Chronic exposure to polychlorinated biphenyls (PCBs), a class of ubiquitous environmental toxicants, causes neurocognitive anomalies. The transcription factor RE1-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 dosedependent cell death via the induction of calpain but not of 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 hrs. REST downregulation by small interfering RNA (siRNA) prevented A-1254-induced cell death. In addition, A1254 enhanced the binding of REST to the Synapsin-1 gene promoter, and Synapsin-1 knockdown potentiated A1254-induced cell death. A1254 (10 µg/ml) also increased the expression of the two REST cofactors, namely, the REST corepressor (Co- Rest) and the mammalian SIN3 homolog A transcription regulator (mSin3-A). Moreover, the PCB mixture decreased acetylation of the histone proteins H3 and H4. Interestingly, the histone deacetylase inhibitor trichostatin A prevented such decrease and reduced the A1254-induced neurotoxic effect. Collectively, these results suggest that A-1254 exerts its toxic effect via REST by downregulating Synapsin 1 and by decreasing H3 and H4 acetylation.
- Received March 3, 2011.
- Revision received June 17, 2011.
- Accepted June 20, 2011.
- The American Society for Pharmacology and Experimental Therapeutics