@article {Formisano997, author = {Luigi Formisano and Natascia Guida and Stefania Cocco and Agnese Secondo and Rossana Sirabella and Luca Ulianich and Flora Paturzo and Gianfranco Di Renzo and Lorella M. T. Canzoniero}, title = {The Repressor Element 1-Silencing Transcription Factor Is a Novel Molecular Target for the Neurotoxic Effect of the Polychlorinated Biphenyl Mixture Aroclor 1254 in Neuroblastoma SH-SY5Y Cells}, volume = {338}, number = {3}, pages = {997--1003}, year = {2011}, doi = {10.1124/jpet.111.181289}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Chronic exposure to polychlorinated biphenyls (PCBs), a class of ubiquitous environmental toxicants, causes neurocognitive anomalies. The transcription factor repressor element 1-silencing transcription factor (REST) plays a critical role in neuronal phenotype elaboration in both neural progenitor cells and non-neuronal cells. Here, we investigated the possible relationship between PCBs and REST in neuroblastoma SH-SY5Y cells. In these cells, chronic exposure to the PCB mixture Aroclor 1254 (A-1254; 5{\textendash}30 μg/ml) caused dose-dependent cell death via the induction of calpain but not caspase-3. Intriguingly, this effect was prevented by the calpain inhibitor calpeptin. Furthermore, A-1254 enhanced REST mRNA and protein expression levels after both 24 and 48 h. REST down-regulation by small interfering RNA prevented A-1254-induced cell death. In addition, A-1254 enhanced the binding of REST to the synapsin 1 gene promoter, and synapsin 1 knockdown potentiated A-1254-induced cell death. A-1254 (10 μg/ml) also increased the expression of the two REST cofactors, the REST corepressor and the mammalian SIN3 homolog A transcription regulator. Moreover, the PCB mixture decreased acetylation of the histone proteins H3 and H4. It is noteworthy that the histone deacetylase inhibitor trichostatin A prevented such decreases and reduced the A-1254-induced neurotoxic effect. Collectively, these results suggest that A-1254 exerts its toxic effect via REST by down-regulating synapsin 1 and decreasing H3 and H4 acetylation.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/338/3/997}, eprint = {https://jpet.aspetjournals.org/content/338/3/997.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }