Human Peripheral Blood Mononuclear Cell Function and Dendritic Cell Differentiation Are Affected by Bisphenol-A Exposure

Abstract

Environmental pollutants, including endocrine disruptor chemicals (EDCs), interfere on human health, leading to hormonal, immune and metabolic perturbations. Bisphenol-A (BPA), a main component of polycarbonate plastics, has been receiving increased attention due to its worldwide distribution with a large exposure. In humans, BPA, for its estrogenic activity, may have a role in autoimmunity, inflammatory and allergic diseases. To this aim, we assessed the effect of low BPA doses on functionality of human peripheral blood mononuclear cells (PBMCs), and on in vitro differentiation of dendritic cells from monocytes (mDCs). Fresh peripheral blood samples were obtained from 12 healthy adult volunteers. PBMCs were left unstimulated or were activated with the mitogen phytohemagglutinin (PHA) or the anti-CD3 and anti-CD28 antibodies and incubated in presence or absence of BPA at 0.1 and 1nM concentrations. The immune-modulatory effect of BPA was assessed by evaluating the cell proliferation and the levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), interleukin-10 (IL-10) and interleukin-13 (IL-13) secreted by PBMCs. mDCs were differentiated with IL-4 and GC-CSF with or without BPA and the expression of differentiation/maturation markers (CD11c, CD1a, CD86, HLA-DR) was evaluated by flow cytometry; furthermore, a panel of 27 different cytokines, growth factors and chemokines were assayed in the mDC culture supernatants. PBMCs proliferation significantly increased upon BPA exposure compared to BPA untreated cells. In addition, a significant decrease in IL-10 secretion was observed in PBMCs incubated with BPA, either in unstimulated or mitogen-stimulated cells, and at both 0.1 and 1nM BPA concentrations. Similarly, IL-13 was reduced, mainly in cells activated by antiCD3/CD28. By contrast, no significant changes in IFN-γ and IL-4 production were found in any condition assayed. Finally, BPA at 1nM increased the density of dendritic cells expressing CD1a and concomitantly decreased the expression of HLA-DR and CD86 activation markers. In conclusion, in humans the exposure to BPA causes on PBMCs a significant modulation of proliferative capacity and cytokine production, and on mDCs alteration in differentiation and phenotype. These immune cell alterations suggest that low dose chronic exposure to BPA could be involved in immune deregulation and possibly in the increased susceptibility to develop inflammatory and autoimmune diseases.

Immune Cells in the Uterine Remodeling: Are They the Target of Endocrine Disrupting Chemicals?

“…BPA exposure in human significantly increased in the proliferation of PBMC and modulated their cytokine production leading to a decrease in IL-10 and IL-13 expression. Additionally, BPA altered the phenotype of myeloid DCs by an increased CD1a, but decreased HLA-DR and CD86 expression (178). In contrast, it has been shown that BPA among other bisphenols decreased the expression of CD1a, CD80, CD86, and CD83 but increased the numbers of HLA-DR positive monocyte-derived DCs (179).…”

Differential influences of the BPA, BPS and BPF on in vitro IL-17 secretion by mouse and human T cells

“…Such differences observed between total splenocytes and Th17-polarized CD4 + T cells in IL-17 production after BPA exposure in vitro could be due to J o u r n a l P r e -p r o o f the presence of antigen-presenting cells (APC), such as dendritic cells or macrophages, in the cell suspensions. Indeed, we and other have already reported that BPA is able to modulate dendritic cells, which can induce IL-23 production and therefore ultimately IL-17 enhancing Th17 cell responses (Camarca et al, 2016;Malaisé et al, 2018). Then, whether the other bisphenols, such as BPF or BPS, can modulate the action of APC to induce an enhanced Th17 response will deserve further studies.…”

“…In literature, BPA was reported to decrease significantly human PBMC proliferation, after cellactivation by anti-CD3 and anti-CD28 antibodies only at low concentration and for a longterm exposure (Herz et al, 2017). In an in vitro study, BPA, at concentrations comparable to those found in human serum, might also affect the human immune system homeostasis and reactiveness to external stimuli, by altering both PBMC and monocyte-derived dendritic cells functions (Camarca et al, 2016). Such apparent differences between mouse and human cells linked to Th17 cell phenotype have already been reported (Tuomela et al, 2016).…”

Endocrine Disruptor Compounds—A Cause of Impaired Immune Tolerance Driving Inflammatory Disorders of Pregnancy?

“…Similarly, suppression of type 1 IFNs in human plasmocytoid DCs by phthalates programs a Th2 phenotype in T cells characterized by suppressed IFN-g and enhanced IL-13 production (149). In contrast, BPA exposure increases CD1a expression in human PBMC-derived DCs, enabling them to drive polarization of naïve CD4 + T cells towards a Th1 phenotype (150). While it is evident that EDCs can modulate DC phenotype, further studies are required to understand the specific effects of these DC changes for T cell phenotype, function, and maturation state.…”