Toxicogenomics applied to in vitro Cell Transformation Assay reveals mechanisms of early response to cadmium. (April 2018) - Callegaro, Giulia
Abstract: Cadmium is a well recognized carcinogen, primarily released into the environment by anthropogenic activities. In the effort to understand the early events responsible for cadmium carcinogenesis, we have used an in vitro biological system (the Cell Transformation Assay, CTA), that has been shown to closely model some key stages of the conversion of normal cells into malignant ones. Cadmium-triggered early responses in CTA were analysed through microarray-based toxicogenomics. Metallothioneins represent the earliest cell response, together with Slc30a1 encoding for a ZnT-1 zinc exporter. Other genes were found to be up-regulated in the first 24 h following Cd administration: phospatidylinositol-4-phospate 5-kinase alpha ( Pip5k1a ), glutathione S-transferase ( Gstα 1 – 3 ), Gdf15 and aldolase. However, after the exposure, a number of genes expressing zinc proteins were found to be down-regulated, among which were many olfactory receptors (ORs) coding genes. Cd administration also promoted massive Zn release inside the cell that could be related to moonlighting activities of regulated genes (proteins). On the whole our data suggest that, despite the early involvement of defence mechanisms (metallothionein and GST ), Cd-triggered Zn release, as well as Cd interference with different proteins, may lead to gene expression alterations which later induce metabolic changes, directing the cells towards uncontrolled growth. Graphical abstract: Highlights: Toxicogenomics provides pathways-based profiles of early Cd effects. Metallothioneins and GSTs are the earliest defence response against Cd exposure. Cd triggers the increase of free zinc and the deregulation of zinc homeostasis. Our data support the mechanism of Cd interference with the zinc-proteome.