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Nanotoxicology: A Question of Oxidative Stress

There is general agreement among nanotechnologists that the toxicity of some nanosized particles (NSPs) can be characterized by the specific in vivo effects they produce. For example, some nanoparticles may accelerate the rates of absorption of various molecular species, while others change protein conformation to create new allergens or autoimmune symptoms, create subpopulations of enzymes with transport or carrier deficiencies, or new toxic sequelae as a result of NSP entry into previously protected environments (e.g., brain, thyroid, fetus, or gonadal tissue). However, nearly all NSPs produce oxidative stress through the generation of reactive oxygen species (ROS).

Under normal coupled reduction-oxidation (redox) conditions in the mitochondrion, ROS are generated at a relatively low frequency, but are easily neutralized by antioxidant defenses, principally by the glutathione (GSH) defense system. However, under conditions of excess ROS, GSH is depleted and the oxidized form of glutathione (GSSG) accumulates. The ratio of GSH to GSSG is a signal that determines when a cell mounts a protective or a “self-destruct” response.

In the hierarchical oxidative stress model (Nel A, Xia T, Madler L, Li N. Science 2006;3:622), the normal state is presided over by a high GSH:GSSG ratio. As soon as the  GSH:GSSG ratio decreases slightly, a Tier 1 antioxidant defense pathway is initiated, with the Type-2 neurofibromatosis (Nf-2) signaling pathway triggering the antioxidant response, and generation of Phase II enzymes for conjugation and disposal of the miscreants. When the GSH:GSSG ratio decreases further, the Tier 2 inflammation response pathway is set into motion. In inflammation, signaling pathways such as p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF kappaB) are activated. These pathways turn on genes within the cell to produce inflammation via signaling cytokines and chemokines, both of which are chemicals that alert neighboring cells and processes within the same cell that a critical point in cell viability has been reached. If the amount of GSH continues to drop (Tier 3), the cell enters into a terminal stage. At this point, the cellular environment becomes toxic, and the mitochondria become porous and leak substances that signal the cell to close down in order to protect the rest of the body from its own toxic state. This last stage is called apoptosis, and the cell goes through a process of destroying its own infrastructure through the activation of the caspase cascades, and it prepares to have its remains engulfed by a macrophage, which has already been signaled by cytokines and chemokines to come to this specific site and be ready for a disposal assignment.