The proof of the pudding is in the eating: Metabolic consequences of moderate alcohol exposure before birth

Attitudes and recommendations about drinking alcohol during pregnancy have shifted substantially over the past few decades. The association between heavy alcohol consumption during pregnancy and fetal alcohol spectrum disorder (FASD) has been recognized for many years, with women therefore being recommended not to drink heavily during pregnancy. Children diagnosed with FASD have impaired neurodevelopment, which may affect a range of physical, cognitive, behavioural, emotional and social outcomes (Lange et al. 2017). However, the effects of moderate drinking on neurodevelopmental outcomes are more subtle and have required the use of clever epidemiological approaches such as Mendelian randomization to remove confounding as a result of socioeconomic factors (Zuccolo et al. 2013). Evidence showing that moderate prenatal alcohol exposure (PAE) impairs progeny neurodevelopment in epidemiological studies and after mild to moderate exposure in preclinical models (Comasco et al. 2018) underlies newer recommendations that mothers do not drink any alcohol when pregnant or planning to become pregnant (National Health and Medical Research Council of Australia, 2009; UK Chief Medical Officer, 2016). Although PAE was originally considered to affect mostly the brain, impairing behavioural and cognitive function, it is becoming increasingly evident that PAE has additional adverse impacts on health. A recent systematic review identified strong preclinical evidence for impaired metabolic outcomes in progeny exposed to PAE, particularly from studies in rats (Akison et al. 2019). Metabolic effects of PAE included impaired glucose (glucose intolerance and/or insulin resistance) and lipid metabolism (dyslipidaemia and/or hypercholesterolaemia), and increased adiposity (Akison et al. 2019). There were very few clinical studies available that assessed effects of PAE on metabolic outcomes in children, and these were of high levels of exposure, either from report or based on the presence of facial features characteristic of high exposure (Akison et al. 2019). Similarly, published preclinical studies have mostly investigated effects of ‘high’ rather than ‘mild’ or ‘moderate’ alcohol exposure, with peak maternal blood alcohol concentrations of 0.1–0.3% (Akison et al. 2019). These preclinical studies were also models of chronic rather than acute exposure, with daily or continuous (drinking water) maternal exposure to ethanol for at least 1 week. What therefore remained unclear is whether occasional moderate alcohol exposure before birth also impaired progeny metabolism. Given the known adverse effects of PAE on human health, studies to test such questions cannot ethically be performed in humans. As reported in this issue of the Journal of Physiology, Nguyen et al. (2019) therefore assessed the metabolic health of rat progeny whose mothers consumed moderate levels of alcohol for only 2 days during mid-pregnancy. Blood alcohol concentrations peaked at 0.05%, 1 h after alcohol was given to the pregnant dams, and were less than 0.005% at 5 h after alcohol consumption (Nguyen et al. 2019), producing circulating alcohol profiles probably similar to those in pregnant women who do drink, who report occasional consumption of one or two standard drinks. Although glucose control measured as fasting blood glucose concentration and glucose tolerance during a glucose tolerance test were not impaired in male or female young adult offspring, there was evidence of insulin resistance in the males (Nguyen et al. 2019). This included higher fasting circulating insulin, suggesting that more insulin is required to maintain normal glucose levels, and a smaller glucose response to insulin administration in PAE males compared to controls (Nguyen et al. 2019). Expression and activation (phosphorylation) of Akt, a proximal component of the insulin signalling pathway, was similar in liver and skeletal muscle of PAE and control males. Gene expression of the insulin receptor and of the main glucose transporter (Glut4) in skeletal muscle and adipose tissue was also unaffected by PAE (Nguyen et al. 2019). Curiously, protein levels of total (pan-AKT) and activated (pAKTThr308) were higher in adipose tissue from PAE than control males, suggesting that PAE alters insulin signalling in fat (Nguyen et al. 2019), although these changes would be expected to enhance rather than impair insulin action in this tissue. Whether the insulin resistance observed in young adult males after PAE progresses to glucose intolerance or diabetes with ageing or other challenges such as obesity, or whether metabolic phenotypes emerge in females, remains to be assessed. Overall, the results of the study by Nguyen et al. (2019) provide important evidence showing that even acute and moderate ethanol exposure in utero during early fetal development can impair metabolic outcomes in progeny. This adds further weight to the evidence showing that moderate alcohol consumption during pregnancy adversely affects progeny health and supports policy and recommendations to avoid alcohol consumption when pregnant or planning to become pregnant. These findings also have important implications for those children and adults who were exposed to alcohol during pregnancy, identifying the need to screen and treat individuals diagnosed with FASD across multiple health domains, rather than focussing solely on neurodevelopmental outcomes.