Effects of periconceptional maternal alcohol intake and a postnatal high-fat diet on obesity and liver disease in male and female rat offspring

Abstract

The effects of maternal alcohol consumption around the time of conception on offspring are largely unknown and difficult to determine in a human population. This study utilized a rodent model to examine if periconceptional alcohol (PC:EtOH) consumption, alone or in combination with a postnatal high-fat diet (HFD), resulted in obesity and liver dysfunction. Sprague-Dawley rats were fed a control or an ethanol-containing [12.5% (vol/vol) EtOH] liquid diet from 4 days before mating until 4 days of gestation ( n = 12/group). A subset of offspring was fed a HFD between 3 and 8 mo of age. In males, PC:EtOH and HFD increased total body fat mass ( P < 0.05, P < 0.0001); in females, only HFD increased fat mass ( P < 0.0001). PC:EtOH increased microvesicular liver steatosis in male, but not female, offspring. Plasma triglycerides, HDL, and cholesterol were increased in PC:EtOH-exposed males ( P < 0.05), and LDL, cholesterol, and leptin (Lep) were increased in PC:EtOH-exposed females ( P < 0.05). mRNA levels of Tnf-α and Lep in visceral adipose tissue were increased by PC:EtOH in both sexes ( P < 0.05), and Il-6 mRNA was increased in males ( P < 0.05). These findings were associated with reduced expression of microRNA-26a, a known regulator of IL-6 and TNF-α. Alcohol exposure around conception increases obesity risk, alters plasma lipid and leptin profiles, and induces liver steatosis in a sex-specific manner. These programmed phenotypes were similar to those caused by a postnatal HFD, particularly in male offspring. These results have implications for the health of offspring whose mothers consumed alcohol around the time of conception.

Adverse Health Outcomes in Offspring Associated With Fetal Alcohol Exposure: A Systematic Review of Clinical and Preclinical Studies With a Focus on Metabolic and Body Composition Outcomes

“…This resulted in a peak BAC of 0.03% 0.5 hour after fresh diet was first offered for the day, but by 1 hour, BAC was negligible (Probyn et al., ). The 12.5% v/v diet reported by Gårdebjer and colleagues (, ) resulted in a peak BAC of ~0.18 to 0.25% 0.5 hour after fresh diet was offered, dropping to ~0.07% at 3 hours and ~0.05% at 5 hours as reported previously (Gårdebjer et al., ). Some studies reported the concentration as percentage of EtOH‐derived calories (EDC), with most studies providing 35% EDC.…”

“…). Only 2 studies by Gårdebjer and colleagues (, ) treated specifically around the periconceptional period, which included exposure for 1 estrous cycle prior to mating/conception and for the first 4 days of pregnancy, prior to implantation. Ludena and colleagues () and Lopez‐Tejero and colleagues () also included a preconception exposure period of 4 weeks.…”

“…However, there were a variety of ways that researchers provided an isocaloric alternative for the control group in lieu of EtOH treatment (Table ). Probyn and colleagues () and Gårdebjer and colleagues (, ) adjusted their control liquid diet formulas to account for extra calories provided by EtOH or different consumption rates, respectively. Zimmerberg and colleagues (Zimmerberg, ; Zimmerberg et al., ,, ) used a pair‐feeding approach, by including control dams individually “yoked” to an alcohol group dam, which received the same volume of liquid diet with maltodextrin substituted for EtOH.…”

Fetal alcohol spectrum disorder predisposes to metabolic abnormalities in adulthood

“…Human studies suggest that children and adolescents with FASDs have increased body fat, a higher incidence of obesity, and hypertension (18,19). However, despite additional reports using animal models suggesting that perinatal and gestational alcohol exposure are connected to poor metabolic health outcomes, there are multiple studies indicating that PAE is not associated with increased fat mass or metabolic syndrome following specific alcohol exposure windows (12,18,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). These conflicting reports highlight the need to clarify which adverse health outcomes are associated with PAE and to define disease mechanisms.…”

Prenatal alcohol exposure programs offspring disease: Insulin resistance in adult males in a rat model of acute exposure

“…Our result is similar to that found in a previous low-dose model in rats (Probyn et al ., 2013), as well as a study in mice with EtOH exposure restricted to late gestation (Amos-Kroohs et al ., 2018). However, other higher dose models have reported increased adiposity in PAE offspring compared to controls, particularly in males (Dobson et al ., 2012; Gardebjer et al ., 2018; Zhang et al ., 2018).…”