Activation of retinoic acid-related orphan receptor γ(t) by parabens and benzophenone UV-filters

Silvia G Inderbinen; Manuel Kley; Michael Zogg; Manuel Sellner; André Fischer; Jacek Kędzierski; Stéphanie Boudon; Anton M Jetten; Martin Smieško; Alex Odermatt

doi:10.1016/j.tox.2022.153159

Activation of retinoic acid-related orphan receptor γ(t) by parabens and benzophenone UV-filters

Toxicology. 2022 Apr 15:471:153159. doi: 10.1016/j.tox.2022.153159. Epub 2022 Mar 23.

Authors

Affiliations

¹ Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland; Swiss Centre for Applied Human Toxicology and Department of Pharmaceutical Sciences, University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland.
² Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
³ Computational Pharmacy, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 61, 4056 Basel, Switzerland.
⁴ Swiss Centre for Applied Human Toxicology and Department of Pharmaceutical Sciences, University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland; Computational Pharmacy, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 61, 4056 Basel, Switzerland.
⁵ Swiss Centre for Applied Human Toxicology and Department of Pharmaceutical Sciences, University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland.
⁶ Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111. T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
⁷ Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland; Swiss Centre for Applied Human Toxicology and Department of Pharmaceutical Sciences, University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland. Electronic address: alex.odermatt@unibas.ch.

PMID: 35337918
DOI: 10.1016/j.tox.2022.153159

Abstract

Retinoic acid-related orphan receptor γt (RORγt) regulates immune responses and its impaired function contributes to inflammatory and autoimmune diseases and may promote skin cancer. Synthetic inverse RORγt agonists block the production of Th17-associated cytokines including interleukin (IL)-17A and IL-22 and are under investigation for treatment of such pathologies. Unintentional RORγt activation in skin, following exposure to environmental chemicals, may promote inflammatory skin disease. Parabens and UV-filters, frequently used as additives in cosmetics and body care products, are intensively inspected for endocrine disrupting properties. This study assessed whether such compounds can interfere with RORγ activity using a previously established tetracycline-inducible reporter gene assay in CHO cells. These transactivation experiments revealed hexylparaben, benzylparaben and benzophenone-10 as RORγ agonists (EC₅₀ values: 144 ± 97 nM, 3.39 ± 1.74 µM and 1.67 ± 1.04 µM, respectively), and they could restore RORγ activity after suppression by an inverse agonist. Furthermore, they enhanced RORγt-dependent transcription of the pro-inflammatory IL-17A and/or IL-22 genes in the murine T-cell model EL4. Virtual screening of a cosmetics database for structurally similar chemicals and in vitro testing of the most promising hits revealed benzylbenzoate, benzylsalicylate and 4-methylphenylbenzoate as RORγ agonists (low micromolar EC₅₀ values). Moreover, an analysis of mixtures of the newly identified RORγ agonists suggested additive effects. This study presents novel RORγ(t) agonistic structural scaffolds. By activating RORγ(t) the identified parabens and UV-filters may potentially aggravate pathophysiological conditions, especially skin diseases where highest exposure of such chemicals can be expected. Follow-up studies should assess whether such compounds, either alone or as mixtures, can reach relevant concentrations in tissues and target cells to activate RORγ(t) in vivo.

Keywords: Immune disease; Inflammation; Paraben; Retinoic acid-related orphan receptor gamma; Th17 cell; UV-filter.