNK)-specific phosphorylations were examined for their correlation to three functional responses: proliferation, caspase activation, and prolactin (PRL) release. Methods: We detected ERK and JNK phosphorylations by fixed-cell immunoassays, identified the predominant mER initiating the signaling with selective inhibitors, estimated cell numbers by crystal violet assays, measured caspase activity by cleavage of fluorescent caspase substrates, and measured PRL release by radioimmunoassay. Results: BPS phosphoactivated ERK within 2.5 min in a nonmonotonic dose-dependent manner (10-15 to 10-7 M). When combined with 10-9 M E2, the physiologic estrogen's ERK response was attenuated. BPS could not activate JNK, but it greatly enhanced E2-induced JNK activity. BPS induced cell proliferation at low concentrations (femtomolar to nanomolar), similar to E2. Combinations of both estrogens reduced cell numbers below those of the vehicle control and also activated caspases. Earlier activation of caspase 8 versus caspase 9 demonstrated that BPS initiates apoptosis via the extrinsic pathway, consistent with activation via a membrane receptor. BPS also inhibited rapid (≤ 1 min) E2-induced PRL release. Conclusion: BPS, once considered a safe substitute for BPA, disrupts membrane-initiated E2-induced cell signaling, leading to altered cell proliferation, cell death, and PRL release.",
    keywords = "Bisphenol S, ERα, ERK activation, JNK activation, Membrane estrogen receptors, Nongenomic effects, Prolactinoma cell line, Xenoestrogens",
    author = "Ren{\'e} Vi{\~n}as and Watson, {Cheryl S.}",
    year = "2013",
    doi = "10.1289/ehp.1205826",
    language = "English (US)",
    volume = "121",
    pages = "352--358",
    journal = "Environmental Health Perspectives",
    issn = "0091-6765",
    publisher = "Public Health Services, US Dept of Health and Human Services",
    number = "3",

    }

    TY - JOUR

    T1 - Bisphenol S disrupts estradiol-induced nongenomic signaling in a rat pituitary cell line

    T2 - Effects on cell functions

    AU - Viñas, René

    AU - Watson, Cheryl S.

    PY - 2013

    Y1 - 2013

    N2 - Background: Bisphenol A (BPA) is a well-known endocrine disruptor that imperfectly mimics the effects of physiologic estrogens via membrane-bound estrogen receptors (mERα, mERβ, and GPER/GPR30), thereby initiating nongenomic signaling. Bisphenol S (BPS) is an alternative to BPA in plastic consumer products and thermal paper. Objective: To characterize the nongenomic activities of BPS, we examined signaling pathways it evoked in GH3/B6/F10 rat pituitary cells alone and together with the physiologic estrogen estradiol (E2). Extracellular signal-regulated kinase (ERK)- and c-Jun-N-terminal kinase (JNK)-specific phosphorylations were examined for their correlation to three functional responses: proliferation, caspase activation, and prolactin (PRL) release. Methods: We detected ERK and JNK phosphorylations by fixed-cell immunoassays, identified the predominant mER initiating the signaling with selective inhibitors, estimated cell numbers by crystal violet assays, measured caspase activity by cleavage of fluorescent caspase substrates, and measured PRL release by radioimmunoassay. Results: BPS phosphoactivated ERK within 2.5 min in a nonmonotonic dose-dependent manner (10-15 to 10-7 M). When combined with 10-9 M E2, the physiologic estrogen's ERK response was attenuated. BPS could not activate JNK, but it greatly enhanced E2-induced JNK activity. BPS induced cell proliferation at low concentrations (femtomolar to nanomolar), similar to E2. Combinations of both estrogens reduced cell numbers below those of the vehicle control and also activated caspases. Earlier activation of caspase 8 versus caspase 9 demonstrated that BPS initiates apoptosis via the extrinsic pathway, consistent with activation via a membrane receptor. BPS also inhibited rapid (≤ 1 min) E2-induced PRL release. Conclusion: BPS, once considered a safe substitute for BPA, disrupts membrane-initiated E2-induced cell signaling, leading to altered cell proliferation, cell death, and PRL release.

    AB - Background: Bisphenol A (BPA) is a well-known endocrine disruptor that imperfectly mimics the effects of physiologic estrogens via membrane-bound estrogen receptors (mERα, mERβ, and GPER/GPR30), thereby initiating nongenomic signaling. Bisphenol S (BPS) is an alternative to BPA in plastic consumer products and thermal paper. Objective: To characterize the nongenomic activities of BPS, we examined signaling pathways it evoked in GH3/B6/F10 rat pituitary cells alone and together with the physiologic estrogen estradiol (E2). Extracellular signal-regulated kinase (ERK)- and c-Jun-N-terminal kinase (JNK)-specific phosphorylations were examined for their correlation to three functional responses: proliferation, caspase activation, and prolactin (PRL) release. Methods: We detected ERK and JNK phosphorylations by fixed-cell immunoassays, identified the predominant mER initiating the signaling with selective inhibitors, estimated cell numbers by crystal violet assays, measured caspase activity by cleavage of fluorescent caspase substrates, and measured PRL release by radioimmunoassay. Results: BPS phosphoactivated ERK within 2.5 min in a nonmonotonic dose-dependent manner (10-15 to 10-7 M). When combined with 10-9 M E2, the physiologic estrogen's ERK response was attenuated. BPS could not activate JNK, but it greatly enhanced E2-induced JNK activity. BPS induced cell proliferation at low concentrations (femtomolar to nanomolar), similar to E2. Combinations of both estrogens reduced cell numbers below those of the vehicle control and also activated caspases. Earlier activation of caspase 8 versus caspase 9 demonstrated that BPS initiates apoptosis via the extrinsic pathway, consistent with activation via a membrane receptor. BPS also inhibited rapid (≤ 1 min) E2-induced PRL release. Conclusion: BPS, once considered a safe substitute for BPA, disrupts membrane-initiated E2-induced cell signaling, leading to altered cell proliferation, cell death, and PRL release.

    KW - Bisphenol S

    KW - ERα

    KW - ERK activation

    KW - JNK activation

    KW - Membrane estrogen receptors

    KW - Nongenomic effects

    KW - Prolactinoma cell line

    KW - Xenoestrogens

    UR - http://www.scopus.com/inward/record.url?scp=84874624091&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84874624091&partnerID=8YFLogxK

    U2 - 10.1289/ehp.1205826

    DO - 10.1289/ehp.1205826

    M3 - Article

    C2 - 23458715

    AN - SCOPUS:84874624091

    VL - 121

    SP - 352

    EP - 358

    JO - Environmental Health Perspectives

    JF - Environmental Health Perspectives

    SN - 0091-6765

    IS - 3

    ER -