Estrogenic endocrine disruptors Molecular mechanisms of action原版完整详细.docx

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1、Contents lists available at ScienceDirectEnvironment Internationalj ournal homepage : ocate/ envintEnvironment International 83 (2015) 1140ReviewEstrogenic endocrine disruptors: Molecular mechanisms of actionRyoiti Kiyama a, Yuko Wada-Kiyama ba Biomedical Research Institute, National Institute of Ad

2、vanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japanb Department of Physiology, Nippon Medical School, Bunkyo-ku, Tokyo 113-8602, Japana r t i c l ei n f o Article history:Received 16 December 2014Received in revised form 26 May 2015Accepted 27 May 2015Ava

3、ilable online 11 June 2015Keywords: Endocrine disruptor Estrogen actionMolecular mechanism TechonologySignal transduction Toxicity pathwaya b s t r a c t A comprehensive summary of more than 450 estrogenic chemicals including estrogenic endocrine disruptors is provided here to understand the complex

4、 and profound impact of estrogen action. First, estrogenic chemicals are categorized by structure as well as their applications, usage and effects. Second, estrogenic signaling is examined by the molecular mechanism based on the receptors, signaling pathways, crosstalk/bypassing and autocrine/ parac

5、rine/homeostatic networks involved in the signaling. Third, evaluation of estrogen action is discussed by focusing on the technologies and protocols of the assays for assessing estrogenicity. Understanding the molecular mechanisms of estrogen action is important to assess the action of endocrine dis

6、ruptors and will be used for risk management based on pathway-based toxicity testing. 2015 Elsevier Ltd. All rights reserved.Contents1. Introduction 122. Estrogenic chemicals 122.1. Structure-based categorization of estrogenic chemicals 132.1.1. Phenolic estrogens 132.1.2. Non-phenolic estrogens 132

7、.1.3. Chemical basis for estrogen action 182.2. Function-based categorization of estrogenic chemicals 182.2.1. Food additives/dietary supplements182.2.2. Pesticides 182.2.3. Pharmacological estrogens 222.2.4. Plasticizers 222.2.5. Pollutants223. Molecular mechanisms of estrogenic signaling 223.1. Re

8、ceptors243.1.1. Nuclear receptors 243.1.2. Membrane receptors253.1.3. Other membrane receptors253.2. Cell functions and signaling pathways 253.2.1. Apoptosis253.2.2. Carcinogenesis 263.2.3. Cell growth and proliferation263.2.4. Differentiation/development263.2.5. Inammation263.3. Signaling networks2

9、63.3.1. Crosstalk/bypassing273.3.2. Autocrine/paracrine signaling 273.3.3. Homeostatic networks 27* Corresponding author.E-mail address: kiyama.raist.go.jp (R. Kiyama).http:/dx.doi.org/10.1016/j.envint.2015.05.012 0160-4120/ 2015 Elsevier Ltd. All rights reserved.R. Kiyama, Y. Wada-Kiyama / Environm

10、ent International 83 (2015) 1140134. Evaluation of estrogen action 274.1. Assays for detecting estrogen action 284.1.1. Ligand-binding assay284.1.2. Reporter-gene assay284.1.3. Yeast two-hybrid assay294.1.4. Transcription assay 294.1.5. Protein assay294.1.6. Cell assay294.1.7. Animal test304.1.8. Si

11、gnaling pathway analysis304.2. Pathway-based risk assessment305. Conclusion and future prospects 31Acknowledgments 31References311. IntroductionEstrogen is a female hormone that plays a role in menstrual and estrous reproductive cycles. The role of estrogen is thus complex and includes involvement i

12、n the physiology of reproductive organs and tissues (e.g., breast, ovary and endometrium), lipid metabolism, protein synthesis, behavior (e.g., lordosis behavior) and diseases (e.g., cancer and neurodegenerative/cardiovascular diseases) (Deroo and Korach, 2006; Gillies and McArthur, 2010). While thr

13、ee major estrogens, estrone, estradiol and estriol, are known, there are a number of estro- genic chemicals of natural and industrial origins, as mostly character- ized by comparing them with the major estrogens. Furthermore, estrogenic chemicals are those that are not only directly responsible for

14、activating or inhibiting estrogen action, but also those indirectly modulating its action; thus, a variety of chemicals should be considered to understand its action. Estrogenic chemicals are thus considered as a type of important chemicals acting as an endocrine disruptor, which is dened as “an exo

15、genous agent that interferes with the production, re- lease, transport, metabolism, binding, action or elimination of naturalhormones in the body responsible for the maintenance of homeostasis and the regulation of developmental processes” (Kavlock et al., 1996).During our research for characterizat

16、ion of estrogenic chemicals, we found that quite a number of chemicals have been reported to be estro- genic. They were analyzed by a number of different assays and evaluat- ed by different criteria to judge that they are estrogenic. Furthermore, their mechanisms of action seem to be quite complicat

17、ed. As we failed to nd a comprehensive list of estrogenic chemicals in literatures, we examined potentially estrogenic chemicals one by one to nd why they were reported to be estrogenic.2. Estrogenic chemicalsThe mechanism of estrogenic signaling at the cellular level is sum- marized in Fig. 1 (see

18、also Kiyama and Zhu, 2014; Kiyama et al., 2014). Estrogenic signal networks can be categorized into intracellular and ex- tracellular types. The genomic pathway, which involves transcription of target genes, and the non-genomic pathway, which rapidly transduces signals mediated by membrane-bound est

19、rogen receptors (ERs) and/Intracellular NetworkExtracellular NetworkGenomic PathwayNon-genomic PathwayAutocrine/ParacrineSignalingEstrogenEstrogenHormone/ GF/CytokineMembrane EROther ReceptorCrosstalkBypassingSSigignnaalilninggSignalingProteinsProteinSignaling-pathway Analysis (S)Yeast Two- hybrid A

20、ssay (Y)EstrogenPol IICo-regulatorNuclear ERTranscriptionProteinFunctionERETarget GeneProtein Assay (P)Cell Assay (C)Transcription Assay (T)Ligand-binding Assay (L)Animal Test (A)Reporter-gene Assay (R)Fig. 1. Signaling pathways, crosstalk and autocrine/paracrine/homeostatic signaling networks of es

21、trogenic chemicals.or other receptors through crosstalk and/or bypassing, belong to the former, while the pathways of autocrine and/or paracrine signaling,in assay systems, which were reported for the chemicals summarized below.which involve other hormones, growth factors and cytokines, belong to th

22、e latter.The genomic pathway, or the classical pathway, is initiated by the binding of chemicals (or ligands) with the nuclear ERs, ER and ER, and the ligand-bound ERs act as transcription factors to up-regulate or down-regulate the transcription of target genes or estrogen-responsive genes, in tran

23、scription machinery containing RNA polymerase II and co-regulators of transcription, such as RIP-140, p300/CBP and SRC-1 (Parker, 1998; Moggs and Orphanides, 2001). On the other hand, estrogen binds to the membrane or cytoplasmic recep- tors and stimulates signaling proteins through the non-genomic

24、path- way, which occurs rapidly, sometimes just minutes after stimulation, and involves a number of signaling pathways. This type of signaling starts by the binding of ligands to membrane/cytoplasmic ERs, and several ERs, including G-protein-coupled estrogen receptor 1 (GPER), have been identied. Ho

25、wever, several new receptors and variants of known receptors were identied, such as ER-X and ER-36 (see Section 3), increasing the complexity of estrogenic signaling. Estrogen- related receptors also mediate estrogenic signaling. Meanwhile, recent studies have revealed that intracellular networks co

26、operate with various types of autocrine and/or paracrine signaling, and thus cells in different tissues or locations are also involved in the extracellular networks (see Section 3).One of the reasons why a number of new signaling pathways were identied recently is the availability of a variety of ne

27、w technologies to detect estrogenic chemicals (Fig. 1); they revealed the novel charac- teristics of chemicals, such as biphasic and metabolic effects detected by cell proliferation assay, the activity of selective estrogen-receptor mod- ulators (SERMs) detected by cell assay and new estrogen-respon

28、sive genes detected by DNA microarray assay (see Section 4). Thus, estro- genic chemicals include chemicals or their metabolites that have not only estrogenic effects but also anti-estrogenic ones, and they transduce signals to estrogen signaling through crosstalk, bypassing and extracel- lular netw

29、orks.2.1. Structure-based categorization of estrogenic chemicalsTo understand the action of estrogenic chemicals at the molecular level, especially at the cell signaling level, we categorized estrogenic chemicals based on several characteristics. First, the estrogenic chemicals categorized by struct

30、ure are summarized in Table 1. A number of estrogenic chemicals are phenolics, and phenolic estrogens include simple phenols, phenolic acids/phenolic alde- hydes, acetophenones, tyrosine derivatives, phenylacetic acids, hydroxycinnamic acids, phenylpropenes, coumarins/isocoumarins/ chromones, naphth

31、oquinones, bisphenols, benzophenones, stil- benes/stilbenoids, anthraquinones, chalcones/chalconoids, a- vones/avonoids, lignans/neolignans, diarylheptanoids, avolans and hydroxylated polycyclic aromatic hydrocarbons (PAHs). On the other hand, chemicals without a phenolic ring can also show estrogen

32、ic activity, which include anilines, carboranes, indoles, metalloestrogens, peruorinated compounds, phthalates, PAHs and terpenes/terpenoids (monoterpenes, sesquiterpenes, diterpenes, triterpenes, tetraterpenes, sterols, steroids, saponins and meroterpenes).While estrogenic or anti-estrogenic activi

33、ty can be detected by vari- ous methods (see Section 4), they have limitations in their sensitivity (e.g., concentration-dependent activity), distinguishing agonists/ antagonists and specicity (e.g., cell/tissue types and signaling path- ways). Thus, the same estrogenic chemicals can show contradict

34、ory results (listed in Tables 1 and 2), such as differences in estrogenic and anti-estrogenic, agonistic and antagonistic, and ligand/pathway- dependent and -independent responses, differences in increased and decreased gene expression or enzymatic activity, as well as differencesThe list of chemica

35、ls showing contradictory results in estrogenicity.Phlorizin (Wang et al., 2010), quercetin/naringenin (Marino et al., 2012), naringin (Guo et al., 2011), epigallocatechin 3-gallate (Kuruto-Niwa et al., 2000), glabridin (Tamir et al., 2000), enterodiol/enterolactone (Feng et al., 2008),3-methylcholan

36、threne (Swedenborg et al., 2008), abietic acid/botulin/-sitosterol (Mellanen et al., 1996), methoxychlor (Lemaire et al., 2006), bifenthrin/permethrin (Brander et al., 2012), raloxifene (Lee et al., 2011), tamoxifen (Jiang et al., 1995; Obrero et al., 2002), PCBs (Zhang et al., 2014a) and BDE 47 (Ka

37、rpeta et al., 2014).Biphasic activity, where estrogenic activity was observed at low concentrations and anti-estrogenic activity at high concentrations, has been reported for phytoestrogens (Wang, 2002). Enterolactone, a lignin, stimulates DNA synthesis in MCF-7 cells at 1050 M, but inhibits it at h

38、igher concentrations. Enterolactone was shown to be a selective ER ac- tivator through its interaction with ER (Penttinen et al., 2007). SERMs are the chemicals that show differential (agonist or antagonist) effects on different tissues or cells, where the effects are based on the modula- tion of re

39、ceptor functions by differential interactions between the receptor and the ligand, which would be benecial for the treatment of hormone-responsive cancer and osteoporosis (Maximov et al., 2013). Such effects are likely to occur at downstream pathways, such as in the case of raloxifene (Lee et al., 2

40、011) and tamoxifen (Jiang et al., 1995; Obrero et al., 2002), where ER-dependent and -independent modula- tions of signaling were observed.2.1.1. Phenolic estrogensPhenolic estrogens are categorized by the number of skeletal carbons (Table 1; Vermerris and Nicholson, 2008). While phenol itself is no

41、t estrogenic, simple modications, such as chlorination (pentachlorophenol), nitration (nitrophenol) and alkylation (nonylphenol), confer estrogenicity on the derivatives. The derivatives of phenolic acid and phenolic aldehyde, such as gallic acid, parabens, benzaldehydes, syringic acid and ellagic a

42、cid, show estrogenicity. More complex phenolics and their derivatives, including phenylethanoids (acteoside and martynoside), tyrosine derivatives (thyroid hormone), phenylacetic acid, naphthoquinones, bisphenols, benzophenones and phenylpropanoids, also show estrogenicity. Phenylpropanoids are a gr

43、oup of chemicals synthesized by plants from phenylalanine, and include hydroxycinnamic acids (caffeic acid and ferulic acid), phenylpropenes (anethole and eugenol), coumarins and related chemicals (auraptene, bergapten, daphnetin, esculetin, icariin and icaritin), stilbenes/stilbenoids, anthraquinon

44、es, chalcones/chalconoids and avones/avonoids (anthoxanthins, avanones, avanonols, avans, anthocyanidines, isoavones, isoavanes, isoavenes, coumestans, pterocarpans and avonolignans).PAHs are known to show estrogenicity, which is partly explained bythe presence of hydroxylated phenolic rings (3,9-be

45、nzaanthracene diols and cinanthrenol A; Table 2) or by the introduction of a hydroxyl group after hydroxylation or metabolization within a cell.2.1.2. Non-phenolic estrogensA number of non-phenolics have been identied as estrogenic chemicals, which include anilines, carboranes (boron estrogens), ind

46、oles, metalloestrogens, peruorinated compounds, phthalates, PAHs and ter- penes/terpenoids (Table 1). Anilines are aromatic amines and used as precursors to polyurethane, synthetic dyes and other industrial chemicals. Because of similarities in their structure and biological activity, anilines were

47、expected to show estrogenicity (Hamblen et al., 2003). Carboranes are a group of chemicals composed of boron, carbon and hy- drogen atoms in polyhedral forms, and have advantages for designing new ER agonists/antagonists and SERMs due to their unique three- dimensional structure and superior synthet

48、ic exibility (Armstrong and Valliant, 2007). Indoles consist of a benzene ring fused to a pyrrole ring. Some indoles show estrogenicity without having a phenolic hydroxylTable 1Estrogenic chemicals categorized by structure.Estrogenic chemicalSignaling pathwayReference (assaya) PhenolicbSimple phenol (C6)Alkylphenols (C6C4C6C12)ERTollefsen and Ni