Bisphenol A exposure disrupts the circadian clock system and impairs glycolipid metabolic function in mice liver

Bisphenol A (BPA) is a widely existing endocrine-disrupting chemical that poses potential threats to human and animal health, including inducing metabolic disorders. Although previous studies have reported the adverse effects of BPA on liver glucose and lipid metabolism, the underlying molecular mechanisms remain incompletely elucidated. This study systematically evaluated the effects of BPA exposure on liver glucose and lipid metabolism in mouse hepatocytes (AML12) and mouse models, and detected its association with circadian clock disruption. In vitro models, BPA exposure for 24 h significantly decreased the mRNA and protein expression levels of BMAL1 in AML12 cells, while significantly up-regulating the mRNA expression of Nr1d1 and Dbp. On the contrary, the expression of Nr1d1 and Dbp decreased significantly after 48 h of BPA exposure. It is worthy to note that both mRNA and protein levels of BMAL1 were significantly increased in forskolin synchronized AML12 cells. In addition, the genes related to glucose and lipid metabolism were also detected after BPA exposure. The results showed that BPA exposure significantly increased the expression of Cd36 and Glut2 in non-synchronized AML12 cells. Meanwhile, the elevation of Hmgcr expression and the reduction of Pparα were detected in forskolin synchronized AML12 cells. In vivo models, the results showed that ICR mice exposed to BPA (50 μg kg^-1) for 42 consecutive days exhibited impaired glucose tolerance, decreased insulin sensitivity, increased liver glycogen storage, and decreased liver triglyceride (TG) levels. Meanwhile, the mRNA expression of Nr1d1 was significantly increased in mouse liver after BPA exposure. In addition, the mRNA expression of two lipid metabolism-related genes (Srebp1c and Elovl6) was significantly decreased in mouse liver after BPA treatment, but the expression level of Cd36 was significantly increased. In conclusion, this study demonstrates that BPA exposure impairs the circadian clock system and glucose and lipid metabolism in AML12 cells and mouse liver, providing important evidence that BPA overload in the environment can lead to the incidence of metabolic disorders in mammals. This study highlights the potential regulatory role of circadian clock system in BPA induced mammalian liver metabolic disorders and suggests that BPA may pose more profound potential risks to human and animal health.