The TRPM2-PARP-1 Axis Involvement in Bisphenol A and Nonylphenol-Induced Ferroptosis in Trigeminal Ganglion Cells

Environmental contaminants like bisphenol A (BPA) and nonylphenol (NP) are recognized neurotoxicants; however, the molecular mechanisms underlying their impact on sensory ganglia, specifically the trigeminal ganglion (TG), remain critically underexplored. This study explored the potential of BPA and NP to drive neuronal injury and ferroptosis linked to oxidative stress, acting through the transient receptor potential melastatin 2 (TRPM2)-poly (ADP-ribose) polymerase-1 (PARP1) signaling axis. Forty-two adult male Wistar rats were allocated into seven groups (control, low-dose [25 mg/kg]/high-dose [100 mg/kg] BPA, low-dose [25 mg/kg]/high-dose [100 mg/kg] NP, and low-dose [25 mg/kg]/high-dose [100 mg/kg] BPA + NP) and treated orally for 21 days. We employed a combinatorial approach of biochemical assays and immunohistochemistry to evaluate oxidative stress markers, ferroptosis hallmarks (glutathione peroxidase 4 [GPX4], solute carrier family 7 member 11 [SLC7A11], and transferrin receptor [TfRC]), apoptotic mediators (Caspase-3 and Caspase-9), and inflammatory cytokines, as well as the expression of TRPM2 and PARP-1. Results demonstrated that BPA and NP exposure triggered a robust, dose-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation, concomitant with downregulation of anti-ferroptotic proteins (GPX4 and SLC7A11) and upregulation of TfRC. This toxic insult simultaneously activated apoptotic and inflammatory cascades. Crucially, TRPM2 and PARP-1 were significantly upregulated, implying a potential role for the TRPM2-PARP-1 axis as an upstream modulator of oxidative stress-induced ferroptosis and neuroinflammation. Collectively, these findings provide novel mechanistic insights into phenol-induced neurotoxicity, highlighting the inhibition of the TRPM2-PARP-1 axis as a promising therapeutic strategy to mitigate environmental neurodegeneration in sensory neurons.