5 results on '"Jakopin, Žiga"'
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2. In silico profiling of endocrine-disrupting potential of bisphenol analogues and their halogenated transformation products.
- Author
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Nowak, Karolina and Jakopin, Žiga
- Subjects
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BISPHENOL A , *BISPHENOLS , *EPOXY resins , *ENDOCRINE disruptors , *HALOGENATION - Abstract
Due to its endocrine-disrupting properties, bisphenol A (BPA) is being phased out from plastics, thermal paper and epoxy resins, and its replacements are being introduced into the market. Bisphenols are released into the environment, where they can undergo halogenation. Unlike BPA, the endocrine-disrupting potential of BPA analogues and their halogenated transformation products has not been extensively studied. The aim of this study was to evaluate the endocrine-disrupting potential of 18 BPA analogues and their halogenated derivatives by calculating affinities for 14 human nuclear receptors utilizing the Endocrine Disruptome and VirtualToxLab™ in silico tools. Our simulations identified AR, ERs, and GR as the most favorable targets of bisphenols and their derivatives. Several BPA analogues displayed a higher predicted potential for endocrine disruption than BPA. Our models highlighted BPZ and BPPH as the most hazardous in terms of predicted endocrine activities. Halogenation, in general, was predicted to increase the binding affinity of bisphenols for AR, ERβ, MR, GR, PPARγ, and TRβ. Notably, mono- or 2,2′-di-halogenated bisphenols exhibited the highest potential for endocrine disruption. In vitro corroboration of the obtained results should be the next milestone in evaluating the safety of BPA substitutes and their halogenated transformation products. [Display omitted] • Endocrine-disrupting potential of BPA, BPA analogues, and their halogenated derivatives was investigated in silico. • BPPH, BPTMC and BPZ were identified as the most potent endocrine disruptors. • Halogenation increases predicted binding affinity of bisphenols for AR, ERβ, MR, GR, PPARγ, and TRβ • Mono- or 2,2′-dihalogenated bisphenols exhibited the highest predicted endocrine disrupting potential. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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3. Halogenation of common phenolic household and personal care product ingredients enhances their AhR-modulating capacity.
- Author
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Weiss, Veronika, Gobec, Martina, and Jakopin, Žiga
- Subjects
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PERSONAL care product ingredients , *MONONUCLEAR leukocytes , *TRICLOSAN , *ARYL hydrocarbon receptors , *PARABENS , *HALOGENATION , *ENDOCRINE disruptors - Abstract
The Aryl Hydrocarbon Receptor (AhR), a ligand-activated transcription factor, orchestrates responses to numerous structurally diverse endogenous and exogenous ligands. In addition to binding various xenobiotics, AhR also recognizes endocrine disruptors, particularly those featuring chlorinated or brominated aromatic structures. There is limited data available on the impact of common household and personal care product ingredients let alone their halogenated transformation products. Herein we bridge this knowledge gap by preparing a library of chlorinated and brominated parabens, bisphenols, UV filters, and nonylphenols. An evaluation of total of 125 compounds for agonistic and antagonistic activity on AhR unveiled a low micromolar agonist, Cl 2 BPAF with an EC 50 of 13 μM. Moreover, our study identified several AhR antagonists, with BrBzP emerging as the most potent with an IC 50 of 8.9 μM. To further investigate the functional implications of these compounds, we subjected the most potent agonist and antagonist to a functional assay involving cytokine secretion from peripheral blood mononuclear cells and compared their activity with the commercially available AhR agonist and antagonist. Cl 2 BPAF exhibited an overall immunosuppressive effect by reducing the secretion of proinflammatory cytokines, including IL-6, IFN-γ, and TNF-α, while BrBzP displayed opposite effects, leading to an increase of those cytokines. Notably, the immunomodulatory effects of Cl 2 BPAF surpassed those of ITE, a bona fide AhR agonist, while the impact of BrBzP exceeded that of CH223191, a bona fide AhR antagonist. In summary, our study underscores the potential influence of halogenated transformation products on the AhR pathway and, consequently, their role in shaping the immune responses. [Display omitted] • A comprehensive library of halogenated transformation products was prepared. • Halogenated derivatives can exhibit more pronounced AhR activity than parent compounds. • Cl 2 BPAF was the most potent agonist and BrBzP most potent antagonist of the series. • Cl 2 BPAF decreased LPS-induced inflammatory cytokine secretion from PBMCs. • BrBzP increased LPS-induced inflammatory cytokine secretion from PBMCs. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
4. Halogenated ingredients of household and personal care products as emerging endocrine disruptors.
- Author
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Klančič, Veronika, Gobec, Martina, and Jakopin, Žiga
- Subjects
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PARABENS , *PERSONAL care product ingredients , *ENDOCRINE disruptors , *ANDROGEN receptors , *ARYL hydrocarbon receptors , *ALKYLPHENOL ethoxylates , *SOIL pollution - Abstract
The everyday use of household and personal care products (HPCPs) generates an enormous amount of chemicals, of which several groups warrant additional attention, including: (i) parabens, which are widely used as preservatives; (ii) bisphenols, which are used in the manufacture of plastics; (iii) UV filters, which are essential components of many cosmetic products; and (iv) alkylphenol ethoxylates, which are used extensively as non-ionic surfactants. These chemicals are released continuously into the environment, thus contaminating soil, water, plants and animals. Wastewater treatment and water disinfection procedures can convert these chemicals into halogenated transformation products, which end up in the environment and pose a potential threat to humans and wildlife. Indeed, while certain parent HPCP ingredients have been confirmed as endocrine disruptors, less is known about the endocrine activities of their halogenated derivatives. The aim of this review is first to examine the sources and occurrence of halogenated transformation products in the environment, and second to compare their endocrine-disrupting properties to those of their parent compounds (i.e., parabens, bisphenols, UV filters, alkylphenol ethoxylates). Albeit previous reports have focused individually on selected classes of such substances, none have considered the problem of their halogenated transformation products. This review therefore summarizes the available research on these halogenated compounds, highlights the potential exposure pathways, and underlines the existing knowledge gaps within their toxicological profiles. [Display omitted] • Halogenated transformation products are found in the environment and in human tissues. • Halogenated derivatives disrupt different hormonal pathways than parent compounds. • Halogenation in general decreases estrogen and androgen receptor activation. • Introduction of halogens increases activation of thyroid and aryl hydrocarbon receptors. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
5. Vrednotenje bisfenolov in njihovih transformacijskih produktov kot okoljskih endokrinih motilcev in silico
- Author
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Hočevar, Maja and Jakopin, Žiga
- Subjects
in silico prediction ,transformation products ,ecotoxicologigal effects ,in silico napoved ,ekotoksikološki vpliv ,endocrine activity ,bioakumulacija ,endokrino delovanje ,bioaccumulation ,bisphenols ,halogenation ,halogeniranje ,bisfenoli ,transformacijski produkti - Abstract
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. 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.
- Published
- 2023
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