Signal transduction. A new mediator for an old hormone?

Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Science (Impact Factor: 33.61). 04/2005; 307(5715):1572-3. DOI: 10.1126/science.1110345
Source: PubMed


It is well established that estrogen mediates many of its physiological actions by binding to estrogen receptors in the nucleus,
which then activate the transcription of target genes. However, as
Hewitt, Deroo and Korach
discuss in their Perspective, new work reveals that some of estrogen's effects may be mediated by a nonclassical pathway in
which estrogen binds to non-estrogen receptor membrane proteins such as GPR30 (
et al.).

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    • "EA is the most-studied form of such endocrine disruptor activity [6,10-12]. Chemicals with EA bind to one or more estrogen receptor (ER) subtypes [8,13,14], and can produce various adverse health effects in mammals, such as early menarche, reduced sperm counts and other altered functions of reproductive organs, obesity, and increased rates of some cancers [6,12,15]. Fetal, infant and juvenile mammals have been reported to be especially sensitive to low doses of chemicals that exhibit EA [4-6,12,15]. "
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    ABSTRACT: Background Xenobiotic chemicals with estrogenic activity (EA), such as bisphenol A (BPA), have been reported to have potential adverse health effects in mammals, including humans, especially in fetal and infant stages. Concerns about safety have caused many manufacturers to use alternatives to polycarbonate (PC) resins to make hard and clear, reusable, plastic products that do not leach BPA. However, no study has focused on whether such BPA-free PC-replacement products, chosen for their perceived higher safety, especially for babies, also release other chemicals that have EA. Methods We used two, well-established, mammalian cell-based, assays (MCF-7 and BG1Luc) to assess the EA of chemicals that leached into over 1000 saline or ethanol extracts of 50 unstressed or stressed (autoclaving, microwaving, and UV radiation) BPA-free PC-replacement products. An EA antagonist, ICI 182,780, was used to confirm that agonist activity in leachates was due to chemicals that activated the mammalian estrogen receptor. Results Many unstressed and stressed, PC-replacement-products made from acrylic, polystyrene, polyethersulfone, and Tritan™ resins leached chemicals with EA, including products made for use by babies. Exposure to various forms of UV radiation often increased the leaching of chemicals with EA. In contrast, some BPA-free PC-replacement products made from glycol-modified polyethylene terephthalate or cyclic olefin polymer or co-polymer resins did not release chemicals with detectable EA under any conditions tested. Conclusions This hazard assessment survey showed that many BPA-free PC- replacement products still leached chemicals having significant levels of EA, as did BPA-containing PC counterparts they were meant to replace. That is, BPA-free did not mean EA-free. However, this study also showed that some PC-replacement products did not leach chemicals having significant levels of EA. That is, EA-free PC-replacement products could be made in commercial quantities at prices that compete with PC-replacement products that were not BPA-free. Since plastic products often have advantages (price, weight, shatter-resistance, etc.) compared to other materials such as steel or glass, it is not necessary to forgo those advantages to avoid release into foodstuffs or the environment of chemicals having EA that may have potential adverse effects on our health or the health of future generations.
    Full-text · Article · May 2014 · Environmental Health
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    • "Besides the delayed classical genomic mode of action, estrogen receptors may also act rapidly by interacting with intracellular signaling cascades by associating with membrane structures including G-proteins, caveolins, and receptor tyrosine kinases (Luoma et al. 2008). Estrogen itself induces phosphorylation of ERK1/2 (members of MAPK signaling pathway), activates cyclic-AMP-responsive element binding protein (CREB), Akt/PKB and regulates intracellular Ca 2? levels (Hewitt et al. 2005). Besides this, phenolic structure of estrogen makes it a potent antioxidant and a free radical scavenger. "
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    ABSTRACT: Incidence of Parkinson's disease (PD) is lower in women compared to men (1:1.46), which is reflected in animal models. However, precise mechanisms are unclear. Administration of MPTP (1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine) to female mice does not lead to mitochondrial complex I inhibition as seen in males and the progressive dopaminergic cell loss in substantia nigra (SNpc) is significantly attenuated. Redox driven apoptotic signaling pathways regulated by thiol disulfide oxidoreductase(s) have been implicated in the neurodegeneration seen in PD. Oxidation of thioredoxin leads to activation of apoptosis signal regulating kinase 1 (ASK1; MAPKKK) initiating cell death cascade through MAP kinase(s). Higher constitutive expression of enzymes involved in cellular redox maintenance, such as glutathione reductase, thioredoxin, and thioredoxin reductase is observed in female brain. Exposure to MPTP activates ASK1 in male but not in female mice. Higher expression of Trx in females potentially prevents ASK1 activation. Downstream of ASK1, phosphorylation of p38 MAP kinase is seen in male but not female mice. Expression of DJ-1, the redox sensing protein is higher in females and the loss of nuclear DJ-1, followed by translocation of Daxx (death associated protein) from the nucleus to the cytosol, which promotes ASK1 mediated death cascade is not seen in females. The enzymes involved in redox maintenance potentially could play a crucial role in preventing the activation of redox driven death signaling cascade and offer neuroprotection. Theraupeutic strategies that help maintain redox homeostasis may help prevent the progressive neurodegeneration seen in PD.
    Full-text · Article · Aug 2009 · Neurotoxicity Research
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    • "Estrogen receptors can directly contact G-proteins or transactivate other G-protein coupled receptors, leading to the stimulation of ion channels and phospholipase C (Kelly et al., 2002). In addition, GPR30 is a seven transmembrane domain protein that has been identified as a putative membrane estrogen receptor (Hewitt et al., 2005; Revankar et al., 2005), binds natural estrogens, SERMs and phytoestrogens and is present in the plasma membrane of hippocampal neurons (Funakoshi et al., 2006). Inactivation of GPR30 eliminates the effects of 17β-estradiol on neuroendocrine responses to serotonin receptor 1A agonists, whereas activation of GPR30 in the paraventricular nucleus modulates neuorendocrine responses to serotonin receptor 1A in a manner similar to 17β-estradiol (Xu et al., 2009). "
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    ABSTRACT: Decreasing levels of sex hormones with aging may have a negative impact on brain function, since this decrease is associated with the progression of neurodegenerative disorders, increased depressive symptoms and other psychological disturbances. Extensive evidence from animal studies indicates that sex steroids, in particular estradiol, are neuroprotective. However, the potential benefits of estradiol therapy for the brain are counterbalanced by negative, life-threatening risks in the periphery. A potential therapeutic alternative to promote neuroprotection is the use of selective estrogen receptor modulators (SERMs), which may be designed to act with tissue selectivity as estrogen receptor agonists in the brain and not in other organs. Currently available SERMs act not only with tissue selectivity, but also with cellular selectivity within the brain and differentially modulate the activation of microglia, astroglia and neurons. Finally, SERMs may promote the interaction of estrogen receptors with the neuroprotective signaling of growth factors, such as the phosphatidylinositol 3-kinase/glycogen synthase kinase 3 pathway.
    Full-text · Article · Jun 2009 · Psychoneuroendocrinology
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