Replacing BPA: Structural Substitutes BPAF Binding to the Progesterone Receptor Elevates Breast Cancer Risk

Abstract As the global production of bisphenol analogs (BPs) surges to replace regulated bisphenol A (BPA), their pervasive environmental presence and uncharacterized breast cancer risk raise critical public health concerns. Herein, the environmental risks of BPs are deciphered by linking their structural affinity for the progesterone receptor (PR), a master regulator of breast cancer, to oncogenic outcomes across experimental tiers. Molecular simulations reveal that environmental BPAF and BPB exhibited stronger binding to the PR‐ligand binding domain (LBD) than BPA. Chemical assays confirm persistent PR‐LBD structural changes after BPs exposure, mimicking endocrine disruption patterns. The cellular thermal shift assay also confirms the interaction between the PR and BPs. In vitro, BPAF and BPF boost PR expression at human‐relevant concentrations. In addition, BPAF elevates PR expression, and the enhanced migratory and invasive capacities are effectively suppressed by the PR inhibitor. Toxicological Prioritization Index‐based risk stratification, weighted by the binding affinity of BPs to the PR and cellular toxicity, ranks BPAF as the highest‐risk analog. Alarmingly, low‐dose BPAF exposure (30 µg kg ⁻¹ ) accelerates mammary tumor growth in mice, paralleling PR upregulation in tumor tissues. This study underscores that substituting BPA with structurally akin analogs merely shifts, rather than mitigates, environmental health risks.