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

Karunarathne, Wisurumuni Arachchilage Hasitha Maduranga; Molagoda, Ilandarage Menu Neelaka; Choi, Yung Hyun; Park, Sang Rul; Lee, Seungheon; Kim, Gi-Young

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

2021

In addition to endocrine disruption, bisphenol A (BPA) is known to induce inflammation through the activation of nuclear factor-κB (NF-κB). However, detailed studies on the mechanism of NF-κB activation by BPA have not been sufficiently conducted. In the present study, we observed that low concentrations of BPA (≤1 μM) upregulated the release of proinflammatory mediators, including nitric oxide (NO) and prostaglandin E₂ (PGE₂), as well as proinflammatory cytokines, including tumor necrosis factor (TNF)-α, 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-κB signaling pathway. Additionally, BPA increased morphological abnormalities and mortality in zebrafish larvae and enhanced the dispersal of macrophages and neutrophils 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 indicates 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.

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