Low-dose exposure to bisphenols A, F and S of human primary adipocyte impacts coding and non-coding RNA profiles

PLoS One. 2017 Jun 19;12(6):e0179583. doi: 10.1371/journal.pone.0179583. eCollection 2017.


Bisphenol A (BPA) exposure has been suspected to be associated with deleterious effects on health including obesity and metabolically-linked diseases. Although bisphenols F (BPF) and S (BPS) are BPA structural analogs commonly used in many marketed products as a replacement for BPA, only sparse toxicological data are available yet. Our objective was to comprehensively characterize bisphenols gene targets in a human primary adipocyte model, in order to determine whether they may induce cellular dysfunction, using chronic exposure at two concentrations: a "low-dose" similar to the dose usually encountered in human biological fluids and a higher dose. Therefore, BPA, BPF and BPS have been added at 10 nM or 10 μM during the differentiation of human primary adipocytes from subcutaneous fat of three non-diabetic Caucasian female patients. Gene expression (mRNA/lncRNA) arrays and microRNA arrays, have been used to assess coding and non-coding RNA changes. We detected significantly deregulated mRNA/lncRNA and miRNA at low and high doses. Enrichment in "cancer" and "organismal injury and abnormalities" related pathways was found in response to the three products. Some long intergenic non-coding RNAs and small nucleolar RNAs were differentially expressed suggesting that bisphenols may also activate multiple cellular processes and epigenetic modifications. The analysis of upstream regulators of deregulated genes highlighted hormones or hormone-like chemicals suggesting that BPS and BPF can be suspected to interfere, just like BPA, with hormonal regulation and have to be considered as endocrine disruptors. All these results suggest that as BPA, its substitutes BPS and BPF should be used with the same restrictions.

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Benzhydryl Compounds / chemistry
  • Benzhydryl Compounds / toxicity*
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Databases, Factual
  • Down-Regulation / drug effects*
  • Endocrine Disruptors / toxicity*
  • Humans
  • Phenols / chemistry
  • Phenols / toxicity*
  • RNA, Messenger / metabolism
  • RNA, Untranslated / metabolism*
  • Sulfones
  • Up-Regulation / drug effects*


  • Benzhydryl Compounds
  • Endocrine Disruptors
  • Phenols
  • RNA, Messenger
  • RNA, Untranslated
  • Sulfones
  • bisphenol F
  • bis(4-hydroxyphenyl)sulfone
  • bisphenol A

Grants and funding

This study was funded by the Centre National de la Recherche Scientifique (www.cnrs.fr), the Ministère de l’Ecologie, du Développement Durable et de l’Energie” (MEDDE) according to the “Programme National de Recherche sur les Perturbateurs Endocriniens” (13-MRES-PNRPE-2-CVS-044; http://www.developpement-durable.gouv.fr), and the European Research Council (ERC-2011-ADG; https://erc.europa.eu). The authors thank the UMR 8199 LIGAN-PM Genomics platform (Lille, France) which belongs to the 'Federation de Recherche' 3508 Labex EGID (European Genomics Institute for Diabetes; ANR-10-LABX-46) and was supported by the ANR Equipex 2010 session (ANR-10-EQPX-07-01; 'LIGAN-PM') for support in global data processing and qPCR. The LIGAN-PM Genomics platform (Lille, France) is also supported by the FEDER and the Region Nord-Pas-de-Calais-Picardie. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.