Involvement of the nitric oxide/protein kinase G pathway in polychlorinated biphenyl‐induced cell death in SH‐SY 5Y neuroblastoma cells

Abstract

Polychlorinated biphenyls (PCB) are persistent environmental contaminants whose chronic exposure can affect nervous system development and function. The cellular and molecular mechanisms underlying neuronal damage are not yet clear. In the present study, we investigated whether nitric oxide (NO) could be involved in aroclor 1254 (A1254; a PCB mixture)-induced cytotoxicity in SH-SY5Y human neuroblastoma cells. Prolonged exposure (24 hr) to A1254 (10-100 microg/ml) caused a dose-dependent reduction of cell viability that was attenuated in the presence of a calcium entry blocker, gadolinum (Gd(3+)) at 10 microM, a concentration able to block voltage-sensitive calcium channels. In addition, A1254 caused an increase of cytosolic calcium that was dependent on extracellular calcium, as measured by fura-2 videomicroscopy. A1254-induced calcium rise may stimulate NO production through an activation of neuronal NOS (nNOS). Indeed, the concomitant addition of the selective nNOS inhibitor N(omega)-propyl-L-arginine (NPLA) and A1254 prevented cell injury, suggesting that NO production plays a major role in A1254-evoked cell injury. Furthermore, the exposure (14 hr) to A1254 (30 microg/ml) produced an up-regulation of the expression of beta isoform of nNOS. This up-regulation was calcium dependent and was accompanied by an enhancement of NO production as demonstrated by an increase of nitrite formation. Moreover, A1254-induced cell injury was prevented when KT 5823, a selective cGMP/PKG inhibitor, was added concomitantly to 30 microg/ml A1254. These results suggest that PCB-induced cell death in neuroblastoma cells is mediated by an activation of the cGMP/PKG pathway triggered by NO production.

An in vitro approach to assess the toxicity of certain food contaminants: Methylmercury and polychlorinated biphenyls

“…MeHg is known to primarily target neurons (Sanfeliu et al, 2001;Kaur et al, 2006), though glial cells may also play a role in its neurotoxicity (Shanker et al, 2003). Previous in vitro studies have shown that PCBs can target both neurons and astroglial cells (Madia et al, 2004;Canzoniero et al, 2006). Primary neurons appeared to be more susceptible than neuronal cell lines to the toxicity of all three compounds, but this was not the case with astroglial cells.…”

cGMP‐dependent cone photoreceptor degeneration in the cpfl1 mouse retina

“…The importance of excessive cGMP accumulation for cell death is highlighted further by a number of reports relating cGMP-dependent PKG activity to neurodegeneration (Loweth et al, 1997;Canals et al, 2003;Canzoniero et al, 2006). How exactly excessive PKG activity induces cell death is not clear, although this may involve phosphorylation of VASP, which, apart from regulating cell migration, has also been linked to cell death (Deguchi et al, 2002;Hou et al, 2006).…”

Permanently compromised NADPH-diaphorase activity within the osmotically activated supraoptic nucleus after in utero but not adult exposure to Aroclor 1254

“…There is evidence that most of the dual actions of NO may be targets of PCBs. For example, short-term exposure to Aroclor 1254 exposure in vitro increases NO signaling and its downstream effectors, cGMP/PKG, in neuroblastoma cells, leading to cell death (Canzoniero et al, 2006). On the other hand, dopaminergic cell death has been linked to inhibition of NO signaling by PCBs (Kang et al, 2002;Yun et al, 2005), suggesting that dysregulation of NO signaling, either in the positive or negative direction, can have marked effects on cell survival.…”