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.

除了内分泌干扰外，双酚A（BPA）还通过激活核因子-κB（NF-κB）诱导炎症。然而，关于双酚A激活NF-κB的机制的详细研究尚未充分进行。在本研究中，我们观察到低浓度的BPA（≤1μM）上调促炎性介质的释放，包括一氧化氮（NO）和前列腺素E ₂（PGE ₂）以及促炎性细胞因子，包括肿瘤坏死因子（TNF）-α，白介素（IL）-12和IL-6。分子建模预测，与Toll样受体4（TLR4）/髓样分化因子2（MD2）复合物对接的BPA激活下游分子，包括髓样分化主要反应88（MyD88）和与IL-1受体相关的激酶4（IRAK-4） ）并导致NF-κB信号通路的上调。另外，BPA增加了斑马鱼幼虫的形态异常和死亡率，并增强了巨噬细胞和嗜中性粒细胞在全身的扩散，从而引起内毒素血症样疾病。但是，一种特定的TLR4抑制剂TLR4-IN-C34可以减轻BPA引起的死亡率和形态异常，这表明TLR4 / MD2复合物是BPA诱导的免疫毒性的分子靶标。总体而言，我们的结果表明，低浓度的BPA是TLR4 / MD2复合物的潜在激动剂，可增强免疫反应并最终导致内毒素血症样疾病。