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: Luigi Formisano, Natascia Guida, Stefania Cocco, Agnese Secondo, Rossana Sirabella, Luca Ulianich, Flora Paturzo, Gianfranco Di Renzo, Lorella M T Canzoniero
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 338 Issue 3 Pg. 997-1003 (Sep 2011) ISSN: 1521-0103 [Electronic] United States
• PMID: 21693630 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antithyroid Agents
• Histones
• RE1-silencing transcription factor
• RNA, Antisense
• RNA, Small Interfering
• Repressor Proteins
• SIN3A transcription factor
• Synapsins
• Chlorodiphenyl (54% Chlorine)
• RNA
• Calpain
• Caspase 3
• Sin3 Histone Deacetylase and Corepressor Complex

Topics

• Acetylation
• Antithyroid Agents (toxicity)
• Blotting, Western
• Calpain (biosynthesis)
• Caspase 3 (biosynthesis)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chlorodiphenyl (54% Chlorine) (toxicity)
• Chromatin Immunoprecipitation
• Histones (metabolism)
• Humans
• Immunoprecipitation
• Mitochondria (drug effects)
• Neurons (drug effects)
• Neurotoxicity Syndromes (pathology)
• RNA (biosynthesis, isolation & purification)
• RNA, Antisense (pharmacology)
• RNA, Small Interfering (pharmacology)
• Repressor Proteins (drug effects, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Sin3 Histone Deacetylase and Corepressor Complex
• Synapsins (metabolism)