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

64 Scopus citations

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 - Jun 9 2009

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Keywords

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

ASJC Scopus subject areas

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

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