Involvement of beta-catenin in cytoskeleton disruption following adult neural stem cell exposure to low-level silver nanoparticles

摘要

Silver nanoparticles (AgNPs) are increasingly incorporated in consumer products to confer antibacterial properties. AgNPs are shed during everyday use of these products, resulting in ingestion or inhalation and bioaccumulation in tissues including the brain. While these low levels of AgNPs do not induce DNA fragmentation typical of apoptosis or necrosis, they do interfere with cytoskeletal structure and dynamics in cultured differentiating adult neural stem cells (NSCs). Moreover, these cells form f-actin inclusions in response to 1 mu g/ml AgNPs. Here, we report that these cytoskeletal inclusions colocalize with aggregates of the signaling protein beta-catenin, a modulator of cytoskeletal dynamics. Pharmacological alteration of beta-catenin signaling reduced formation of f-actin inclusions. AgNP exposure also resulted in a reduction of neurite length in differentiating NSCs, which was mimicked by pharmacological activation of beta-catenin signaling. Conversely, pharmacological inhibition of the Wnt/beta-catenin signaling pathway resulted in increased neurite lengths in control cells, but did not reverse the neurite collapse induced by AgNP exposure. Substantial changes in neurite length, in response to low-level AgNP or pharmacological manipulation of beta-catenin signaling, occurred within the first six hours of exposure and were most evident in cells differentiating towards neural-like morphologies. We conclude that low-level exposure to AgNP, such as that resulting from use of consumer products, may disrupt beta-catenin signaling in neural cells in an indirect or non-additive manner. Exposure to AgNP shed from consumer products at levels currently considered safe, may therefore alter physiological function of neural cells. This is of concern particularly regarding children, whose brains contain many developing neurons, and who may face bioaccumulation of AgNP over decades of exposure.