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

Area of Science:

• Immunology
• Toxicology
• Molecular Biology

Background:

• Bisphenol A (BPA) is recognized for endocrine disruption and inflammation induction via nuclear factor-κB (NF-κB) activation.
• The precise mechanisms underlying BPA-induced NF-κB activation require further elucidation.

Purpose of the Study:

• To investigate the detailed molecular mechanisms by which BPA activates NF-κB.
• To explore the role of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD2) complex in BPA-induced immunotoxicity.

Main Methods:

• Molecular modeling to predict BPA interaction with the TLR4/MD2 complex.
• In vitro assessment of proinflammatory mediator and cytokine release.
• Zebrafish larvae model to evaluate BPA's in vivo effects on development and immune cell distribution.
• Utilizing a specific TLR4 inhibitor (TLR4-IN-C34) to assess its protective effects.

Main Results:

• Low BPA concentrations (≤1 μM) upregulated nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), and IL-6.
• Molecular modeling suggested BPA binds to TLR4/MD2, activating downstream signaling (MyD88, IRAK-4) and upregulating NF-κB.
• BPA induced morphological abnormalities, mortality, and immune cell dispersal in zebrafish larvae, mimicking an endotoxemia-like disorder.
• TLR4 inhibition significantly mitigated BPA-induced adverse effects.

Conclusions:

• BPA acts as a potential agonist of the TLR4/MD2 complex at low concentrations.
• BPA exposure intensifies immune responses and can lead to an endotoxemia-like disorder through TLR4/MD2 pathway activation.
• The TLR4/MD2 complex is a key molecular target for BPA-induced immunotoxicity.