Vrednotenje bisfenolov in njihovih transformacijskih produktov kot okoljskih endokrinih motilcev in silico

Hočevar, Maja (author), Jakopin, Žiga (mentor)

Bisfenoli sodijo med najbolj proizvajane spojine na svetu in jih najpogosteje uporabljamo kot monomere pri sintezi polikarbonatnih plastik in epoksi smol. Bisfenoli prehajajo v vodno okolje preko procesa izluževanja iz vodovodnih in kanalizacijskih cevi iz umetnih mas. Ljudje smo bisfenolom izpostavljeni predvsem preko vodovodne vode in hrane. Bisfenoli so v vodnem okolju, kjer je prisoten hipoklorit, podvrženi transformaciji s kloriranjem in bromiranjem. Nastali transformacijski produkti so lahko bolj toksični od starševske spojine, zato so bile poleg osnovnih bisfenolov predmet raziskovanja. Večina bisfenolov ima visoke vrednosti logP, zaradi česar so odporni proti biološki razgradnjii in nagnjeni k procesu bioakumulacije. V magistrski nalogi smo osmim bisfenolom in njihovim transformacijskim produktom kloriranja in bromiranja s pomočjo dveh programov, in sicer Endocrine Disruptome in VegaNIC, napovedali okoljski vpliv, akutno toksičnost ter endokrino delovanje. In silico metode nam pomagajo pri usmeritvi in vivo ter in vitro študij na področja, ki zahtevajo bolj natančno vrednotenje bisfenolov in njihove usode v okolju. Iz vrednosti logP in generiranih napovedi programa VegaNIC za odpornost proti biološki razgradnji, obstojnosti v sedimentu in napovedi faktorja bioakumulacije smo ugotovili, da se s transformacijo poveča obstojnost bisfenolov v sedimentu in tudi, da večina preučevanih bisfenolov ni biorazgradljiva. Najvišji bioakumulacijski faktor ima bisfenol P, najnižjega pa bisfenol S. Ob preučevanju akutne toksičnosti so rezultati pokazali, da ima najvišje vrednosti LC50 bisfenol S, zaradi česar je uvrščen med netoksične spojine, najbolj akutno toksična spojina je tetrabromobisfenol P. V splošnem so bromirani transformacijski produkti bolj akutno toksični kot klorirani. Endokrini potencial smo določili s programom Endocrine Disruptome na podlagi afinitete vezave spojin na 14 človeških jedrnih receptorjev. Ugotovili smo, da imajo bisfenoli napovedano afiniteto za vezavo na AR, AR an., ERα, ERβ, ERβ an., GR, MR, PPARγ ter receptorja TRα in TRβ. Pri vseh bisfenolih smo opazili trend povečanja verjetnosti vezave po transformaciji, predvsem pri monosubstituiranih in disubstituiranih transformacijskih produktih. Opazili smo tudi, da imajo večjo verjetnost vezave na receptorje klorirani transformacijski produkti v primerjavi z bromiranimi. Rezultati, ki smo jih pridobili s pomočjo in silico metod, nakazujejo na povečanje bioakumulacije, akutne toksičnosti ter endokrine toksičnosti bisfenolov po transformaciji.

• Language: Slovenian
• Keywords: bisfenoli, halogeniranje, transformacijski produkti, bioakumulacija, in silico napoved, endokrino delovanje, ekotoksikološki vpliv
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2023
• PID: 20.500.12556/RUL-146752
• Publication date in RUL: 10.06.2023

Secondary language

• Language: English
• Title: In silico evaluation of bisphenols and their transformation products as environmental endocrine disruptors

Abstract

Bisphenols are among the most massively produced chemicals in the world, due to their use for manufacturing polycarbonate plastics and epoxy resins. Their occurrence in drinking water and sewage systems is caused by leaching from bisphenol-containing plastic pipes. For people most common exposure is from drinking water and food. In aquatic environments, bisphenols commonly undergo transformation by chlorination and bromination, due to presence of hypochlorite. Products of this transformation have the potential of being more toxic than its parent compound, that is why they were the subject of research in this thesis. Most bisphenols have a high logP value which makes them more resilient for biodegradation and have a higher tendency to accumulate in tissues. In this thesis we predicted logP values, environmental impact, acute toxicity and endocrine activity for eight bisphenols and their transformation products by using two programs Endocrine Disruptome and VegaNIC. In silico methods guide us toward areas in research that lack in vivo and in vitro studies for better endocrine and environmental profiling of transformation products of bisphenols. We estimated environmental fate of bisphenols based on their logP values and program VegaNIC predictions to find that transformation can increase the stability of bisphenols and that most bisphenols are not biodegradable. Bisphenol P showed the highest bioaccumulation factor and bisphenol S the lowest among studied bisphenols. When assessing acute toxicity, the results showed the least toxic studied compound in this thesis to be bisphenol S and the most to be tetrabromobisphenol P. Brominated transformation products showed to be more acutely toxic than their chlorinated counterparts. The results of endocrine activity showed that the analyzed bisphenols exhibit the highest probability of binding to the AR, AR an., ERα, ERβ, ERβ an., GR, MR, PPARγ, TRα and TRβ human receptors. Increase in probability of binding for transformation products was noticed for all studied bisphenols. Mono- and disubstituted transformation products showed a higher probability of binding to nuclear receptors, also chlorinated transformation products were more likely to increase the probability of binding than brominated. The results we obtained by in silico methods indicate greater bioaccumulation, acute toxicity and endocrine activity after bisphenols undergo chlorination and bromination.

• Keywords: bisphenols, halogenation, transformation products, bioaccumulation, in silico prediction, endocrine activity, ecotoxicologigal effects