Abstract
Alcohol consumption before or during pregnancy poses serious health risks to the fetus; however, the underlying mechanisms involved remain obscure. Here, we investigated whether ethanol consumption before pregnancy affects maternal or fetal health and whether pharmacological inhibition of CYP2E1, a major ethanol oxidation enzyme, by 4-methylpyrazole (4-MP) has therapeutic effects. We found that ethanol consumption (5%) 2 weeks before pregnancy resulted in a decrease in the number of viable fetuses and abnormal fetal development, and these effects were accompanied by impaired maternal glucose homeostasis and hepatic steatosis during pregnancy. Neonates of ethanol-fed mice had postnatal macrosomia and significantly decreased growth rates during the lactation period. However, treatment with 4-MP, a CYP2E1 inhibitor, markedly ameliorated the reduction in insulin action and glucose disposal responsiveness in the livers of ethanol-fed mice. Blockage of CYP2E1 significantly reduced the alteration in hepatic lipid deposition, fatty acid oxidation, mitochondrial energy status, and macrophage infiltration observed in ethanol-fed mice. Finally, there was a positive correlation between postnatal macrosomia or growth retardation and increased inflammatory responses. Collectively, our study suggests that even moderate ethanol intake may be detrimental to fetal development and may cause growth retardation through maternal metabolic disorders.