Prenatal alcohol exposure (PAE) impairs fetal growth and neurodevelopment. Although alcohol is well known to alter metabolism, its impact on these processes during pregnancy is largely unexplored. Here, we investigate how alcohol affects maternal–fetal glucose metabolism using our established mouse binge model of PAE. In the dam, alcohol reduces the hepatic abundance of glucose and glycolytic intermediates, and the gluconeogenic enzymes glucose-6-phosphtase and phosphoenolpyruvate carboxykinase. Fasting blood glucose is also reduced. In a healthy pregnancy, elevated maternal gluconeogenesis and insulin resistance ensures glucose availability for the fetus. Glucose and insulin tolerance tests reveal that alcohol impairs the dam's ability to acquire insulin resistance. Alcohol-exposed dams have enhanced glucose clearance (p < .05) in early gestation, after just two days of alcohol, and this persists through late term when fetal glucose needs are maximal. However, maternal plasma insulin levels, hepatic insulin signaling, and the abundance of glucose transporter proteins remain unchanged. In the PAE fetus, the expression of hepatic gluconeogenic genes is elevated, and there is a trend for elevated blood and liver glucose levels. In contrast, fetal brain and placental glucose levels remain low. This reduced maternal fasting glucose, reduced hepatic glucose, and elevated glucose clearance inversely correlated with fetal body and brain weight. Taken together, these data suggest that alcohol blunts the adaptive changes in maternal glucose metabolism that otherwise enhance fetal glucose availability. Compensatory attempts by the fetus to increase glucose pools via gluconeogenesis do not normalize brain glucose. These metabolic changes may contribute to the impaired fetal growth and brain development that typifies PAE.
The authors declare that they have no conflicts of interests.
DATA AVAILABILITY STATEMENT
All the processed data are available as manuscript tables/figures or supplementary information.
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- 1, , , , . Alcohol consumption and binge drinking during pregnancy among adults aged 18-49 years—United States, 2018-2020. MMWR Morb Mortal Wkly Rep. 2022; 71(1): 10-13.
- 2, , , et al. Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders. Pediatrics. 2016; 138(2):e20154256.
- 3, , , et al. Fetal alcohol spectrum disorders. Nat Rev Dis Primers. 2023; 9(1):11.
- 4, , . Effects of pregnancy and nutritional status on alcohol metabolism. Alcohol Res Health. 2007; 30(1): 55-59.
- 5. Improving maternal nutrition for better pregnancy outcomes. Proc Nutr Soc. 2015; 74(4): 454-459.
- 6, , , et al. Maternal alcohol use and nutrition during pregnancy: diet and anthropometry. Alcohol Clin Exp Res. 2017; 41(12): 2114-2127.
- 7, , , , . Effects of nutrition and gestational alcohol consumption on fetal growth and development. Nutr Rev. 2022; 80(6): 1568-1579.
- 8, , , , . The effect of alcohol consumption on insulin sensitivity and glycemic status: a systematic review and meta-analysis of intervention studies. Diabetes Care. 2015; 38(4): 723-732.
- 9, , , . Alcohol-related hypoglycemia in rural Uganda: socioeconomic and physiologic contrasts. Int J Emerg Med. 2011; 4:5.
- 10, , , . Effect of moderate alcoholic beverage consumption on insulin sensitivity in insulin-resistant, nondiabetic individuals. Metabolism. 2009; 58(3): 387-392.
- 11, , , . Inhibition of hepatic gluconeogenesis by ethanol. Biochem J. 1969; 112(1): 117-124.
- 12, . Mechanism of ethanol suppression of gluconeogenesis. Inhibition of phosphoenolpyruvate synthesis from glutamate and alpha-ketaglutarate. J Biol Chem. 1970; 245(12): 3179-3185.
- 13, , , , , . Fetal alcohol growth restriction and cognitive impairment. Pediatrics. 2016; 138(2):e20160775.
- 14, , , . Exploring the causes and consequences of maternal metabolic maladaptations during pregnancy: lessons from animal models. Placenta. 2020; 98: 43-51.
- 15. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr. 2000; 71(5 Suppl): 1256S-1261S.
- 16. Metabolic adaptations in pregnancy and their implications for the availability of substrates to the fetus. Eur J Clin Nutr. 2000; 54(Suppl 1): S47-S51.
- 17. Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc. 2006; 117: 321-339; discussion 339-340.
- 18. Recent observations on the regulation of fetal metabolism by glucose. J Physiol. 2006; 572(Pt 1): 17-24.
- 19, , . Maternal carbohydrate metabolism and its relationship to fetal growth and body composition. Am J Obstet Gynecol. 1995; 172(5): 1464-1470.
- 20, , , , , . Elevated insulin sensitivity and beta-cell function during pregnancy in mothers of growth-restricted newborns. Am J Physiol Endocrinol Metab. 2011; 301(1): E25-E30.
- 21, , , et al. Alcohol consumption before pregnancy causes detrimental fetal development and maternal metabolic disorders. Sci Rep. 2020; 10(1):10054.
- 22, . Effects of ethanol on glucose turnover in pregnant rats. Metabolism. 1989; 38(2): 149-152.
- 23, , . Hypoglycemia in the fetal alcohol syndrome in rat. Brain Dev. 1982; 4(2): 97-103.
- 24, , . Comparative metabolic effects of chronic ethanol intake and undernutrition in pregnant rats and their fetuses. Alcohol Clin Exp Res. 1988; 12(2): 197-200.
- 25, , . Ethanol-induced intrauterine growth retardation: correlation with placental glucose transfer. Alcohol Clin Exp Res. 1986; 10(2): 167-170.
- 26, , . Maternal alcohol ingestion inhibits fetal glucose uptake and growth. Neurotoxicol Teratol. 1989; 11(3): 215-219.
- 27. The effect of maternal ethanol infusion on placental blood flow and fetal glucose metabolism in sheep. Alcohol Alcohol. 1990; 25(4): 413-416.
- 28, . Impaired glucose homeostasis during postimplantation pregnancy in the mouse following acute exposure to ethanol, with particular reference to the uterus and embryo. Biochem Med Metab Biol. 1992; 47(1): 54-65.
- 29, , , , , . Untargeted metabolome analysis reveals reductions in maternal hepatic glucose and amino acid content that correlate with fetal organ weights in a mouse model of fetal alcohol spectrum disorders. Nutrients. 2022; 14(5): 1096.
- 30, , . AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr. 1993; 123(11): 1939-1951.
- 31, , , et al. An enriched biosignature of gut microbiota-dependent metabolites characterizes maternal plasma in a mouse model of fetal alcohol spectrum disorder. Sci Rep. 2021; 11(1):248.
- 32, , , . Growth and behavioral differences in a C57BL/6J mouse model of prenatal alcohol exposure. Alcohol. 2021; 97: 51-57.
- 33, , , et al. Housekeeping gene variability in the liver of alcoholic patients. Alcohol Clin Exp Res. 2012; 36(2): 258-266.
- 34, , , , , . Fetal anemia and elevated hepcidin in a mouse model of fetal alcohol spectrum disorder. Pediatr Res. 2023; 94: 503-511.
- 35, , , , , . Effect of maternal carbohydrate metabolism on fetal growth. Obstet Gynecol. 1998; 92(1): 8-12.
- 36, . Fetal nutrition: how we become what we are. J Pediatr Gastroenterol Nutr. 2001; 33(3): 233-244.
- 37, , . Association of maternal hypoglycemia with low birth weight and low placental weight: a retrospective investigation. J Am Osteopath Assoc. 2011; 111(3): 148-152.
- 38, , , . Association of maternal hypoglycemia on the glucose challenge test and small for gestational age infants [06D]. Obstet Gynecol. 2020; 135: S9-S40.
- 39, . Association between low blood glucose increase during glucose tolerance tests in pregnancy and impaired fetal growth. Acta Obstet Gynecol Scand. 2014; 93(11): 1160-1169.
- 40, , , , . The association between low 50 g glucose challenge test values and adverse pregnancy outcomes. J Womens Health (Larchmt). 2018; 27(6): 801-807.
- 41, , , , , . Use of the 50-g glucose challenge test to predict small-for-gestational-age neonates. J Diabetes. 2020; 12(11): 791-797.
- 42, , . In utero fuel homeostasis: lessons for a clinician. Indian J Endocrinol Metab. 2013; 17(1): 60-68.
- 43, , , et al. Intrauterine growth restriction increases fetal hepatic gluconeogenic capacity and reduces messenger ribonucleic acid translation initiation and nutrient sensing in fetal liver and skeletal muscle. Endocrinology. 2009; 150(7): 3021-3030.
- 44, , , et al. Foetal and neonatal energy metabolism in pigs and humans: a review. Vet Med. 2011; 56(5): 215-225.
- 45, , , , , . Alcohol-induced developmental origins of adult-onset diseases. Alcohol Clin Exp Res. 2016; 40(7): 1403-1414.
- 46, . Developmental origins of health and disease: the relevance to developing nations. Int Health. 2018; 10(2): 66-70.
- 47, , , . Prenatal alcohol exposure programmes offspring disease: insulin resistance in adult males in a rat model of acute exposure. J Physiol. 2019; 597(23): 5619-5637.
- 48, , , et al. Fetal alcohol spectrum disorder predisposes to metabolic abnormalities in adulthood. J Clin Invest. 2020; 130(5): 2252-2269.
- 49 Blood Circulation in the Fetus and Newborn. Health Encyclopedia. University of Rochester Medical Center. Accessed July 25, 2023. https://www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=90&ContentID=P02362
- 50, . Physiology, fetal circulation. StatPearls; 2023.
- 51, , , et al. The impact of umbilical vein blood flow and glucose concentration on blood flow distribution to the fetal liver and systemic organs in healthy pregnancies. FASEB J. 2020; 34(9): 12481-12491.
- 52, , , et al. Fetal liver blood flow distribution: role in human developmental strategy to prioritize fat deposition versus brain development. PloS One. 2012; 7(8):e41759.
- 53, , , , . Maternal diabetes alters the development of ductus venosus shunting in the fetus. Acta Obstet Gynecol Scand. 2018; 97(8): 1032-1040.
- 54, , , , . Venous liver blood flow and regulation of human fetal growth: evidence from macrosomic fetuses. Am J Obstet Gynecol. 2011; 204(5):429 e421-427.
- 55, , . Ductus venosus shunting in the fetal venous circulation: regulatory mechanisms, diagnostic methods and medical importance. Ultrasound Obstet Gynecol. 2006; 27(4): 452-461.
- 56, , , . Ductus venosus shunting in growth-restricted fetuses and the effect of umbilical circulatory compromise. Ultrasound Obstet Gynecol. 2006; 28(2): 143-149.
- 57, , , , , . Simultaneous measurements of umbilical venous, fetal hepatic, and ductus venosus blood flow in growth-restricted human fetuses. Am J Obstet Gynecol. 2004; 190(5): 1347-1358.
- 58, . Fetal cerebral circulation as target of maternal alcohol consumption. Alcohol Clin Exp Res. 2018; 42(6): 1006-1018.
- 59, , , . Binge alcohol exposure in the second trimester attenuates fetal cerebral blood flow response to hypoxia. J Appl Physiol (1985). 2007; 102(3): 972-977.
- 60, , . Development of brain vessels in human embryos and fetuses in conditions of prenatal exposure to alcohol. Neurosci Behav Physiol. 2008; 38(4): 373-376.
- 61, , . Ethanol exposure during pregnancy persistently attenuates cranially directed blood flow in the developing fetus: evidence from ultrasound imaging in a murine second trimester equivalent model. Alcohol Clin Exp Res. 2012; 36(5): 748-758.
- 62, , , , . Decreased glucose transporter 1 gene expression and glucose uptake in fetal brain exposed to ethanol. Life Sci. 1992; 51(7): 527-536.
- 63, . Mechanisms of alcohol-induced damage to the developing nervous system. Alcohol Res Health. 2001; 25(3): 175-184.
- 64, , , . Glucose homeostasis and the neonatal brain: a sweet relationship. Neonatal Netw. 2020; 39(3): 137-146.