Combinations of physiologic estrogens with xenoestrogens alter ERK phosphorylation profiles in rat pituitary cells

Background: Estrogens are potent non genomic 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. 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 immuno assay, 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. Te 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 non monotonic responses/inhibitions. Te 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 efca-cious an XE, the more it disrupts actions of physiologic estrogens. Tis 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).