Decidual Disrupting Effects of Low-Dose Benzophenone-Type UV Filters in Human Endometrial Stromal Cells via ER/PR/FOXO1 Signaling

Abstract

Exposure to endocrine disrupting chemicals (EDCs), particularly benzophenone (BP)-type UV filters, has been epidemiologically linked to endometrium-related reproductive risks in women. However, their effects on hormone-driven endometrial events and key receptor signaling at the human cellular level remain unexplored. Herein, using human primary endometrial stromal cells (HESCs), we investigated the disrupting effects of five BP congeners and deciphered the underlying mechanism on decidualization, a functional change of the endometrium preparing for pregnancy. BP-8, its two metabolites, BP-3, and BP-1 at 10 nM significantly disrupted progesterone-dependent decidualization in HESCs, marked by 1.5–1.8-fold and 2.2–2.6-fold upregulation of IGFBP-1 and LEFTY, respectively. Decidual transcriptional activators, WNT-FOXO1, were significantly induced by BPs, which are implicated in G2 phase cell arrest (from 3.26% to 8.93%) and apoptosis (from 12.29% to 25.61%). Mechanistically, the inhibition of estrogen receptor α (ERα) effectively alleviated these decidual disrupting effects. BPs increased the transcription of ERα and progesterone receptor (PR) signaling and enhanced nuclear translocation and interaction between ERα and PR during decidualization. The ERα-mediated enhancement of PR signaling activity by BPs was further validated in progesterone response element-luciferase transfected cells. Collectively, our findings elucidate the molecular pathway through which BPs disrupt endometrial decidualization via ERα/PR/FOXO1, providing critical mechanistic insights for the reproductive risk assessment of BPs and structurally related EDCs.