Sublethal bisphenol A compromises BV-2 microglial immunity by disrupting TLR4 signaling through the ROS/Nrf2-Keap1/HO-1 axis.

Bisphenol A (BPA), a ubiquitous environmental contaminant, is increasingly recognized as a neurotoxicant. Epidemiological and experimental evidence links BPA exposure with neurodegenerative diseases and abnormal neurobehavior, implicating it as a risk factor for neuronal dysfunction and cognitive impairment. Given the critical role of microglia in maintaining brain immune homeostasis, we investigated whether BPA interfered with microglial immune reactivity, which may be one of the reasons why BPA causes neuropathological alterations. Using an in vitro BV-2 microglial model, sublethal BPA exposure, with or without lipopolysaccharide (LPS), was assessed for immunoinflammatory responses. BPA, without compromising cell viability, suppressed basal immune activity and attenuated LPS-induced responses. This was evidenced by reduced secretion of pro- and anti-inflammatory cytokines, alterations in NLRP3 inflammasome-related signaling (including caspase-1 and IL-1β processing), and dysregulated expression of antioxidants, motility-related proteins, and zinc-dependent metalloproteinases. These changes were associated with downregulation of MAPK, Akt, and NF-κB pathways, alongside ROS-dependent upregulation of the Nrf2-Keap1/heme oxygenase-1 (HO-1) axis, which interfered with both quiescent and LPS-driven Toll-like receptor 4 (TLR4) signaling. Collectively, these findings suggest that sublethal BPA interferes with TLR4-related immunoinflammatory signaling in microglia, potentially via modulation of the ROS/Nrf2-Keap1/HO-1 axis. Given that disruption of brain innate immunity may elevate the risk of developing neuropathies, this work highlights the potential impact of BPA, particularly on microglial immune function.