22 Mixed metal oxide exposure drives astrocytic activation <i>in vitro</i> and in vivo

Abstract Metal imbalance is a key characteristic of many of these neurodegenerative disorders (NDDs), that is driven by environmental metal exposures. Epidemiological studies have implicated metals such as iron (Fe) and manganese (Mn) in NDD pathophysiology. The role of metal mixture in driving NDDs is underexplored. Astrocytes have been associated with metal exposure-associated NDDs. These cells play a key role in metal homeostasis in the brain, but metal overexposure can push astrocytes from homeostatic to a pathological state. To understand the astrocytic response to mixed metals, we conducted both in vitro studies utilizing occupationally relevant metal exposures. We demonstrated that the characteristics of the astrocytic response depended on oxidation state of the metal—metal oxides versus metal chloride exposures. Exposure to metal oxide mixtures resulted in increased mitochondrial deficits and inflammatory markers in comparison to the metal chloride mixture exposure. This highlights the importance of replicating human exposures by matching both the chemical species and mixture composition. Next, we explored the effects of mixed metal oxide inhalation on neurodegeneration. We developed a novel sub-acute exposure model that was capable of recapitulating the characteristics of welding inhalation exposures. Exposure to mixed metal oxides in our rodent model led to astrocytic activation in a region-specific manner, which was demonstrated in both small animal MRI and immunohistochemistry (IHC). Furthermore, these regions can be functionally associated with the behavioural alterations we have characterized. This work has demonstrated a cell-specific vulnerability of astrocytes to mixed metal oxide exposure and the regional sensitivity in inhalation exposures.