Beyond the role of 17β-estradiol (E2) in reproduction and during the menstrual cycle, it has been shown to modulate numerous physiological processes such as cell proliferation, apoptosis, inflammation and ion transport in many tissues. The pathways in which estrogens affect an organism have been partially described, although many questions still exist regarding estrogens' interaction with biomacromolecules. Hence, the present study showed the interaction of four oligonucleotides (17, 20, 24 and/or 38-mer) with E2. The strength of these interactions was evaluated using optical methods, showing that the interaction is influenced by three major factors, namely: oligonucleotide length, E2 concentration and interaction time. In addition, the denaturation phenomenon of DNA revealed that the binding of E2 leads to destabilization of hydrogen bonds between the nitrogenous bases of DNA strands resulting in a decrease of their melting temperatures (Tm). To obtain a more detailed insight into these interactions, MALDI-TOF mass spectrometry was employed. This study revealed that E2 with DNA forms non-covalent physical complexes, observed as the mass shifts for app. 270 Da (Mr of E2) to higher molecular masses. Taken together, our results indicate that E2 can affect biomacromolecules, as circulating oligonucleotides, which can trigger mutations, leading to various unwanted effects.

Department of Chemistry and Biochemistry Faculty of Agronomy Mendel University in Brno Zemedelska 1 CZ 613 00 Brno Czech Republic

Department of Ecology and Diseases of Game Fish and Bees Faculty of Veterinary Hygiene and Ecology University of Veterinary and Pharmaceutical Sciences Palackeho 1 3 CZ 612 42 Brno Czech Republic

Zobrazit více v PubMed

Benotti M.J., Trenholm R.A., Vanderford B.J., Holady J.C., Stanford B.D., Snyder S.A. Pharmaceuticals and endocrine disrupting compounds in US drinking water. Environ. Sci. Technol. 2009;43:597–603. doi: 10.1021/es801845a. PubMed DOI

Boyd G.R., Reemtsma H., Grimm D.A., Mitra S. Pharmaceuticals and personal care products (PPCPs) in surface and treated waters of Louisiana, USA and Ontario, Canada. Sci. Total Environ. 2003;311:135–149. doi: 10.1016/S0048-9697(03)00138-4. PubMed DOI

Kolpin D.W., Furlong E.T., Meyer M.T., Thurman E.M., Zaugg S.D., Barber L.B., Buxton H.T. Pharmaceuticals, hormones, and other organic wastewater contaminants in US streams, 1999–2000: A national reconnaissance. Environ. Sci. Technol. 2002;36:1202–1211. doi: 10.1021/es011055j. PubMed DOI

Jiang W.W., Yan Y., Ma M., Wang D.H., Luo Q., Wang Z.J., Satyanarayanan S.K. Assessment of source water contamination by estrogenic disrupting compounds in China. J. Environ. Sci. 2012;24:320–328. doi: 10.1016/S1001-0742(11)60746-8. PubMed DOI

Snyder E.M., Snyder S.A., Kelly K.L., Gross T.S., Villeneuve D.L., Fitzgerald S.D., Villalobos S.A., Giesy J.P. Reproductive responses of common carp (Cyprinus carpio) exposed in cages to influent of the Las Vegas Wash in Lake Mead, Nevada, from late winter to early spring. Environ. Sci. Technol. 2004;38:6385–6395. doi: 10.1021/es049690n. PubMed DOI

Isobe T., Serizawa S., Horiguchi T., Shibata Y., Managaki S., Takada H., Morita M., Shiraishi H. Horizontal distribution of steroid estrogens in surface sediments in Tokyo Bay. Environ. Pollut. 2006;144:632–638. doi: 10.1016/j.envpol.2006.01.030. PubMed DOI

David A., Fenet H., Gomez E. Alkylphenols in marine environments: Distribution monitoring strategies and detection considerations. Mar. Pollut. Bull. 2009;58:953–960. doi: 10.1016/j.marpolbul.2009.04.021. PubMed DOI

Boulay F., Perdiz D. 17β-Estradiol modulates UVB-induced cellular responses in estrogen receptors positive human breast cancer cells. J. Photochem. Photobiol. B Biol. 2005;81:143–153. doi: 10.1016/j.jphotobiol.2005.05.008. PubMed DOI

Yan Z.H., Lu G.H., Wu D.H., Ye Q.X., Xie Z.X. Interaction of 17 beta-estradiol and ketoconazole on endocrine function in goldfish (Carassius auratus) Aquat. Toxicol. 2013;132:19–25. PubMed

Heldring N., Pike A., Andersson S., Matthews J., Cheng G., Hartman J., Tujague M., Strom A., Treuter E., Warner M., et al. Estrogen receptors: How do they signal and what are their targets. Physiol. Rev. 2007;87:905–931. doi: 10.1152/physrev.00026.2006. PubMed DOI

Lee H.R., Jeung E.B., Cho M.H., Kim T.H., Leung P.C.K., Choi K.C. Molecular mechanism(s) of endocrine-disrupting chemicals and their potent oestrogenicity in diverse cells and tissues that express oestrogen receptors. J. Cell. Mol. Med. 2013;17:1–11. doi: 10.1111/j.1582-4934.2012.01649.x. PubMed DOI PMC

Tang X.J., Naveedullah, Hashmi M.Z., Zhang H., Qian M.R., Yu C.N., Shen C.F., Qin Z.H., Huang R.L., Qiao J.N., et al. A preliminary study on the occurrence and dissipation of estrogen in livestock wastewater. Bull. Environ. Contam. Toxicol. 2013;90:391–396. doi: 10.1007/s00128-012-0912-4. PubMed DOI

Macon M.B., Fenton S.E. Endocrine disruptors and the breast: Early life effects and later life disease. J. Mammary Gland Biol. Neoplasia. 2013;18:43–61. doi: 10.1007/s10911-013-9275-7. PubMed DOI PMC

Jenkins S., Betancourt A.M., Wang J., Lamartiniere C.A. Endocrine-active chemicals in mammary cancer causation and prevention. J. Steroid Biochem. Mol. Biol. 2012;129:191–200. doi: 10.1016/j.jsbmb.2011.06.003. PubMed DOI

Ombra M.N., di Santi A., Abbondanza C., Migliaccio A., Avvedimento E.V., Perillo B. Retinoic acid impairs estrogen signaling in breast cancer cells by interfering with activation of LSD1 via PKA. Biochim. Biophys. Acta. 2013;1829:480–486. doi: 10.1016/j.bbagrm.2013.03.003. PubMed DOI

Lacroix M., Leclercq G. Relevance of breast cancer cell lines as models for breast tumours: An update. Breast Cancer Res. Treat. 2004;83:249–289. doi: 10.1023/B:BREA.0000014042.54925.cc. PubMed DOI

Resende F.A., de Oliveira A.P.S., de Camargo M.S., Vilegas W., Varanda E.A. Evaluation of estrogenic potential of flavonoids using a recombinant yeast strain and MCF7/BUS cell proliferation assay. PLoS One. 2013;8 doi: 10.1371/journal.pone.0074881. PubMed DOI PMC

Cavalieri E.L., Rogan E.G. Depurinating estrogen-DNA adducts in the etiology and prevention of breast and other human cancers. Future Oncol. 2010;6:75–91. doi: 10.2217/fon.09.137. PubMed DOI PMC

Cavalieri E.L., Stack D.E., Devanesan P.D., Todorovic R., Dwivedy I., Higginbotham S., Johansson S.L., Patil K.D., Gross M.L., Gooden J.K., et al. Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc. Natl. Acad. Sci. USA. 1997;94:10937–10942. doi: 10.1073/pnas.94.20.10937. PubMed DOI PMC

Abbondanza C., de Rosa C., D’Arcangelo A., Pacifico M., Spizuoco C., Piluso G., Di Zazzo E., Gazzerro P., Medici N., Moncharmont B., et al. Identification of a functional estrogen-responsive enhancer element in the promoter 2 of PRDM2 gene in breast cancer cell lines. J. Cell. Physiol. 2012;227:964–975. doi: 10.1002/jcp.22803. PubMed DOI

Hung Y.C., Chang W.C., Chen L.M., Chang Y.Y., Wu L.Y., Chung W.M., Lin T.Y., Chen L.C., Ma W.L. Non-genomic estrogen/estrogen receptor alpha promotes cellular malignancy of immature ovarian teratoma in vitro. J. Cell. Physiol. 2014;229:752–761. doi: 10.1002/jcp.24495. PubMed DOI

Cirillo F., Nassa G., Taralla R., Stellato C., De Filippo M.R., Arribrosino C., Baumann M., Nyman T.A., Weisz A. Molecular mechanisms of selective estrogen receptor modulator activity in human breast cancer cells: Identification of novel nuclear cofactors of antiestrogen-ER alpha complexes by interaction proteomics. J. Proteome Res. 2013;12:421–431. doi: 10.1021/pr300753u. PubMed DOI

Heldring N., Isaacs G.D., Diehl A.G., Sun M., Cheung E., Ranish J.A., Kraus W.L. Multiple sequence-specific DNA-binding proteins mediate estrogen receptor signaling through a tethering pathway. Mol. Endocrinol. 2011;25:564–574. doi: 10.1210/me.2010-0425. PubMed DOI PMC

Acconcia F., Kumar R. Signaling regulation of genomic and nongenomic functions of estrogen receptors. Cancer Lett. 2006;238:1–14. doi: 10.1016/j.canlet.2005.06.018. PubMed DOI

McGlynn L.M., Tovey S., Bartlett J.M.S., Doughty J., Cooke T.G., Edwards J. Interactions between MAP kinase and oestrogen receptor in human breast cancer. Eur. J. Cancer. 2013;49:1176–1186. doi: 10.1016/j.ejca.2012.11.020. PubMed DOI

Heger Z., Zitka O., Krizkova S., Beklova M., Kizek R., Adam V. Molecular biology of beta-estradiol-estrogen receptor complex binding to estrogen response element and the effect on cell proliferation. Neuroendocrinol. Lett. 2013;34:123–129. PubMed

Losel R.M., Falkenstein E., Feuring M., Schultz A., Tillmann H.C., Rossol-Haseroth K., Wehling M. Nongenomic steroid action: Controversies, questions, and answers. Physiol. Rev. 2003;83:965–1016. PubMed

Suman M., Giacomello M., Corain L., Ballarin C., Montelli S., Cozzi B., Peruffo A. Estradiol effects on intracellular Ca2+ homeostasis in bovine brain-derived endothelial cells. Cell Tissue Res. 2012;350:109–118. doi: 10.1007/s00441-012-1460-2. PubMed DOI

Candelaria N.R., Liu K., Lin C.Y. Estrogen receptor alpha: Molecular mechanisms and emerging insights. J. Cell. Biochem. 2013;114:2203–2208. doi: 10.1002/jcb.24584. PubMed DOI

Imaoka T., Nishimura M., Doi K., Tani S., Ishikawa K., Yamashita S., Ushijima T., Imai T., Shimada Y. Molecular characterization of cancer reveals interactions between ionizing radiation and chemicals on rat mammary carcinogenesis. Int. J. Cancer. 2014;134:1529–1538. doi: 10.1002/ijc.28480. PubMed DOI

Wang Y.C., Lin W.L., Lin Y.J., Tang F.Y., Chen Y.M., Chiang E.P.I. A novel role of the tumor suppressor GNMT in cellular defense against DNA damage. Int. J. Cancer. 2014;134:799–810. doi: 10.1002/ijc.28420. PubMed DOI

Saeed M., Zahid M., Gunselman S.J., Rogan E., Cavalieri E. Slow loss of deoxyribose from the N7deoxygruanosine adducts of estradiol-3,4-quinone and hexestrol-3,4’-quinone. Implications for mutagenic activity. Steroids. 2005;70:29–35. doi: 10.1016/j.steroids.2004.09.011. PubMed DOI

Peng B., Chen X., Du K.J., Yu B.L., Chao H., Ji L.N. Synthesis, characterization and DNA-binding studies of ruthenium(II) mixed-ligand complexes containing dipyrido 1,2,5 oxadiazolo 3,4-b quinoxaline. Spectroc. Acta A Mol. Biomol. Spectr. 2009;74:896–901. doi: 10.1016/j.saa.2009.08.031. PubMed DOI

Syed S.N., Schulze H., Macdonald D., Crain J., Mount A.R., Bachmann T.T. Cyclic denaturation and renaturation of double-stranded DNA by redox-state switching of DNA intercalators. J. Am. Chem. Soc. 2013;135:5399–5407. doi: 10.1021/ja311873t. PubMed DOI

Vizard D.L., White R.A., Ansevin A.T. Comparison of theory to experiment for DNA thermal-denaturation. Nature. 1978;275:250–251. doi: 10.1038/275250a0. PubMed DOI

Breslauer K.J., Frank R., Blocker H., Marky L.A. Predicting DNA duplex stability from the base sequence. Proc. Natl. Acad. Sci. USA. 1986;83:3746–3750. doi: 10.1073/pnas.83.11.3746. PubMed DOI PMC

Melchior W.B., Vonhippe P.H. Alteration of relative stability of dA-dT and dG-dC base pairs in DNA. Proc. Natl. Acad. Sci. USA. 1973;70:298–302. doi: 10.1073/pnas.70.2.298. PubMed DOI PMC

Srinivasan J.R., Liu Y.H., Venta P.J., Siemieniak D., Killeen A.A., Zhu Y.D., Lubman D.M. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry as a rapid screening method to detect mutations causing Tay-Sachs disease. Rapid Commun. Mass Spectrom. 1997;11:1144–1150. doi: 10.1002/(SICI)1097-0231(19970630)11:10<1144::AID-RCM981>3.0.CO;2-Q. PubMed DOI

Zhang L.K., Gross M.L. Matrix-assisted laser desorption/ionization mass spectrometry methods for oligodeoxynucleotides: Improvements in matrix, detection limits, quantification, and sequencing. J. Am. Soc. Mass Spectrom. 2000;11:854–865. doi: 10.1016/S1044-0305(00)00161-6. PubMed DOI

Yu F., Xu S.Y., Pan C.S., Ye M.L., Zou H.F., Guo B.C. A matrix of 3,4-diaminobenzophenone for the analysis of oligonucleotides by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Nucleic Acids Res. 2006;34:1–7. doi: 10.1093/nar/gkj405. PubMed DOI PMC

Ohara K., Smietana M., Vasseur J.J. Characterization of specific noncovalent complexes between guanidinium derivatives and single-stranded DNA by MALDI. J. Am. Soc. Mass Spectrom. 2006;17:283–291. doi: 10.1016/j.jasms.2005.11.005. PubMed DOI

Tang K., Fu D.J., Kotter S., Cotter R.J., Cantor C.R., Koster H. Matrix-assisted laser desorption/ionization mass-spectrometry of immobilized duplex DNA probes. Nucleic Acids Res. 1995;23:3126–3131. doi: 10.1093/nar/23.16.3126. PubMed DOI PMC

Hop C., Bakhtiar R. An introduction to electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry: Essential tools in a modern biotechnology environment. Biospectroscopy. 1997;3:259–280. doi: 10.1002/(SICI)1520-6343(1997)3:4<259::AID-BSPY2>3.0.CO;2-#. DOI

Gilar M., Belenky A., Wang B.H. High-throughput biopolymer desalting by solid-phase extraction prior to mass spectrometric analysis. J. Chromatogr. A. 2001;921:3–13. doi: 10.1016/S0021-9673(01)00833-0. PubMed DOI

Chifotides H.T., Koomen J.M., Kang M.J., Tichy S.E., Dunbar K.R., Russell D.H. Binding of DNA purine sites to dirhodium compounds probed by mass spectrometry. Inorg. Chem. 2004;43:6177–6187. doi: 10.1021/ic040040u. PubMed DOI

Tsuchiya Y., Nakajima M., Yokoi T. Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett. 2005;227:115–124. doi: 10.1016/j.canlet.2004.10.007. PubMed DOI

Nussinov R., Tsai C.J., Mattos C. “Pathway drug cocktail”: Targeting Ras signaling based on structural pathways. Trends Mol. Med. 2013;19:695–704. doi: 10.1016/j.molmed.2013.07.009. PubMed DOI

Farmer P.B., Sweetman G.M.A. Mass-spectrometric detection of carcinogen adducts. J. Mass Spectrom. 1995;30:1369–1379. doi: 10.1002/jms.1190301002. DOI

Saeed M., Rogan E., Cavalieri E. Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol: The defining link to natural estrogens. Int. J. Cancer. 2009;124:1276–1284. doi: 10.1002/ijc.24113. PubMed DOI PMC

Hendry L.B., Roach L.W., Mahesh V.B. Multidimensional screening and design of pharmaceuticals by using endocrine pharmacophores. Steroids. 1999;64:570–575. doi: 10.1016/S0039-128X(99)00035-5. PubMed DOI

Olmsted S.L., Tongcharoensirikul P., McCaskill E., Gandiaga K., Labaree D., Hochberg R.B., Hanson R.N. Synthesis and evaluation of 17 alpha-E-20-(heteroaryl)norpregn-1,3,5(10),20 tetraene-3,17 beta-diols 17 alpha-(heteroaryl)vinyl estradiols as ligands for the estrogen receptor-alpha ligand binding domain (ER alpha-LBD) Bioorg. Med. Chem. Lett. 2012;22:977–979. doi: 10.1016/j.bmcl.2011.12.003. PubMed DOI PMC

Izzotti A., Larghero P., Longobardi M., Cartiglia C., Camoirano A., Steele V.E., de Flora S. Dose-responsiveness and persistence of microRNA expression alterations induced by cigarette smoke in mouse lung. Mutat. Res. Fundam. Mol. Mech. Mutagen. 2011;717:9–16. doi: 10.1016/j.mrfmmm.2010.12.008. PubMed DOI