Preeclampsia (PE) is a pregnancy-specific disease that causes maternal symptoms such as high blood pressure and adverse pregnancy outcomes. 2-methoxyestradiol (2-MeO-E₂), an endogenous metabolite of 17β-estradiol (E₂) formed by catechol-O-methyltransferase (COMT), plays an important role in pregnancy. Our earlier studies have shown that polyphenols present in coffee can inhibit COMT activity, which may inhibit the formation of 2-MeO-E₂ and contribute to PE. Therefore, the current study aims to investigate the possible effect and mechanism of coffee intake during pregnancy on PE in rats. Coffee is administered with or without the co-treatment of 2-MeO-E₂ to pregnant rats from the10^th to the18^th day of pregnancy. The results show that pregnant rats with coffee intake had prominent fetal growth restriction, hypertension, and proteinuria, which can be ameliorated by co-treatment of 2-MeO-E₂. In addition, coffee treatment leads to significantly decreased serum 2-MeO-E₂. Therefore, the PE symptoms induced by coffee treatment are probably mediated by decreased 2-MeO-E_2. In sum, our findings provide a new mechanistic insight into how coffee intake could lead to increased risk of PE, and demonstrate the effectiveness of 2-MeO-E₂ supplementation as a potential therapeutic agent for PE.

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