title: Rapid actions of xenoestrogens disrupt normal estrogenic signaling.
abstract: Some chemicals used in consumer products or manufacturing (e.g. plastics, surfactants, pesticides, resins) have estrogenic activities; these xenoestrogens (XEs) chemically resemble physiological estrogens and are one of the major categories of synthesized compounds that disrupt endocrine actions. Potent rapid actions of XEs via nongenomic mechanisms contribute significantly to their disruptive effects on functional endpoints (e.g. cell proliferation/death, transport, peptide release). Membrane-initiated hormonal signaling in our pituitary cell model is predominantly driven by mERα with mERβ and GPR30 participation. We visualized ERα on plasma membranes using many techniques in the past (impeded ligands, antibodies to ERα) and now add observations of epitope proximity with other membrane signaling proteins. We have demonstrated a range of rapid signals/protein activations by XEs including: calcium channels, cAMP/PKA, MAPKs, G proteins, caspases, and transcription factors. XEs can cause disruptions of the oscillating temporal patterns of nongenomic signaling elicited by endogenous estrogens. Concentration effects of XEs are nonmonotonic (a trait shared with natural hormones), making it difficult to design efficient (single concentration) toxicology tests to monitor their harmful effects. A plastics monomer, bisphenol A, modified by waste treatment (chlorination) and other processes causes dephosphorylation of extracellular-regulated kinases, in contrast to having no effects as it does in genomic signaling. Mixtures of XEs, commonly found in contaminated environments, disrupt the signaling actions of physiological estrogens even more severely than do single XEs. Understanding the features of XEs that drive these disruptive mechanisms will allow us to redesign useful chemicals that exclude estrogenic or anti-estrogenic activities.
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA. Electronic address: cswatson@utmb.edu.
authors.forename: Cheryl S
authors.initials: CS
authors.lastname: Watson
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA. Electronic address: hu.guangzhen@mayo.edu.
authors.forename: Guangzhen
authors.initials: G
authors.lastname: Hu
authors.affiliation: Center for Biomedical Engineering, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA. Electronic address: aapauluc@utmb.edu.
authors.forename: Adriana A
authors.initials: AA
authors.lastname: Paulucci-Holthauzen
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D051242:Caveolin 1 / Q000378:metabolism; D045424:Complex Mixtures / Q000494:pharmacology; D045166:Estradiol Congeners / Q000494:pharmacology* / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004970:Estrone / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D010902:Pituitary Gland / Q000166:cytology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D051242:Caveolin 1; D045424:Complex Mixtures; D045166:Estradiol Congeners; D047628:Estrogen Receptor alpha; D004970:Estrone; D048049:Extracellular Signal-Regulated MAP Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D010636:Phenols; C495537:Cav1 protein, rat; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: Endocrine disruptors; Environmental estrogens; Estrogen receptor-α; G proteins; Mitogen-activated protein kinases; Nongenomic