20.500.12556/RUL-154020 Halogenation of common phenolic household and personal care product ingredients enhances their AhR-modulating capacity 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 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. aryl hydrocarbon receptor halogenated transformation products parabens bisphenols UV filters cytokine release AhR arilni ogljikovodikov receptor halogenirani transformacijski produkti parabeni bisfenoli UV filtri sprostitev citokinov hormonski motilci imunski odziv true false true Angleški jezik Slovenski jezik Članek v reviji 2024-01-19 12:50:54 2024-01-19 12:50:58 2024-05-22 03:48:12 0000-00-00 00:00:00 2024 0 0 9 str. Vol. 350, art. 141116 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 612.43:620.266.1:616-097 0045-6535 10.1016/j.chemosphere.2024.141116 179509251 1-s2.0-S0045653524000092-main.pdf 1-s2.0-S0045653524000092-main.pdf 1 D770C5A0A7B2203E089C08C4B83F42A1 bcd2de982bfa44d38da600fc30b1e2bfa3dcfeaf42fe457ad8eccb46d4545b91 d57cb17f-1761-11ef-b8e5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=183769 https://www.sciencedirect.com/science/article/pii/S0045653524000092 1 02eb8cbd-b6c1-11ee-b009-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=180151 Fakulteta za farmacijo 0 0 0