Unravelling bisphenol A-induced hepatotoxicity: Insights into oxidative stress, inflammation, and energy dysregulation

Bisphenol A (BPA), a prevalent plastic monomer and endocrine disruptor, negatively impacts metabolic functions. This study examines the chronic effects of eco-relevant BPA concentrations on hepatotoxicity, focusing on redox balance, inflammatory response, cellular energy sensors, and metabolic homeostasis in male Swiss albino mice. Chronic BPA exposure resulted in reactive oxygen species (ROS) accumulation, altered hepatic antioxidant defense, lipid peroxidation, and NOX4 expression, leading to reduced cell viability. Additionally, BPA exposure significantly upregulated hepatic pro-inflammatory cytokine genes (Tnf-alpha, Il-1 beta, Il-6), NOS2, and arginase II, correlating with increased TLR4 expression, NF-kappa B phosphorylation, and a dose-dependent decrease in I kappa B alpha levels. BPA-induced NF-kappa B nuclear localization and inflammasome activation (NLRP3, cleaved caspase-1, IL-1 beta) established an inflammatory milieu. Perturbations in hepatic AMPK alpha phosphorylation, SIRT1, and PGC-1 alpha, along with elevated p38 MAPK phosphorylation and ER alpha expression, indicated BPA-induced energy dysregulation. Furthermore, increased PLA2G4A, COX1, COX2, and PTGES2 expression in BPA-treated liver correlated with hyperlipidemia, hepatic FASN expression, steatosis, and visceral adiposity, likely due to disrupted energy sensors, oxidative stress, and inflammasome activation. Elevated liver enzymes (ALP, AST, ALT) and apoptotic markers indicated liver damage. Notably, N-acetylcysteine (NAC) priming reversed BPA-induced hepatocellular ROS accumulation, NF-kappa B-inflammasome activation, and intracellular lipid accumulation, while upregulating cellular energy sensors and attenuating ER alpha expression, suggesting NAC's protective effects against BPA-induced hepatotoxicity. Pharmacological inhibition of the NF-kappa B/NLRP3 cascade in BAY11-7082 pretreated, or NLRP3 immunodepleted hepatocytes reversed BPA's negative impact on SIRT1/p-AMPK alpha/PGC-1 alpha and intracellular lipid accumulation, providing mechanistic insights into BPA-induced metabolic disruption.