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

Retinoic acid-related orphan receptor gamma t (ROR gamma t) regulates immune responses and its impaired function contributes to inflammatory and autoimmune diseases and may promote skin cancer. Synthetic inverse ROR gamma t 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 ROR gamma t 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 ROR gamma activity using a previously established tetracycline-inducible reporter gene assay in CHO cells. These transactivation experiments revealed hexylparaben, benzylparaben and benzophenone-10 as ROR gamma agonists (EC50 values: 144 +/- 97 nM, 3.39 +/- 1.74 mu M and 1.67 +/- 1.04 mu M, respectively), and they could restore ROR gamma activity after suppression by an inverse agonist. Furthermore, they enhanced ROR gamma t-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 ROR gamma agonists (low micromolar EC50 values). Moreover, an analysis of mixtures of the newly identified ROR gamma agonists suggested additive effects. This study presents novel ROR gamma(t) agonistic structural scaffolds. By activating ROR gamma(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 ROR gamma(t) in vivo.

Automated summary

ROR gamma t is a key protein that regulates immune responses, and impaired function may contribute to inflammatory and autoimmune diseases and promote skin cancer. Certain chemicals commonly used in cosmetics and body care products have been found to activate ROR gamma t and potentially worsen skin diseases. Further research is needed to assess the concentrations of these compounds in tissues and target cells, and their significance in activating ROR gamma t.