biostudies-literatureBolt MJCPRITNIEHS NIH HHSNIEHSNIH109275https://www.ebi.ac.uk/biostudies/studies/S-EPMC10926205biostudies-literatureUnknown27(3)The initial step in estrogen-regulated transcription is the binding of a ligand to its cognate receptors, named estrogen receptors (ERα and ERβ). Phytochemicals present in foods and environment can compete with endogenous hormones to alter physiological responses. We screened 224 flavonoids in our engineered biosensor ERα and ERβ PRL-array cell lines to characterize their activity on several steps of the estrogen signaling pathway. We identified 83 and 96 flavonoids that can activate ERα or ERβ, respectively. While most act on both receptors, many appear to be subtype-selective, including potent flavonoids that activate ER at sub-micromolar concentrations. We employed an orthogonal assay using a transgenic zebrafish <i>in vivo</i> model that validated the estrogenic potential of these compounds. To our knowledge, this is the largest study thus far on flavonoids and the ER pathway, facilitating the identification of a new set of potential endocrine disruptors acting on both ERα and ERβ.iScienceCharacterization of flavonoids with potent and subtype-selective actions on estrogen receptors alpha and beta.PMC10926205P42 ES027704P30 ES030285Abbott DHNeugebauer KASingh PKSafari KMancini MABolt MJMancini MGStossi FGorelick DAOceguera JfalseCharacterization of flavonoids with potent and subtype-selective actions on estrogen receptors alpha and beta.The initial step in estrogen-regulated transcription is the binding of a ligand to its cognate receptors, named estrogen receptors (ERα and ERβ). Phytochemicals present in foods and environment can compete with endogenous hormones to alter physiological responses. We screened 224 flavonoids in our engineered biosensor ERα and ERβ PRL-array cell lines to characterize their activity on several steps of the estrogen signaling pathway. We identified 83 and 96 flavonoids that can activate ERα or ERβ, respectively. While most act on both receptors, many appear to be subtype-selective, including potent flavonoids that activate ER at sub-micromolar concentrations. We employed an orthogonal assay using a transgenic zebrafish <i>in vivo</i> model that validated the estrogenic potential of these compounds. To our knowledge, this is the largest study thus far on flavonoids and the ER pathway, facilitating the identification of a new set of potential endocrine disruptors acting on both ERα and ERβ.2024-01-01T00:00:00Z2024 Mar2026-07-01T03:12:41.719Z2025-04-04T21:30:57.568ZS-EPMC109262053846956410.1016/j.isci.2024.109275