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Vrednotenje estrogene aktivnosti mešanic izbranih bisfenolov in njihovih metabolitov
Blažič, Manja (Author), Peterlin Mašič, Lucija (Mentor) More about this mentor... This link opens in a new window, Gramec Skledar, Darja (Co-mentor)

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Abstract
Preko uživanja hrane in vode, vdihovanja plinov in dotikanja stvari v okolici v naše telo nenehno prehajajo številne sintezne in naravne spojine. Nekatere izmed teh lahko vplivajo na delovanje našega endokrinega sistema in s tem povzročajo različne neugodne zdravstvene izide. Ena takih spojin je bisfenol A, ki pa se zaradi številnih odmevnih študij, ki so poročale o njegovih škodljivih učinkih na zdravje, v zadnjem desetletju delno nadomešča z drugimi bisfenolnimi analogi. Posledica tega je, da smo pogosto izpostavljeni mešanicam različnih bisfenolov in še številnim drugim spojinam. V toksikologiji se tako daje vedno večji poudarek na vrednotenje mešanic, saj le-to ponuja natančnejši prikaz toksičnosti, kot tradicionalni način posamičnega testiranja spojin. Cilji našega dela so bili testiranje estrogene aktivnosti posameznih bisfenolov A, AF, C, F, S in Z na estrogenski receptor α (ERα), vrednotenje estrogenih učinkov dvokomponentnih mešanic bisfenola A z drugimi bisfenoli, vrednotenje estrogenega delovanja mešanice vseh šestih testiranih bisfenolov in ocena estrogene aktivnosti produktov bisfenolov A, AF in S po prestali 1. ali 2. fazi metabolizma. Za izvedbo poskusov smo uporabili hERα-HeLa-9903 celično linijo in meritve izvajali s pomočjo luciferaznega testa. Pred pričetkom testiranj smo s kontrolnimi spojinami preverili pravilno delovanje celične linije in opravili test z resazurinom za preverjanje morebitne citotoksičnosti spojin. Za citotoksično se je izkazala le 25 μM mešanica vseh šestih opazovanih bisfenolov, ki smo jo zato iz analize izpustili. Vseh šest testiranih bisfenolov se je po kriterijih OECD 455 protokola izkazalo za agoniste ERα. Jakost njihovega estrogenega delovanja je padala po sledečem vrstnem redu: bisfenol AF, Z, C, A, F, S. Iz meritev jakosti estrogenega delovanja posameznih bisfenolov smo izračunali aditivni model, katerega rezultate smo primerjali z meritvami jakosti estrogenega delovanja mešanic bisfenolov. Vrednosti so se med seboj zelo dobro ujemale, iz česar sklepamo, da imajo mešanice bisfenolov aditiven način součinkovanja na ERα. V testih metabolizma bisfenolov se je izkazalo, da sta najpomembnejša mehanizma metabolne detoksikacije bisfenolov encimski reakciji glukuronidacije in sulfatiranja. V primeru oksidativnega metabolizma bisfenolov, je bilo znižanje estrogene aktivnosti relativno nizko. Vzrok je lahko počasnejša kinetika reakcij ali pa nastanek estrogensko aktivnih produktov. Za določitev tega bi bile potrebne dodatne raziskave.

Language:Slovenian
Keywords:bisfenoli, estrogenski receptor α, mešanice, aditivni model, metabolizem
Work type:Master's thesis/paper (mb22)
Organization:FFA - Faculty of Pharmacy
Year:2020
Views:202
Downloads:110
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Secondary language

Language:English
Title:Evaluation of estrogenic activity of bisphenols' mixtures and their metabolites
Abstract:
Through the consumption of food and water, the inhalation of air, and the physical contact with objects in the environment, many synthetic and natural compounds are constantly passing into our bodies. Some of these can affect the functioning of our endocrine system and, thus, lead to various adverse health effects. One such compound is bisphenol A, which has been partially replaced by other bisphenol analogs in the past decade due to the numerous attention-attracting studies that reported its adverse health effects. As a result, we are often exposed to mixtures of various bisphenols and many other toxins. Therefore, there is an increasing emphasis in toxicology on the assessment of mixtures, since it offers a more accurate evaluation of toxicity as the individual testing of compounds. The objectives of our work were to test the estrogenic activity of bisphenols A, AF, C, F, S, and Z on the estrogen receptor α (ERα), to evaluate the estrogenic effects of two-component mixtures of bisphenol A with other bisphenols and to determine the estrogenic activity of the mixture of all six bisphenols. Additionally, we evaluated estrogenic activities of the products of bisphenols A, AF, and S after phase 1 or 2 metabolisms. To perform the assays, the hERα-HeLa-9903 cell line was used and measurements were made using luciferase assay. Before testing bisphenols, four control compounds were used to test the proper cell line functioning and a resazurin assay was performed to check for potential cytotoxicity of the tested bisphenols. Only a 25 μM mixture of all six bisphenols proved cytotoxic and was, therefore, omitted from the analysis. All six of the tested bisphenols proved to be ERα agonists. The potency of their estrogenic activity decreased in the following order: bisphenol AF, Z, C, A, F, and S. From the measurements of the estrogenic potency of the individually tested bisphenols, the concentration addition model was calculated. The obtained results were compared to the measured estrogenic potency of the mixtures of bisphenols. The values matched very well, suggesting that the mixtures of bisphenols have an additive mode of action on the ERα. The bisphenol metabolism tests have shown that the most important mechanisms of metabolic detoxification of bisphenols are the enzymatic reactions of glucuronidation and sulfation. In the case of oxidative metabolism of bisphenols, however, the decrease of estrogenic activity was relatively low. This may be due to slower kinetics of the reactions or the formation of estrogen-active products.

Keywords:bisphenols, estrogen receptor α, mixtures, concentration addition, metabolism

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