Halogenated bisphenol A alternatives inhibit aldo-keto reductase 1C1 and induce metabolic alterations in human adipocytes.

Bisphenol A (BPA) is a widely used plastic monomer with well-established endocrine-disrupting properties and emerging evidence for metabolism-disrupting effects. Following regulatory restrictions, structurally modified alternatives, including halogenated derivatives, have been introduced, but information on their metabolic effects remains scarce. Hence, we analyzed proteomic and metabolomic responses in SGBS human adipocytes after exposure to BPA and five analogues (TBBPA, TCBPA, BPS, TBBPS, and TCBPS), including environmentally relevant concentrations of 10 nM. Intracellular target proteins were identified using thermal proteome profiling (TPP). All tested alternatives significantly increased intracellular triglyceride levels, indicating adipogenic potential. Proteomic and metabolomic analyses revealed alterations in lipid and energy metabolism and the central carbon cycle. TPP identified protein targets within steroid hormone pathways, fatty acid, central carbon, and amino acid metabolism, which were confirmed by nano differential scanning fluorimetry. Among these, AKR1C1 showed strong binding interactions with the tested bisphenols, resulting in reduced enzymatic activity. Pharmacological inhibition of AKR1C1 induced metabolic changes resembling those caused by BPS and its halogenated derivates. Overall, these findings identify AKR1C1 as a potential molecular target of halogenated bisphenols and demonstrate that these compounds disrupt adipocyte metabolism highlighting the importance of mechanistic data of chemical risk assessment.