Low-Dose Bisphenol-A Impairs Adipogenesis and Generates Dysfunctional 3T3-L1 Adipocytes

PLoS One. 2016 Mar 4;11(3):e0150762. doi: 10.1371/journal.pone.0150762. eCollection 2016.

Abstract

Environmental endocrine disruptors (EDCs), including bisphenol-A (BPA), have been recently involved in obesity and diabetes by dysregulating adipose tissue function. Our aim was to examine whether prolonged exposure to low doses of BPA could affect adipogenesis and adipocyte metabolic functions. Therefore, 3T3-L1 pre-adipocytes were cultured for three weeks with BPA 1 nM to mimic human environmental exposure. We evaluated BPA effect on cell proliferation, differentiation, gene expression and adipocyte metabolic function. BPA significantly increased pre-adipocyte proliferation (p<0.01). In 3T3-L1 adipocytes differentiated in the presence of BPA, the expression of Peroxisome proliferator-activated receptor gamma (PPARγ), Fatty Acid Binding Protein 4/Adipocyte Protein 2 (FABP4/AP2) and CCAAT/enhancer binding protein (C/EBPα) was increased by 3.5, 1.5 and 3 folds, respectively. Mature adipocytes also showed a significant increase in lipid accumulation (p<0.05) and alterations of insulin action, with significant reduction in insulin-stimulated glucose utilization (p<0.001). Moreover, in mature adipocytes, mRNA levels of Leptin, interleukin-6 (IL6) and interferon-γ (IFNγ) were significantly increased (p<0.05). In conclusion, BPA prolonged exposure at low doses, consistent with those found in the environment, may affect adipocyte differentiation program, enhancing pre-adipocyte proliferation and anticipating the expression of the master genes involved in lipid/glucose metabolism. The resulting adipocytes are hypertrophic, with impaired insulin signaling, reduced glucose utilization and increased pro-inflammatory cytokine expression. Thus, these data supported the hypothesis that BPA exposure, during critical stages of adipose tissue development, may cause adipocyte metabolic dysfunction and inflammation, thereby increasing the risk of developing obesity-related diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipocytes / pathology*
  • Adipogenesis / drug effects*
  • Adipogenesis / genetics
  • Animals
  • Benzhydryl Compounds / toxicity*
  • Biomarkers / metabolism
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Proliferation / drug effects
  • Gene Expression Regulation / drug effects
  • Glucose / metabolism
  • Inflammation / pathology
  • Inflammation Mediators / metabolism
  • Insulin / metabolism
  • Lipid Droplets / drug effects
  • Lipid Droplets / metabolism
  • Lipid Metabolism / drug effects
  • Mice
  • Phenols / toxicity*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / drug effects

Substances

  • Benzhydryl Compounds
  • Biomarkers
  • Inflammation Mediators
  • Insulin
  • Phenols
  • RNA, Messenger
  • Glucose
  • bisphenol A

Grants and funding

This work was supported in part by MIUR-PRIN (Ministero dell'Istruzione, dell'Università e della Ricerca-Progetti di Ricerca di Interesse Nazionale) [prot. 2010MCLBCZ], MIUR-FIRB MERIT (Ministero dell'Istruzione, dell'Università e della Ricerca-Fondo per gli Investimenti della Ricerca di Base Medical Research in Italy)[RBNE08NKH7], Associazione Italiana per la Ricerca sul Cancro [AIRC n: IG 12136], European Foundation for the Study of Diabetes [EFSD, EFSD Diabetes and Cancer Program 2011]. The funders had not role in study design, data collection and analysis, decision to publish or preparation of the manuscript.