Different metals have different mechanisms for toxicity. In flies, DAF-16, the homolog of the FOXO family in humans, can be effected by exposure to different metals which activate cell signaling pathways to achieve it. Copper is an insulin mimetic and long-term exposure may result in insulin resistance and it inhibits the G-6-P promoter which is important in the healthy maintenance of glutathione (See figure)and is regulated by FOXO and insulin.
Mercury has significant effects on Nrf2 expression in monocytes for awhile but inhibits thioredoxin. Wataha explains monocytes can adapt to trace amounts of mercury that are introduced through the environmental such as dental work and fish consumption and will not compromise immune function. Because the Nrf2 pathway is involved, its normal function is imperative to this adaptive response. Messer et al demonstrated that mercury did not generate oxidative stress in his study but did alter redox states at levels that are not generally considered as chronic mercury toxicity. The levels he tested were levels common in the blood of patients that have had dental work and also showed a decrease in mitochondrial activity of 50% at relatively low Hg levels. Lewis demonstrated that nickel may dysregulate cytokine production and the amount of influence may depend on Nrf2 but with no interaction of FOXO, no oxidative stress or cytotoxic effects(Eckers). Copper on the other hand, is 100 times more toxic than nickel. Cadmium elicits endoplasmic reticulum stress (Hiramatsu).
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