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.
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; 5-30 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.
authors.affiliation: Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, Naples, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Formisano
authors.forename: Natascia
authors.initials: N
authors.lastname: Guida
authors.forename: Stefania
authors.initials: S
authors.lastname: Cocco
authors.forename: Agnese
authors.initials: A
authors.lastname: Secondo
authors.forename: Rossana
authors.initials: R
authors.lastname: Sirabella
authors.forename: Luca
authors.initials: L
authors.lastname: Ulianich
authors.forename: Flora
authors.initials: F
authors.lastname: Paturzo
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Di Renzo
authors.forename: Lorella M T
authors.initials: LM
authors.lastname: Canzoniero
mesh_terms: D000107:Acetylation; D013956:Antithyroid Agents / Q000633:toxicity*; D015153:Blotting, Western; D002154:Calpain / Q000096:biosynthesis; D053148:Caspase 3 / Q000096:biosynthesis; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020111:Chlorodiphenyl (54% Chlorine) / Q000633:toxicity*; D047369:Chromatin Immunoprecipitation; D006657:Histones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D016372:RNA, Antisense / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D016704:Synapsins / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D013956:Antithyroid Agents; D002154:Calpain; D053148:Caspase 3; D020111:Chlorodiphenyl (54% Chlorine); D006657:Histones; D012313:RNA; D016372:RNA, Antisense; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D016704:Synapsins; D000099229:RE1-Silencing Transcription Factor; C099683:SIN3A transcription factor