Bisphenol A exposure induces cholesterol synthesis and hepatic steatosis in C57BL/6 mice by down-regulating the DNA methylation levels of SREBP-2

Abstract

Bisphenol A (BPA), a major plasticizers that are commonly used for lining of beverage or food-storage containers, has been shown to increase cholesterol levels with molecular mechanism not clear. The present study was aimed to investigate the effects of BPA exposure on liver cholesterol synthesis and hepatic steatosis in male C57BL/6 mice and its underlying mechanisms. Male C57BL/6 mice were exposed to different doses (50, 500 and 5000 μg/kg/day) of BPA through diet for 16 weeks. Exposure to low doses (50 and 500 μg/kg/day) of BPA increased hepatic cholesterol content and the expression levels of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and sterol regulatory element binding proteins-2 (SREBP-2). DNA methylation analysis further showed that mice exposed to low-dose BPA decreased the DNA methylation levels of SREBP-2. Moreover, low doses of BPA exposure increased the expression levels of SREBP-1c and stearoyl-CoA desaturase 1 in the liver, and induced hepatic lipid synthesis and fat accumulation. Our results suggest that low-dose BPA exposure could induce hepatic cholesterol synthesis through decreasing the DNA methylation levels of SREBP-2 and subsequently up-regulating the expression of genes related to cholesterol synthesis in the liver, which causes cholesterol accumulation and further induces liver lipid synthesis and hepatic steatosis.