Endocrine Abstracts

Introduction: Environmental pollutants especially those endowed with endocrine disrupting activities have been shown to contribute to metabolic related diseases suggesting that hormonal deficit conditions as observed in post-menopausal women may constitute aggravating conditions. To explore this hypothesis, we used the model developed in the laboratory which consists in a chronically exposure of mice to low-dosed chemicals in mixture incorporated in a high-fat-high-sucrose diet (HFHSD). Within the present study, mice were ovariectomized to mimic hormonal deficit.

Methods: Five week-old C57Bl6/J mice fed a HFHSD were divided in sub-groups depending on surgery (sham, ovariectomy (Ovx), Ovx+E2 implants) performed by week 7. Half of the Ovx and Ovx+E2 were exposed to a mixture of 2,3,7,8-TCDD (dioxin), polychlorobiphenyl (PCB)153, DEHP (phthalate) and bisphenol A at doses resulting in mice exposure at the Tolerable Daily Intake dose range (TDI) for each pollutant. The other half received vehicle only. Protocol lasted 15 weeks. A glucose tolerance test was performed and we measured several blood parameters and hepatic TG and cholesterol accumulation. Gene expression studies were performed by RT-qPCR in the liver and adipose tissues.

Results: Ovariectomised mice exhibited enhanced body weight and fat pads, glucose intolerance and insulin resistance (normalized by E2 replacement) but no hepatic TG accumulation. A set of estrogen-regulated genes was also identified in the liver and the adipose tissues at the mRNA level. Exposure to the mixture of pollutants did not impact body weight or glucose tolerance but adiponectin levels were altered. In addition, it resulted in enhanced hepatic lipid deposition and in changes in the mRNA level of genes related to lipid metabolism. Specifically, genes impacted included Nr1h3, Nr0b2, Cd36 and Cyp7a1 but not Esr1 in a direction distinct from the one triggered by E2 replacement. Pollutant exposure also differentially impacted the subcutaneous and visceral adipose tissues at the gene expression mRNA level, especially estrogen receptors reproducing part of the effects elicited by E2 treatment.

Conclusion: These data support the concept of the cocktail effect if considering that the dosage of the pollutants in the mixture is based on the TDI dose, thus not expected to generate an adverse effect. Interestingly, we found that the pollutant mixture triggered effects distinct or mimicking E2 treatment, depending on the metabolic tissue considered. These findings may have implications for the understanding of the potential role of environmental contaminants in the development of metabolic diseases, especially in females during the menopausal transition.