Effects of Maternal Tetramethyl Bisphenol F Exposure on Neurodevelopment and Behavior in Mouse Offspring

Bisphenol A (BPA) has long been used in plastics, resins, and food packaging materials; however, extensive research has demonstrated its reproductive, developmental, and endocrine-disrupting effects. Consequently, BPA has been increasingly restricted and replaced with structural analogues. Among these, tetramethyl bisphenol F (TMBPF) has emerged as one of the most widely used substitutes, particularly in epoxy resins and food-can coatings. Although initially regarded as a safer alternative, accumulating evidence suggests that TMBPF may exert multiple toxicological effects, raising concerns about its potential developmental neurotoxicity. The present study aimed to investigate the neurodevelopmental effects of TMBPF using both in vitro and in vivo approaches. First, a developmental neurotoxicity assay employing Sox1-GFP mouse embryonic stem cells was used to evaluate cytotoxicity using the cell counting kit-8 assay and neural differentiation based on green fluorescent protein (GFP) fluorescence intensity. The results indicated developmental neurotoxic potential according to the established discrimination index. Subsequently, pregnant and lactating mice were exposed to TMBPF daily from gestational day 10.5 to postnatal day 20, and their offspring were assessed for behavioral performance as well as changes in the expression of neurodevelopment-related genes in the brain. Behavioral analyses encompassed multiple domains, including memory and learning, social behavior, anxiety-related responses, and spontaneous locomotor activity, suggesting alterations in these functional outcomes. Molecular analyses further demonstrated changes associated with dopaminergic and cholinergic signaling, synaptic plasticity, neuronal activity markers, neuropeptides, and inflammatory pathways. Collectively, these findings provide the first evidence in a mammalian model that maternal exposure to TMBPF may influence offspring neurodevelopment. These findings suggest potential implications for human exposure to TMBPF, particularly through food-contact materials, and warrant further mechanistic and dose-response studies.