Combinations of Physiologic Estrogens with Xenoestrogens Alter ERK Phosphorylation Profiles in Rat Pituitary Cells

Background: Estrogens are potent nongenomic phospho-activators of extracellular-signalregulated kinases (ERKs). A major concern about the toxicity of xenoestrogens (XEs) is potential alteration of responses to physiologic estrogens when XEs are present simultaneously. Objectives: We examined estroge...

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Bibliographic Details
Published in:Environmental health perspectives 2011-01, Vol.119 (1), p.104-112
Main Authors: Jeng, Yow-Jiun, Watson, Cheryl S.
Format: Article
Language:English
Subjects:
Activation
Agonists
Animals
Biological and medical sciences
Bisphenol A
Cell growth
Cell Line, Tumor
Cell lines
Cell Proliferation - drug effects
Dose response relationship
Endocrine Disruptors - toxicity
Environmental aspects
Environmental health
Environmental Pollutants - toxicity
Estrogen
Estrogen receptors
Estrogens
Estrogens - toxicity
Extracellular Signal-Regulated MAP Kinases - metabolism
Genetic aspects
Kinases
Ligands
Medical sciences
Nanostructure
Neurons
Phenols - toxicity
Phosphorylation
Phosphorylation - drug effects
Phosphotransferases
Physiological aspects
Pituitary Gland - drug effects
Pituitary Gland - enzymology
Rats
Receptors
Receptors, Estrogen - metabolism
Signal Transduction - drug effects
Toxicity
Toxicology
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Summary:Background: Estrogens are potent nongenomic phospho-activators of extracellular-signalregulated kinases (ERKs). A major concern about the toxicity of xenoestrogens (XEs) is potential alteration of responses to physiologic estrogens when XEs are present simultaneously. Objectives: We examined estrogen-induced ERK activation, comparing the abilities of structurally related XEs (alkylphenols and bisphenol A) to alter ERK responses induced by physiologic concentrations (1 nM) of estradiol (E₂), estrone (E₁), and estriol (E₃). Methods: We quantified hormone/mimetic-induced ERK phosphorylations in the GH₃/B6/F10 rat pituitary cell line using a plate immunoassay, comparing effects with those on cell proliferation and by estrogen receptor subtype-selective ligands. Results: Alone, these structurally related XEs activate ERKs in an oscillating temporal pattern similar (but not identical) to that with physiologic estrogens. The potency of all estrogens was similar (active between femtomolar and nanomolar concentrations). XEs potently disrupted physiologic estrogen signaling at low, environmentally relevant concentrations. Generally, XEs potentiated (at the lowest, subpicomolar concentrations) and attenuated (at the highest, picomolar to 100 nM concentrations) the actions of the physiologic estrogens. Some XEs showed pronounced nonmonotonic responses/inhibitions. The phosphorylated ERK and proliferative responses to receptor-selective ligands were only partially correlated. Conclusions: XES are both imperfect potent estrogens and endocrine disruptors; the more efficacious an XE, the more it disrupts actions of physiologic estrogens. This ability to disrupt physiologic estrogen signaling suggests that XEs may disturb normal functioning at life stages where actions of particular estrogens are important (e.g., development, reproductive cycling, pregnancy, menopause).
ISSN:0091-6765
1552-9924
DOI:10.1289/ehp.1002512