title: Combinations of physiologic estrogens with xenoestrogens alter ERK phosphorylation profiles in rat pituitary cells.
abstract: BACKGROUND
  Estrogens are potent nongenomic phospho-activators of extracellular-signal-regulated kinases (ERKs). A major concern about the toxicity of xenoestrogens (XEs) is potential alteration of responses to physiologic estrogens when XEs are present simultaneously.
  
  
  OBJECTIVE
  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).
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555-0645, USA.
authors.forename: Yow-Jiun
authors.initials: YJ
authors.lastname: Jeng
authors.forename: Cheryl S
authors.initials: CS
authors.lastname: Watson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D052244:Endocrine Disruptors / Q000633:toxicity; D004785:Environmental Pollutants / Q000633:toxicity*; D004967:Estrogens / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D010636:Phenols / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D010902:Pituitary Gland / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D004967:Estrogens; D010636:Phenols; D011960:Receptors, Estrogen; D048049:Extracellular Signal-Regulated MAP Kinases