Integrative genetic, single-cell and mechanistic dissection identifies bisphenol a as a causal driver of preeclampsia via fibroblast-derived IL-6/STAT3 signaling.

In hypertensive disorders of pregnancy, particularly preeclampsia, epidemiological associations have increasingly implicated the endocrine disruptor Bisphenol A (BPA), but robust mechanistic evidence remains elusive. Building upon accumulating clinical concern and in vivo data, we pursued an integrative, multi-omic investigation to dissect whether BPA causally and directly contributes to placental maladaptation and vascular dysfunction. Two-sample Mendelian randomization analyses using large European-ancestry genome-wide association datasets demonstrated a significant, directionally concordant relationship between genetically instrumented BPA exposure and preeclampsia risk, supporting causation rather than simple correlation. Single-cell transcriptomic analysis of the maternal-fetal interface identified stromal fibroblasts as a dominant source and target of interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling. Molecular docking and Molecular Dynamics Simulations revealed that BPA binds stably within hydrophobic pockets of IL-6 and, to a lesser extent, STAT3, thereby providing a plausible physical mechanism for ligand-mediated pathway activation. Complementary experiments in human HTR-8/SVneo trophoblasts showed that nanomolar BPA exposure induced dose- and time-dependent STAT3 phosphorylation, promoted IL-6-STAT3 complex formation, and upregulated prototypical downstream genes, including SOCS3, MMP9 and IL-8, hallmarks of inflammation and extracellular matrix remodeling. The concordance between genetic, cellular, structural and functional datasets delineate an integrated cascade in which BPA perturbs fibroblast-centered IL-6/STAT3 signalling, precipitating pro-inflammatory and remodeling responses consistent with preeclampsia pathophysiology. These findings elevate BPA from an associative to a mechanistically credible, modifiable risk factor and nominate stromal IL-6/STAT3 signaling as a therapeutic target for preventing environmentally induced placental disorders.