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.
Footnotes
This work was supported by COFIN 2008; the Ministero della Salute, Ricerca Sanitaria [Grant RF-FSL352059]; Ricerca Finalizzata 2006; the Ministero della Salute, Ricerca Oncologica 2006; the Ministero della Salute, Progetto Strategico 2007; and the Ministero della Salute, Progetto Ordinario 2007.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.181289.
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ABBREVIATIONS:
- PCB
- polychlorinated biphenyl
- A-1254
- Aroclor 1254
- RE1
- repressor element 1
- REST
- RE1-silencing transcription factor
- CoREST
- REST corepressor
- siREST
- small interfering RNA against REST
- siCTL
- scrambled control
- HDAC
- histone deacetylase
- TSA
- trichostatin A
- DMSO
- dimethyl sulfoxide
- MTT
- 3[4,5-dimethylthiazol-2-y1]-2,5-diphenyltetrazolium bromide
- ChIP
- chromatin immunoprecipitation
- RT
- reverse transcriptase
- PCR
- polymerase chain reaction
- RNAi
- RNA interference
- FACS
- fluorescence-activated cell-sorting analysis
- FITC
- fluorescein isothiocyanate
- PI
- propidium iodide
- ODN-AS
- antisense oligonucleotides
- mSin3A
- mammalian Sin3 homolog A.
- Received March 3, 2011.
- Accepted June 20, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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