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.
Highlights
Alcohol consumption before or during pregnancy poses serious health risks to the fetus; the underlying mechanisms involved remain obscure
Toe deformities defined with fused toes (Ft) were observed in neonates from the ethanol-fed mice group (53 normal healthy and 4 Ft in offspring), while no abnormalities were observed in neonates of the pair-fed mice group (Fig. 1c)
We provided evidence that ethanol consumption before pregnancy is closely associated with the abnormal development of the pup, including macrosomia and growth retardation, which are correlated with maternal metabolic disorders (Fig. S3)
Summary
Alcohol consumption before or during pregnancy poses serious health risks to the fetus; the underlying mechanisms involved remain obscure. 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. Maternal alcohol consumption during pregnancy has been associated with the disruption of metabolic pathways in the mother, impairing fetal development and postnatal growth[1,2]. Alcohol consumption is associated with low food intake and low blood glucose levels in rodents[10,11,12], drinking before pregnancy, in particular, may cause maternal metabolic disorders and may impair fetal development by altering the first maternal adjustment of nutrient metabolism. We hypothesized that ethanol consumption-mediated oxidative stress may further exacerbate the changes in maternal metabolic homeostasis observed during pregnancy, resulting in impaired maternal metabolism and fetal growth. The aim of this study was to explore whether drinking before pregnancy affects maternal metabolic homeostasis and fetal growth during pregnancy and to determine the exact regulatory mechanisms involved in poor pregnancy outcomes
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