Bisphenol A exacerbates anxiety-like behavior and neuroinflammation in prefrontal cortex of adult obese mice

Aims: Bisphenol A (BPA) is an endocrine-disrupting chemical inducing several damages such as neurotoxicity, immunotoxicity, and metabolic disorders. Obesity is the main risk factor for the increased occurrence of meta-bolic alterations as well as mood disorders. Here, we investigated in obese mice the effects of BPA on anxiety-like behavior, associated with neuroinflammation and immune activation. Main methods: Male C57Bl/6J mice were divided into 4 groups: control group (STD) receiving chow diet and BPA vehicle; STD group treated with BPA (50 mu g/kg/die); high-fat diet (HFD) group receiving BPA vehicle; HFD group treated with BPA. BPA treatment started 12 weeks after HFD feeding and lasted 3 weeks. Key findings: The open field and elevated plus-maze tests showed in HFD + BPA group the worsening of HFD-induced anxiety-like behavior. The anxiogenic effects of BPA also emerged from hyperactivation of the hypothalamus-pituitary-adrenal gland axis, determined by the increased transcription of Crh and its receptor in the prefrontal cortex (PFC). Furthermore, BPA activated NLRP3 inflammasome and exacerbated the neuro-inflammation induced by HFD, increasing IL-1 beta, TNF-alpha and monocyte chemoattractant protein (MCP)-1 in PFC. Furthermore, it induced inflammation and monocyte recruitment in hypothalamus and amygdala. Contextually, BPA significantly amplified the immune activation caused by lipid overload as evidenced by the increased expression of TLR-4 and MCP-1 in the PFC and triggered mastocytosis in the hypothalamus rather than STD mice. Significance: All these data show that sub-chronic BPA exposure represents an additional risk factor for mood disorders strictly related to obesity, enhancing neuroinflammation and immune activation triggered by HFD feeding.