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

Abstract

2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant that could exert significant neurotoxicity in the human nervous system. Nevertheless, the molecular mechanism underlying TCDD-mediated neurotoxicity has not been clarified clearly. Herein, we investigated the potential role of TCDD in facilitating premature senescence in astrocytes and the underlying molecular mechanisms. Using the senescence-associated β-galactosidase (SA-β-Gal) assay, we demonstrated that TCDD exposure triggered significant premature senescence of astrocyte cells, which was accompanied by a marked activation of the Wingless and int (WNT)/β-catenin signaling pathway. In addition, TCDD altered the expression of senescence marker proteins, such as p16, p21 and GFAP, which together have been reported to be upregulated in aging astrocytes, in both dose- and time-dependent manners. Further, TCDD led to cell-cycle arrest, F-actin reorganization and the accumulation of cellular reactive oxygen species (ROS). Moreover, the ROS scavenger N-acetylcysteine (NAC) markedly attenuated TCDD-induced ROS production, cellular oxidative damage and astrocyte senescence. Notably, the application of XAV939, an inhibitor of WNT/β-catenin signaling pathway, ameliorated the effect of TCDD on cellular β-catenin level, ROS production, cellular oxidative damage and premature senescence in astrocytes. In summary, our findings indicated that TCDD might induce astrocyte senescence via WNT/β-catenin and ROS-dependent mechanisms.

An Endogenous Anti-aging Factor, Sonic Hedgehog, Suppresses Endometrial Stem Cell Aging through SERPINB2

“…Recent studies have demonstrated that toxic exposure triggers apparent premature senescence in both human and experimental animal models as an age-related risk factor. 30,31 In our previous study, we observed a positive correlation between toxic exposure and significantly enhanced SERPINB2 expression in adult stem cells in vitro and in vivo. 32 We therefore hypothesized in the present study that both replicative and oxidative stress-induced cellular senescence may enhance SERPINB2 expression and that it can regulate the effect of SHH on alleviating senescence-induced endometrial stem cell dysfunctions ( Figure 4A).…”

Astrocyte senescence: Evidence and significance

“…Since PD patients share many aspects of cellular senescence including inflammation (Yan et al, ), oxidative stress (Dias, Junn, & Mouradian, ), and mitochondrial dysfunction (Jiang, Jiang, Zuo, & Gu, ) and astrocytes have been shown to senesce in response to various stressors, it has been proposed that astrocyte senescence in response to environmental toxins could be a contributor to PD (Chinta et al, ). Indeed, astrocytes treated with TCDD underwent premature senescence with growth arrest accompanied by cytoskeletal remodeling and increases in p16, p21, and SA‐β gal (Nie et al, ). Since this phenotype included an increase in ROS levels, it was thought that TCDD might be inducing astrocyte senescence via oxidative stress.…”

Molecular Hydrogen Alleviates Cellular Senescence in Endothelial Cells

“…13, 14 AhR is a ligand-activated transcription factor for which dioxins act as ligands. In its steady state, AhR is localized in the cytoplasm but migrates to the nucleus when it binds to a ligand such as TCDD and forms a complex with AhR nuclear translocator (Arnt) localized in the nucleus.…”