MITOCHONDRIAL TOXICITY INDUCED BY DICHLORODIPHENYLETHYLENE IN RAT LIVER AND IN HUMAN HEPATOCYTES

Nutrition represents a crucial point to maintain a good health status. The intake of harmful substances through contaminated foods can generates toxicity in many organs, especially in the liver. Our study was focused on the effects of Dichlorodiphenylethylene (DDE), the main metabolite of Dichlorodiphenylethane (DDT), in vivo, on rat liver, and in vitro, on the hepatocarcinoma cell line Huh7, to compare the cellular responses activated by the two different experimental models. In vivo study was performed following a treatment of 4 weeks using 10 mg/kg b.w. DDE daily via gavage. The results showed that DDE induces mitochondrial ROS production, particularly H2O2, followed by oxidative damage. In addition, DDE showed a pro-inflammatory activity with the recruitment and activation of monocytes/macrophages in the liver and stimulated mitochondrial pathways of apoptosis. In vitro studies were carried out after a dose-response pilot experiment (increasing concentration of DDE, with a constant time of 24h exposure). The DDE dose chosen (30μM) for the subsequent experiments was the lowest able to generate the increase of mitochondrial ROS, as occurred in vivo. The results showed H2O2 and cellular ROS accumulation in presence of DDE. In addition, reduction of mitochondrial respiratory capacity and ATP production were observed, together with the activation of the mitochondrial apoptotic pathway. These data indicate that DDE acts predominantly on mitochondria, producing responses linked to the oxidative damage. Further data showed variations in mitochondrial dynamics and biogenesis, and activation of UPR signalling, to partially contain the oxidative damage. Collecting in vivo and in vitro data allowed us to conclude that DDE, at low doses, give rise to prooxidant, pro-inflammatory and pro-apoptotic effects. Cells try to limit the damages activating a cascade of responses able to regulate cellular metabolism towards survival or death. Finally, our data also demonstrated that the in vitro hepatocarcinoma cell line Huh7 is a good model for preliminary studies on hepatic toxicology.