Sex-dependent dysregulation of human neutrophils responses​ by bisphenol A

Abstract Background: The study objective was to assess the impact of a xenoestrogen—bisphenol A (BPA) (at the environmental concentration and 100-fold increased dose)—on selected functions of neutrophils, as well as to compare the effect of this compound and 17-β-estradiol (E2) (at the physiological concentration) on the studied functions of these cells in women and men.Methods and Results: Analysis of the results obtained for both sexes demonstrated a reduction in the chemotactic potential of neutrophils after exposure to BPA. In the presence of BPA, the phagocytic activity, as measured via the SCORE index, was found to be elevated in the neutrophils from women and reduced in those isolated for men. Exposure to BPA resulted in an increased percentage of neutrophils expressing CD14 and CD284 (TLR4), as well as an increased percentage of NET-forming cells, in the case of both sexes. In addition, a reduced capacity to release NETs was observed in cells that were preincubated with xenoestrogen and then stimulated with LPS. The stimulating role of BPA and 17-β-estradiol in the activation of NADPH oxidase, evaluated using NBT stimulation test, was evident only in the neutrophils from women. No influence of E2 could be observed on the expression of CD14 and CD284 by neutrophils, their chemotactic potential and phagocytic activity, and the amount of NETs for both sexes. The study further showed that BPA intensified the NO production and iNOS expression in the neutrophils from both sexes. In addition, an increase in expression was found for all the tested proteins of the PI3K/AKT pathway for men.Conclusions: The conducted study demonstrated that BPA influenced the functions of neutrophils associated with locomotion and pathogen elimination, which may disturb the response of these cells in both women and men. Furthermore, neutrophils isolated from women were found to be more susceptible to the effect of BPA in terms of oxygen-dependent killing, compared to those obtained from men. The variable results of the tests conducted in the presence of BPA indicated the stronger effect of xenoestrogen on human neutrophils compared to that of 17-β-estradiol.