Oxidative stress and mitochondrial uncoupling protein 2 expression in hepatic steatosis induced by exposure to xenobiotic DDE and high fat diet in male Wistar rats

Abstract

Oxidative stress plays a key role in steatohepatitis induced by both xenobiotic agents and high fat diet (HFD). The present study aimed to evaluate hepatic oxidative stress and anti-oxidant systems response in rats exposed to HFD and/or non-toxic dose of dichlorodiphenyldichloroethylene (DDE), the first metabolite of dichlorodiphenyltrichloroethane. Groups of 8 rats were so treated for 4 weeks: 1- standard diet (N group); 2- standard diet plus DDE (10 mg/kg b.w.) (N+DDE group); 3- HFD (D group); 4- HFD plus DDE (D+DDE group). Oxidative stress was analyzed by determining malondialdehyde as lipid peroxidation product, while the anti-oxidant systems were evaluating by measuring the levels of the principal cytosolic and mitochondrial antioxidant proteins and enzymes, namely superoxide dismutase 1 and 2 (SOD1, SOD2), glutathione peroxidase 1 (GPx1) and uncoupling protein 2 (UCP2) involved in the control of hepatic reactive oxygens species (ROS) accumulation. The results showed malondialdehyde accumulation in livers of all groups, confirming the pro-oxidant effects of both HFD and DDE, but with a greater effect of DDE in absence of HFD. In addition, we found different levels of the analyzed anti-oxidant systems in the different groups. DDE mainly induced UCP2 and SOD2, while HFD mainly induced GPx1. Noteworthy, in the condition of simultaneous exposure to DDE and HFD, the anti-oxidant response was more similar to the one induced by HFD than to the response induced by DDE. Present findings confirmed that both HFD and xenobiotic exposure induced hepatic oxidative stress and showed that the anti-oxidant defense response was not the same in the diverse groups, suggesting that UCP2 induction could be an adaptive response to limit excessive ROS damage, mainly in condition of xenobiotic exposure.

Combined effects of DDE and hyperlipidic diet on metallothionein expression and synthesis in rat tissues

“…MDA levels increased more under DDE administration, without significant differences between N + DDE (9.71 ± 0.16 nmol) and HF + DDE (9.42 ± 0.49 nmol) groups. In liver, MDA accumulation showed the same trend observed in kidney, with the highest levels of peroxides in DDE‐treated groups, no matter the diet . However, lipid peroxidation in liver was greater than kidney, in all the groups considered; the main differences were found between DDE‐treated groups, being MDA values in liver about 2‐fold higher than in kidney …”

“…In addition, it has been demonstrated that the increase of lipid peroxides is associated to an inhibition of MT synthesis in rat testis . Since our data indicate a hepatic increase of lipid peroxidation following HF‐ and/or DDE‐treatments, it is conceivable that also in the liver lipid peroxides are able to affect MT expression and synthesis, no matter if the peroxides are produced by the dietary fat or the pesticide.…”

Exposure to Dichlorodiphenyldichloroethylene (DDE) and Metallothionein Levels in Rats Fed with Normocaloric or High-Fat Diet: A Review

“…Recently, histological and molecular analysis indicated that oral exposure to a moderately low dose of DDE (10 mg/kg bw) for 4 weeks was able to elicit morphological alterations, cellular oxidative stress, and lipid peroxidation in rat tissues [47,48,56,58]. Studies also evidenced the presence of similar morphological and oxidative damage caused by the fat diet alone [47,48,56,58]. In the liver, an HF diet induced steatosis of hepatocytes, and DDE treatment-tissue inflammation and cellular vacuolization.…”

“…It has also been demonstrated that cells activated the endogenous antioxidant system to protect themselves from the oxidative damage generated in HF-and DDE-treated animals. In particular, increased synthesis and enzymatic activity of SOD1/2 and total GPx antioxidant enzymes and the induction of the mitochondrial uncoupling protein 2 (UCP2) were observed in the hepatocytes the to limit the mitochondrial damage produced by ROS [47,56]. On the contrary, testicular cells showed antioxidant system impairment in the HF-and DDE-treated animals associated with an increase in lipid peroxidation and the apoptotic rate.…”

“…It has been demonstrated that the presence of DDT and its metabolites in animal tissues causes oxidative stress and mitochondrial damage [43][44][45][46][47][48], whereas few data, often controversial, are available on the effects of these substances on MT expression and synthesis. A study performed by Ben Miled and coworkers [49] showed an increase in MT content in hepatocytes of rats receiving a single intraperitoneal injection of 100 mg DDT/kg body weight (bw).…”