2, 3, 7, 8-Tetrachlorodibenzo-P-Dioxin (TCDD) Induces Premature Senescence in Human and Rodent Neuronal Cells via ROS-Dependent Mechanisms

Abstract

The widespread environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent toxicant that causes significant neurotoxicity. However, the biological events that participate in this process remain largely elusive. In the present study, we demonstrated that TCDD exposure triggered apparent premature senescence in rat pheochromocytoma (PC12) and human neuroblastoma SH-SY5Y cells. Senescence-associated β-galactosidase (SA-β-Gal) assay revealed that TCDD induced senescence in PC12 neuronal cells at doses as low as 10 nM. TCDD led to F-actin reorganization and the appearance of an alternative senescence marker, γ-H2AX foci, both of which are important features of cellular senescence. In addition, TCDD exposure altered the expression of senescence marker proteins, such as p16, p21 and p-Rb, in both dose- and time-dependent manners. Furthermore, we demonstrated that TCDD promotes mitochondrial dysfunction and the accumulation of cellular reactive oxygen species (ROS) in PC12 cells, leading to the activation of signaling pathways that are involved in ROS metabolism and senescence. TCDD-induced ROS generation promoted significant oxidative DNA damage and lipid peroxidation. Notably, treatment with the ROS scavenger N-acetylcysteine (NAC) markedly attenuated TCDD-induced ROS production, cellular oxidative damage and neuronal senescence. Moreover, we found that TCDD induced a similar ROS-mediated senescence response in human neuroblastoma SH-SY5Y cells. In sum, these results demonstrate for the first time that TCDD induces premature senescence in neuronal cells by promoting intracellular ROS production, supporting the idea that accelerating the onset of neuronal senescence may be an important mechanism underlying TCDD-induced neurotoxic effects.

2, 3, 7, 8‐Tetrachlorodibenzo‐p‐dioxin induces premature senescence of astrocytes via WNT/β‐catenin signaling and ROS production

“…Many studies implicated a role of the mitochondria disorder in TCDD-induced ROS generation (Aly and Khafagy, 2011;Ilavarasi et al, 2011). In line with the reports, our recent finding also indicated that TCDD could trigger ROS accumulation and oxidative stress to cause premature senescence in neuronal cells (Wan et al, 2014). Because the activation of WNT/β-catenin signaling has been documented to lead to potent mitochondrial ROS production, we proposed that WNT/β-catenin activation might be partially responsible for TCDD-induced ROS generation in astrocytes.…”

“…Coinciding with the notion, ROS have been reported to be crucial mediators of astrocyte senescence under different stressful conditions (Bitto et al, 2010;Liu et al, 2011). In addition, because ROS are involved in mitochondrial dysfunction, changes in mitochondrial biogenesis may also contribute to TCDD-induced premature senescence (Wan et al, 2014). DNA damage is considered of paramount importance in senescence (Barja and Herrero, 2000;Liu et al, 2007;Yoon et al, 2010).…”

Olive oil and its phenolic constituent tyrosol attenuates dioxin-induced toxicity in peripheral blood mononuclear cells via an antioxidant-dependent mechanism

“…Reactive oxygen species (ROS) formation and subsequent peroxidation of membrane lipids, being mainly involved in TCDD toxicity, and the potency of OO and TY in eliminating the ROS and lipid peroxidation products so formed and protecting the PBMC were quantified. Being no exception to previous reports, TCDD significantly enhanced ROS formation and lipid peroxidation in PBMC (Wan et al 2014) (Figure 1). OO and TY, as reported earlier to protect cells from the toxicity of ROS produced due to the stimulus with various toxins and stresses, also protected PBMC from TCDD-induced ROS production and showed a marked decrease in the level of thiobarbituric acid reactive substances (TBARS) (measure of lipid peroxidation) and protected the subsequent destruction of cells.…”

ITE Suppresses Angiogenic Responses in Human Artery and Vein Endothelial Cells: Differential Roles of AhR

“…1C and D). Such decreases in activity of intracellular dehydrogenases enzyme might increase the accumulation of cellular reactive oxygen species, decreasing the cell viability [34]. However, even in this case, it is obvious that the ITE-decreased activity of mitochondrial dehydrogenases in HUVECs is not sufficient to suppress migration of HUVECs.…”