PT - JOURNAL ARTICLE AU - Radha D. Singh AU - Jessica L. Wager AU - Taylor B Scheidl AU - Liam T. Connors AU - Sarah Easson AU - Mikyla A. Callaghan AU - Samuel Alatorre-Hinojosa AU - Lucy H. Swift AU - Pina Colarusso AU - Anshul Jadli AU - Timothy E. Shutt AU - Vaibhav Patel AU - Jennifer A. Thompson TI - Potentiation of Adipogenesis by Reactive Oxygen Species is a Unifying Mechanism in the Pro-adipogenic Properties of Bisphenol A and its New Structural Analogues AID - 10.1101/2022.09.08.507176 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.09.08.507176 4099 - http://biorxiv.org/content/early/2022/10/29/2022.09.08.507176.short 4100 - http://biorxiv.org/content/early/2022/10/29/2022.09.08.507176.full AB - Aims Structural analogues of bisphenol A (BPA), including BPS and BPF, are emerging environmental toxicants as their presence in the environment is rising since new regulatory restrictions were placed on BPA-containing infant products. The adipogenesis-enhancing effect of bisphenols may explain the link between human exposure and metabolic disease; however, underlying molecular pathways remain unresolved.Results Exposure to BPS, BPF, BPA or ROS generators enhanced lipid droplet formation and expression of adipogenic markers after induction of differentiation in adipose-derived progenitors isolated from mice. RNAseq analysis in BPS-exposed progenitors revealed modulation in pathways regulating adipogenesis and responses to oxidative stress. ROS was higher in bisphenol-exposed cells, while co-treatment with antioxidants attenuated adipogenesis and abolished the effect of BPS. There was a loss of mitochondria membrane potential in BPS-exposed cells and mitochondria-derived ROS contributed to potentiation of adipogenesis by BPS and its analogues. Male mice exposed to BPS during gestation had higher whole-body adiposity, as measured by TD-NMR, while postnatal exposure had no impact on adiposity in either sex.Innovation These findings support existing evidence showing a role for ROS in regulating adipocyte differentiation and are the first to highlight ROS as a unifying mechanism that explains the pro-adipogenic properties of BPA and its structural analogues.Conclusion ROS act as signaling molecules in the regulation of adipocyte differentiation and mediate bisphenol-induced potentiation of adipogenesis.Competing Interest StatementThe authors have declared no competing interest.(ADIPOQ)Adiponectin(Fos)AP-1 transcription factor subunit(BPA)Bisphenol A(BPF)bisphenol F(BPS)bisphenol S(Cat)catalase(C/EBPβ)CCAAT/enhancer binding protein beta(EDC)endocrine disrupting chemical(ETC)electron transport chain(FABP4)fatty acid binding protein 4(FASN)fatty acid synthase(GLUT4)glucose transporter type 4(Gpx1)Glutathione peroxidase 1(Klf4)Kruppel-like factor 4(Nr6a1)nuclear receptor sub-family 6 group A member 1(PPARγ)peroxisome proliferator-activated receptor gamma(Ptgs2)prostaglandin endoperoxidase synthase 2(ROS)reactive oxygen species(RBC)red blood cell(SAT)subcutaneous adipose tissue(SCD1)stearoyl-CoA desaturase 1(SVF)stromal vascular fraction(SOD)superoxide dismutase