Prenatal alcohol exposure programmes offspring disease: insulin resistance in adult males in a rat model of acute exposure

Abstract

Key points Prenatal alcohol exposure has the potential to affect fetal development and programme chronic disease in offspring. Previous preclinical models typically use high, chronic doses of alcohol throughout pregnancy to examine effects on offspring, particularly on the brain and behaviour. In this study we use a rat model of moderate, acute, prenatal alcohol exposure to determine if this can be detrimental to maintenance of glucose homeostasis in adolescent and adult offspring. Although female offspring were relatively unaffected, there was evidence of insulin resistance in 6‐month‐old male offspring exposed to prenatal alcohol, suggestive of a pre‐diabetic state. This result suggests that even a relatively low‐dose, acute exposure to alcohol during pregnancy can still programme metabolic dysfunction in a sex‐specific manner. Abstract Alcohol consumption is highly prevalent amongst women of reproductive age. Given that approximately 50% of pregnancies are unplanned, alcohol has the potential to affect fetal development and programme chronic disease in offspring. We examined the effect of an acute but moderate prenatal alcohol exposure (PAE) on glucose metabolism, lipid levels and dietary preference in adolescent and/or adult rat offspring. Pregnant Sprague–Dawley rats received an oral gavage of ethanol (1 g kg−1 maternal body weight, n = 9 dams) or an equivalent volume of saline (control, n = 8 dams) at embryonic days 13.5 and 14.5. PAE resulted in a blood alcohol concentration of 0.05–0.06% 1 h post‐gavage in dams. Fasting blood glucose concentration was not affected by PAE in offspring at any age, nor were blood glucose levels during a glucose tolerance test (GTT) in 6‐month‐old offspring (P > 0.5). However, there was evidence of insulin resistance in PAE male offspring at 6 months of age, with significantly elevated fasting plasma insulin (P = 0.001), a tendency for increased first phase insulin secretion during the GTT and impaired glucose clearance following an insulin challenge (P = 0.007). This was accompanied by modest alterations in protein kinase B (AKT) signalling in adipose tissue. PAE also resulted in reduced calorie consumption by offspring compared to controls (P = 0.04). These data suggest that a relatively low‐level, acute PAE programmes metabolic dysfunction in offspring in a sex‐specific manner. These results highlight that alcohol consumption during pregnancy has the potential to affect the long‐term health of offspring.

Moderate episodic prenatal alcohol does not impact female offspring fertility in rats

“…A detailed description of the source of animals, housing conditions and treatments has been previously reported (Nguyen, et al 2019). Briefly, outbred, nulliparous Sprague-Dawley rats were housed in a temperature- and humidity-controlled environment with an artificial 12 h reversed light-dark cycle and provided with standard laboratory rat chow (Rat & Mouse Meat-Free Diet, Specialty Feeds, Glen Forrest WA, Australia) and water ad libitum.…”

“…Note that one EtOH litter was excluded from further experiments given the litter size was 7 (mean, range for other litters: 15, 11-19). * A separate cohort of offspring from these litters were also examined for metabolic outcomes (reported in Nguyen et al 2019). ^ n =5 at PN3 due to aging error for 1 litter.…”

“…Approximately 150 μl whole blood was collected from pregnant dams via a tail tip bleed at 1 h and 5 h post gavage on E13.5 and 14.5 to measure blood alcohol concentration (BAC) (Nguyen, et al 2019). An additional tail tip bleed at E19.5 was used to measure plasma progesterone levels.…”

“…Plasma BAC was determined by Pathology Queensland (Queensland Health) using an alcohol dehydrogenase enzymatic assay (Beckman Coulter, Lane Cove, NSW, Australia; reference #474947) as previously reported (Nguyen, et al 2019). Steroid hormones were analysed by radioimmunoassay (RIA) as previously described (Kalisch-Smith, et al 2019).…”

“…However, this is not representative of typical reported drinking behaviours in pregnant women, which are often episodic and at low-moderate levels of alcohol, referred to as ‘special occasion’ drinking (McCormack, et al 2017, Muggli, et al 2016). This study, using a rat model of acute, low-level exposure that has been previously reported to result in a blood alcohol concentration (BAC) of ∼0.05%, did not result in fetal growth restriction but still produced sex-specific adverse metabolic outcomes in adult offspring (Nguyen, et al 2019). The timing of exposure corresponded with germ cell cyst or ‘nest’ formation in the ovaries of female offspring, with breakdown of these nests and encapsulation of individual oocytes by somatic cells to form primordial follicles occurring in late gestation and peaking in early postnatal life in rodents (Sarraj and Drummond 2012).…”