Cheminformatic Read-Across Approach Revealed Ultraviolet Filter Cinoxate as an Obesogenic Peroxisome Proliferator-Activated Receptor γ Agonist

This study introduces a novel cheminformatic read-across
approach
designed to identify potential environmental obesogens, substances
capable of disrupting metabolism and inducing obesity by mainly influencing
nuclear hormone receptors (NRs). Leveraging real-valued two-dimensional
features derived from chemical fingerprints of 8435 Tox21 compounds,
cluster analysis and subsequent statistical testing revealed 385 clusters
enriched with compounds associated with specific NR targets. Notably,
one cluster exhibited selective enrichment in peroxisome proliferator-activated
receptor γ (PPARγ) agonist activity, prominently featuring
methoxy cinnamate ultraviolet (UV) filters and obesogen-related compounds.
Experimental validation confirmed that 2-ethoxyethyl 4-methoxycinnamate,
an organic UV filter cinoxate, could selectively bind to PPARγ
(Ki = 18.0 μM), eliciting an obesogenic
phenotype in human bone marrow-derived mesenchymal stem cells during
adipogenic differentiation. Molecular docking and further experiments
identified cinoxate as a potent PPARγ full agonist, demonstrating
a preference for coactivator SRC3 recruitment. Moreover, cinoxate
upregulated transcription levels of genes encoding lipid metabolic
enzymes in normal human epidermal keratinocytes as primary cells exposed
during clinical usage. This study provides compelling evidence for
the efficacy of cheminformatic read-across analysis in prioritizing
potential obesogens, showcasing its utility in unveiling cinoxate
as an obesogenic PPARγ agonist.