Abstract
The widespread environmental pollutant 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) is a non-dioxin-like toxicant. It is a potential carcinogen compound able to induce gap junction (GJ) intercellular communication impairment, probably the first non-genomic event leading to tumor promotion. Although PCBs have been known for many years, the molecular mode of PCB153 action is still unclear. Recent studies from our research group have shown that the toxicant elicits a transient modulation of connexin (Cx) 43-formed GJs in hepatic stem-like WB-F344 cells involving sphingosine 1-phosphate (S1P) path. Taking into account that other strictly related bioactive sphingolipids, such as ceramide (Cer), may have different effects from S1P, here we aim to clarify the signaling paths engaged by PCB153 in the control of GJs, focusing primarily on the role of Cer. Accordingly, we have achieved a combined biomolecular and electrophysiological analysis of GJs in cultured WB-F344 cells treated with PCB153 at different time points. We have found that the toxicant elicited a time-dependent regulation of GJs formed by different Cx isoforms, through a transient modulation of Cer/Cer kinase (CerK) axis and, in turn, of protein phosphatase 2A (PP2A). Our new findings demonstrate the existence of a specific molecular mechanism downstream to Cer, which distinctly affects the voltage-dependent and -independent GJs in liver stem-like cells, and open new opportunities for the identification of additional potential targets of these environmental toxicants.
Highlights
Among environmental pollutants, polychlorinated biphenyls (PCBs) represent a serious problem for human health
The analysis of the voltage dependence estimated by the Gj,ss/Vj plot turned out to be characterized by an asymmetric behavior with a marked voltage dependence only for positive or for negative Vj polarity [15] (Supplemental file Fig.S1, panel c and i)
The analysis of Gj,ss,max showed a preparation, Real-time PCR performed as reported in Methods section; data reported as ΔCt value. c Western blotting and densitometric analysis of Cx43, Cx32, and Cx26 expression
Summary
Among environmental pollutants, polychlorinated biphenyls (PCBs) represent a serious problem for human health. PCBs production has been banned since 1977 because of their adverse effects on the health of humans and animals. PCBs accumulate and persist in the environment due to chemical or biological processes (i.e., volatilization, partitioning). Since highly chlorinated congeners are more slowly metabolized, they accumulate to higher levels especially in fatty tissues, and they are of special relevance to human health. They have a variety of adverse effects, such as endocrine disruption, developmental neurotoxicity, and carcinogenicity [4, 5]. Most PCB exposures are a mixture of non-coplanar and coplanar toxicants. Understanding the underlying mechanisms of the non-genotoxic tumorigenic potential of the non-coplanar PCBs is essential for a thorough evaluation of the risk that environmentally relevant PCBs represent for human health
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