BPA disrupts 17-estradiol-mediated hepatic protection against ischemia/reperfusion injury in rat liver by upregulating the Ang II/AT1R signaling pathway

Abstract

Bisphenol A (BPA), a xenoestrogen commonly used in plastics, may act as an endocrine disruptor, which indicates that BPA might be a public health risk. The present study aimed to investigate the effect of BPA on 17β-estradiol (E2)-mediated protection against liver ischemia/reperfusion (I/R) injury, and to identify the underlying mechanisms using a rat model. A total of 56 male Sprague Dawley rats were randomly divided into the following seven groups: i) Sham; ii) I/R; iii) Sham + BPA; iv) I/R + BPA; v) I/R + E2; vi) I/R + E2 + BPA; and vii) I/R + E2 + BPA + losartan [LOS; an angiotensin II (Ang II) type I receptor (ATIR) antagonist]. A rat model of hepatic I/R injury was established by inducing hepatic ischemia for 60 min followed by reperfusion for 24 h. When ischemia was induced, rats were treated with vehicle, E2, BPA or LOS. After 24 h of reperfusion, blood samples and hepatic tissues were collected for histopathological and biochemical examinations. The results suggested that 4 mg/kg BPA did not significantly alter the liver function, or Ang II and AT1R expression levels in the Sham and I/R groups. However, 4 mg/kg BPA inhibited E2-mediated hepatic protection by enhancing hepatic necrosis, and increasing the release of alanine transaminase, alkaline phosphatase and total bilirubin (P<0.05). Moreover, BPA increased serum and hepatic Ang II levels, as well as AT1R protein expression levels in the E2-treated rat model of liver I/R injury (P<0.05). LOS treatment reversed the negative effects of BPA on hepatic necrosis and liver serum marker levels, although it did not reverse BPA-mediated upregulation of serum and hepatic Ang II levels, or hepatic AT1R expression. Therefore, the present study suggested that BPA disrupted E2-mediated hepatic protection following I/R injury, but did not significantly affect healthy or I/R-injured livers; therefore, the mechanism underlying the effects of BPA may be associated with upregulation of the Ang II/AT1R signaling pathway.