Bisphenol A: A potential Toll-like receptor 4/myeloid differentiation factor 2 complex agonist

In addition to endocrine disruption, bisphenol A (BPA) is known to induce inflammation through the activation of nuclear factor-kappa B (NF-kappa B). However, detailed studies on the mechanism of NF-kB activation by BPA have not been sufficiently conducted. In the present study, we observed that low concentrations of BPA (<= 1 mM) upregulated the release of proinflammatory mediators, including nitric oxide (NO) and prostaglandin E-2 (PGE(2)), as well as proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-12, and IL-6. Molecular modeling predicted that BPA docked with the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD2) complex activates downstream molecules including myeloid differentiation primary response 88 (MyD88) and IL-1 receptor-associated kinase 4 (IRAK-4) and results in the upregulation of the NF-kappa B signaling pathway. Additionally, BPA increased morphological abnormalities and mortality in zebrafish larvae and enhanced the dispersal of macrophages and neu-trophils in the whole body, thereby causing an endotoxemia-like disorder. However, a specific TLR4 inhibitor, TLR4-IN-C34, mitigated BPA-induced mortality and morphological abnormalities, which in-dicates that the TLR4/MD2 complex is a molecular target of BPA-induced immunotoxicity. Collectively, our results indicate that low concentrations of BPA, which is a potential agonist of the TLR4/MD2 complex, can intensify the immune response and eventually cause an endotoxemia-like disorder. (C) 2021 Elsevier Ltd. All rights reserved.

Automated summary

Low concentrations of BPA induce inflammation by activating the NF-kappa B signaling pathway and increasing the release of proinflammatory mediators. Molecular modeling suggests that BPA binds to the TLR4/MD2 complex to initiate downstream molecules and elicit an immune response.