Exposure to Bisphenol S and Bisphenol F Alters Gene Networks Related to Protein Translation and Neuroinflammation in SH-SY5Y Human Neuroblastoma Cells.

Bisphenol A (BPA) replacement chemicals are used in products like food packaging, plastic piping, and sportswear. While they can be toxic, their neurotoxicity is less understood. The aim of this study was to treat differentiated human SH-SY5Y cells with Bisphenol S (BPS) and Bisphenol F (BPF) to investigate mechanisms of toxicity. BPS reduced cell viability (>50 µM at 48 h) more than BPF (>200 µM at 48 h), with concentration- and time-dependent effects. Both induced caspase 3/7 activity at 250 µM after 48 h, though no changes were observed in levels of reactive oxygen species nor mitochondrial ATPase activity. RNA-seq analysis at 0.1 nM revealed distinct transcriptional networks: BPS altered IL15R, causing NF-kB/NFATC activation, and triggered NF-kB signaling through CD8, while BPF affected TLR9 and activated NF-kB targets through TNF. Pathway analysis showed that genes involved in neuroinflammation, protein folding, microglial function, and motor neuron regulation were disrupted, demonstrating that BPS and BPF, even at low, environmentally relevant concentrations, significantly alter gene expression in pathways linked to neuroinflammation, immune signaling, and neurodegenerative diseases. BPS primarily affected ribosomal and immune-related networks, while BPF disrupted oxidative phosphorylation and protein-folding pathways. These alterations suggest mechanisms for long-term neurological effects, highlighting the need for comprehensive evaluations of BPA alternatives.