TCDD inhibits the proliferation of C17.2 cells through the activation of the c-Cbl/β-catenin signaling pathway

Abstract

2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) belongs to the category of persistent environmental pollutants, and gestational exposure to TCDD can lead to cognitive, memory, and motor deficits, as well as altered neuron development in rodents. However, the molecular mechanisms underlying TCDD's neurotoxicity remain unclear. Neural stem cells (NSCs) possess the capacity for self-renewal and can generate various cell types within the brain, playing fundamental roles in brain development and regeneration. This study investigated the impact of TCDD on the proliferation of mouse NSCs, specifically focusing on the C17.2 cell line. The results demonstrated that TCDD inhibited the proliferation of C17.2 cells in a dose-dependent manner. Even low doses of TCDD (5 nM) significantly reduced C17.2 cell proliferation. Regarding the molecular mechanisms, it was found that TCDD induced the degradation of β-catenin, a key regulator of cell proliferation, through the upregulation of the E3 ubiquitin ligase, casitas B-lineage lymphoma (c-Cbl), which was dependent on the aryl-hydrocarbon Receptor (AhR). Furthermore, knockdown of c-Cbl alleviated the TCDD-induced inhibition of C17.2 proliferation and of the reduction of β-catenin expression. Our research provides foundational data to understand the mechanism of TCDD-induced neurotoxicity through the inhibition of NSCs proliferation, and suggests that the c-cbl/β-catenin pathway may serve as a potential therapeutic target for countering the neurotoxicants of TCDD.