Abstract
Environmental endocrine disruptors (EDCs), including bisphenol-A (BPA), have been recently involved in obesity and diabetes by dysregulating adipose tissue function. Our aim was to examine whether prolonged exposure to low doses of BPA could affect adipogenesis and adipocyte metabolic functions. Therefore, 3T3-L1 pre-adipocytes were cultured for three weeks with BPA 1nM to mimic human environmental exposure. We evaluated BPA effect on cell proliferation, differentiation, gene expression and adipocyte metabolic function. BPA significantly increased pre-adipocyte proliferation (p<0.01). In 3T3-L1 adipocytes differentiated in the presence of BPA, the expression of Peroxisome proliferator-activated receptor gamma (PPARγ), Fatty Acid Binding Protein 4/Adipocyte Protein 2 (FABP4/AP2) and CCAAT/enhancer binding protein (C/EBPα) was increased by 3.5, 1.5 and 3 folds, respectively. Mature adipocytes also showed a significant increase in lipid accumulation (p<0.05) and alterations of insulin action, with significant reduction in insulin-stimulated glucose utilization (p<0.001). Moreover, in mature adipocytes, mRNA levels of Leptin, interleukin-6 (IL6) and interferon-γ (IFNγ) were significantly increased (p<0.05). In conclusion, BPA prolonged exposure at low doses, consistent with those found in the environment, may affect adipocyte differentiation program, enhancing pre-adipocyte proliferation and anticipating the expression of the master genes involved in lipid/glucose metabolism. The resulting adipocytes are hypertrophic, with impaired insulin signaling, reduced glucose utilization and increased pro-inflammatory cytokine expression. Thus, these data supported the hypothesis that BPA exposure, during critical stages of adipose tissue development, may cause adipocyte metabolic dysfunction and inflammation, thereby increasing the risk of developing obesity-related diseases.
Highlights
Obesity is a significant public health problem in the developed world, caused by complex interactions among genetic, behavioral and environmental factors [1]
Thereafter, cells cultured with BPA showed a significant increase in number compared to untreated adipocytes (p
Following BPA exposure, both PPARγ and FABP4/AP2 mRNAs were significantly increased at day 8 from the start of the differentiation process, when compared to untreated cells (p
Summary
Obesity is a significant public health problem in the developed world, caused by complex interactions among genetic, behavioral and environmental factors [1]. In the last few years, a role of environmental chemicals in promoting obesity has been suggested, with adverse effects on human health through adipose tissue dysfunction [3,4]. Among these chemical substances, endocrine disrupting compounds (EDCs) have a crucial role in mimicking hormonal activities, in promoting adipogenesis and in development of obesity and diabetes [3,5,6]. Free and conjugated BPA are measurable in human body fluids, such as blood, urine, saliva, amniotic fluid and breast milk [10,11]
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