TY - JOUR T1 - 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 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 997 LP - 1003 DO - 10.1124/jpet.111.181289 VL - 338 IS - 3 AU - Luigi Formisano AU - Natascia Guida AU - Stefania Cocco AU - Agnese Secondo AU - Rossana Sirabella AU - Luca Ulianich AU - Flora Paturzo AU - Gianfranco Di Renzo AU - Lorella M. T. Canzoniero Y1 - 2011/09/01 UR - http://jpet.aspetjournals.org/content/338/3/997.abstract N2 - 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; 5–30 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. ER -