Bisphenol a induces insulin resistance in skeletal muscle by down-regulating the expression of Irs1 through estrogen receptor

To investigate the effect of human relevant doses of bisphenol A (BPA), an endocrine disruptor, on insulin resistance and the underlying mechanisms. Mice were administered with water containing BPA of human relevant doses. C2C12 myocytes were treated with BPA and selective estrogen/androgen receptor down-regulator. Bioinformatic analysis was applied to search for estrogen receptor response element (ERE) in Irs1. Mice were administered with water containing BPA of human relevant dose (2.5 μg/L) or high human relevant dose (25 μg/L) from the day they were born to 8-week-old. The serum levels of fasting glucose and insulin were measured. Differentiated C2C12 myocytes were treated with BPA, and, with or without ICI 182,780 or flutamide. ICI 182,780 and flutamide are selective estrogen and androgen receptor down-regulator. The expression levels of key players in insulin signaling pathway of skeletal muscle and C2C12 myocytes was measured by real-time PCR. The expression levels of key players in lipid metabolism and transportation of skeletal muscle were also measured. Bioinformatic analysis was applied to search for ERE in Irs1. Mice of 25μg /L group exhibited increased fasting insulin levels and visceral adipose weight compared with control. The expression levels of Irs1 were down-regulated in skeletal muscle of mice from both BPA groups. In contrast, the expression levels of other key players in insulin signaling pathway, including Ir, Akt2, As160 and Glut4, showed no difference between BPA and control groups. Furthermore, key players in lipid metabolism and transportation of skeletal muscle, including Fatp1, Cd36, Atgl, Pnpla3, Dgat1and Spt, didn’t show significant difference in expression levels between groups, either. In consistence with results in mice, C2C12 myocytes administered with BPA showed decreased expression of Irs1 compared with control. Treatment of both BPA and flutamide also resulted in decreased transcription of Irs1. In contrast, C2C12 myocytes treated with both BPA and ICI 182,780 showed no difference in the transcription level of Irs1 compared with control, indicating that BPA might down-regulate the expression of Irs1 through estrogen receptor. Furthermore, we found ERE of high score in the promoter of Irs1 through bioinformatic analysis. Human relevant exposure of BPA induces insulin resistance in young mice. BPA may induce insulin resistance in skeletal muscle by down-regulating the expression of Irs1 through estrogen receptor.