Absorbing epithelium of the midgut as the model to study toxicity mechanisms of the heavy metal cadmium.

Cadmium (Cd) is a toxic heavy metal and environmental pollutant. Ever increasing exposure to Cd poses a health concern, because in humans Cd accumulates in kidneys and causes damage to the absorbing epithelium of proximal renal tubules. We used Drosophila as a model to study the mechanisms of Cd toxicity in absorbing cells of the midgut (enterocytes). Chronic exposure of flies to 1mM Cd in the food significantly shortened their lifespan, affected midgut morphology, and activated the esg reporter (esg\u3eGFP). Normally, esg\u3eGFP is expressed in solitary intestinal stem cells, but in response to Cd exposure, its expression expanded over enterocyte clusters, each containing 4 and more cells. This change in esg\u3eGFP signal indicates increased proliferation of midgut stem cells, which might be triggered by Cd-induced cellular damage to enterocytes. Consistently with this observation, experimental overexpression of the anti-apoptotic factor Diap1 in enterocytes significantly increased fly survivorship across various Cd concentrations. We conclude that midgut enterocytes are the critical target that determines Cd tolerance in flies. We used the fly model to further gain insight into the mechanisms of Cd toxicity. Specifically, we addressed whether cells die because Cd induces oxidative stress in midgut enterocytes. However, genetic methods to make enterocytes more resistant to reactive oxygen radicals failed to improve Cd tolerance. Based on these results, we conclude that oxidative stress does not play a major role in Cd-induced death of epithelial cells