Estrone counteracts oxidative stress in rat uterus under obesity

Abstract

We have previously reported uterus is a target tissue of estrone (E1) action, one of the major estrogens produced by ovaries. In this work we evaluated the mechanism of action of the steroid on the regulation of uterine oxidative stress induced by obesity. Uterine explants isolated from Wistar rats bilaterally ovariectomized fed with high-fat-diet (obese rats) were in vitro exposed to E1 for 4 h, and immediately after nitric oxide (NO) and hydrogen peroxide (H₂O₂) release were measured. PD98059 and LY294002 compounds were employed as MEK/ERK and PI3K/Akt inhibitors respectively. Indeed equilin (100–10 μM), an 17β-HSD inhibitor, was used to prevent conversion of E1 to estradiol. After E1 treatment (0.1-50nM), Ut slices exhibited an enhancement in nitric oxide synthesis (27-130% above control, P<0.001), and a reduction in H₂O₂ production (10-40% below control, P<0.01), with the maximal effect observed at 10 nM E1. Estradiol (10nM) exhibited similar action. The preincubation with the inhibitors PD98059 or LY294002 suppressed the reduction in ROS release elicited by the hormone. However the antagonists did not altered the stimulatory action on E1 on NO production (84; 110; 90% above each control, E1; E1+PD¸E1+LY respectively; p<0.01).The presence of Equilin, at all concentrations tested, not modify E1 modulatory action either on NO or H₂O₂ release, suggesting that E1 acts by its own, and not through conversion to estradiol. In summary, in obese uterus, E1 per se exhibited an antioxidative effect through a mechanism of action that partially involved MEK/ERK and PI3K/Akt signaling transduction pathways.