Moyano-Cires Ivanoff, Paula VivianaFlores, AndreaSanjuan, JavierPlaza Hernández, José CarlosGuerra Menéndez, LucíaAbascal, LuisaMateo Sierra, OlgaPino Sans, Javier Del2025-11-112025-11-112025Moyano, P., Flores, A., Sanjuan, J., Plaza, J. C., Guerra-Menéndez, L., Abascal, L., Mateo, O., & Del Pino, J. (2025). Cholinergic Transmission Dysregulation and Neurodegeneration Induced by Thyroid Signaling Disruption Following Butylparaben Single and Repeated Treatment. Biology, 14(10), 1380. https://doi.org/10.3390/biology1410138010.3390/biology14101380https://hdl.handle.net/20.500.14352/125963Author Contributions: Conceptualization, J.d.P., P.M. and A.F.; methodology, J.d.P., P.M., A.F. and J.S.; software, J.d.P., P.M. and A.F.; validation, J.d.P. and P.M.; formal analysis, A.F.; investigation, A.F., L.G.-M., O.M., J.C.P. and J.S.; data curation, J.d.P., P.M. and J.S.; writing—original draft preparation, J.d.P., P.M., A.F., J.C.P., O.M. and L.G.-M.; writing—review and editing, A.F., J.d.P., P.M., J.S., L.G.-M., J.C.P., L.A. and O.M.; visualization, L.G.-M.; supervision, J.d.P., P.M. and A.F.; project administration, J.d.P. and P.M.; funding acquisition, J.d.P. and P.M. All authors have read and agreed to the published version of the manuscript.Butylparaben (BP), a widely used preservative, was implicated in cognitive impairment, though its neurotoxic mechanisms remain elusive. Basal forebrain cholinergic neurons (BFCN) are selectively lost in dementias, contributing to cognitive decline. To explore different mechanisms related with BFCN loss, we employed BF SN56 cholinergic wild-type or silenced cells for Tau, amyloid-beta precursor protein (βApp), acetylcholinesterase (AChE), or glycogen synthase kinase-3 beta (GSK3β) genes, exposing them to BP (0.1-80 µM) for 1 or 14 days alongside triiodothyronine (T3; 15 nM), N-acetylcysteine (NAC; 1 mM), or recombinant heat shock protein 70 (rHSP70; 30 µM). BP disrupted cholinergic transmission by AChE inhibition and provoked cell death through thyroid hormones (THs) pathway disruption, Aβ/p-Tau protein accumulation, AChE-S overexpression, and oxidative stress (OS). Aβ/p-Tau accumulation was correlated with HSP70 downregulation, OS exacerbation, and GSK3β hyperactivation (for p-Tau). BP-induced OS was mediated by reactive oxygen species (ROS) overproduction and nuclear factor erythroid 2-related factor 2 (NRF2) pathway disruption. All observed effects were contingent upon TH signaling impairment. These findings uncover novel mechanistic links between BP exposure and BFCN neurodegeneration, providing a framework for therapeutic strategiesengAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal article2079-7737https://doi.org/10.3390/biology1410138041154783https://www.mdpi.com/2079-7737/14/10/1380https://pubmed.ncbi.nlm.nih.gov/41154783/open access616.4AChEAβHSP70NRF2 partwaySN56 basal forebrain cholinergic neuronsTauButylparabenThyroid hormonesEndocrinología3205.02 Endocrinología