Modulation of cytokine/chemokine production in human macrophages by bisphenol A: A comparison to analogues and interactions with genistein

J Immunotoxicol. 2018 Dec;15(1):96-103. doi: 10.1080/1547691X.2018.1476629.


The immunotoxicant bisphenol A (BPA) may produce toxic effects on organs and systems, in part, by altering the secretion of cytokines and chemokines. However, systematic studies of the effects of BPA, let alone of its analogs and in cases when there are interactions with other chemicals, on innate immunity and cytokine modulation are limited. The objectives of this study were to investigate the immunomodulatory effects of: (1) BPA and its analogs, BPS and BPAF; and (2) the interaction between BPA and genistein (GEN), a partial estrogen agonist or antagonist. BPA, BPS, and BPAF were incubated with PMA-differentiated-U937 cells (a widely used cell line for primary human macrophages) at concentrations of 0, 0.1, 1, 10, 100 µM for up to 96 h. BPA (0, 0.1, 1, 10 µM) and GEN (0, 1, 10 µM) were also applied at various combinations. Cell viability and 30 cytokines/chemokines were measured. The results showed that the cell viability-inhibiting effect of these three bisphenols was BPAF > BPA > BPS. At 0.1 µM, BPA and BPAF generally increased the secretion of cytokines/chemokines, while BPS had minimal effects. All three bisphenols generally suppressed the secretion of cytokines/chemokines at 1 µM, while increased their secretion at 10 µM. The most increased cytokines/chemokines were interferon (IFN)-γ, interleukin (IL)-1RA, IL-8 and MIP-1β, and the most decreased was IL-10. GEN increased cell viability at low BPA concentrations but had no effect when BPA levels were high. In general, GEN attenuated the BPA-induced secretion of cytokines/chemokines but enhanced it at low BPA concentrations. In conclusion, this study showed that BPA, BPS, and BPAF were immunotoxic to macrophages: BPS was the least toxic, while BPAF was the most toxic. Further, GEN reversed suppressive effects on macrophages that resulted from exposure to high concentrations of BPA and produced synergetic effects with BPA at low concentrations.

Keywords: Bisphenol A; U937; bisphenol AF; bisphenol S; chemokine; cytokine; genistein; macrophage.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Air Pollutants, Occupational / toxicity*
  • Benzhydryl Compounds / toxicity*
  • Cell Survival
  • Chemokines / metabolism
  • Cytokines / metabolism
  • Drug Interactions
  • Estrogens / metabolism
  • Genistein / pharmacology*
  • Humans
  • Immunity, Innate / drug effects
  • Inflammation / immunology*
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Phenols / toxicity*
  • Sulfones / toxicity*
  • U937 Cells


  • Air Pollutants, Occupational
  • Benzhydryl Compounds
  • Chemokines
  • Cytokines
  • Estrogens
  • Phenols
  • Sulfones
  • bis(4-hydroxyphenyl)sulfone
  • Genistein
  • bisphenol A
  • 4,4'-hexafluorisopropylidene diphenol