The role of cortisol in chronic binge alcohol-induced cerebellar injury: Ovine model

Abstract

Women who drink alcohol during pregnancy are at high risk of giving birth to children with neurodevelopmental disorders. Previous reports from our laboratory have shown that third trimester equivalent binge alcohol exposure at a dose of 1.75 g/kg/day results in significant fetal cerebellar Purkinje cell loss in fetal sheep and that both maternal and fetal adrenocorticotropin (ACTH) and cortisol levels are elevated in response to alcohol treatment. In this study, we hypothesized that repeated elevations in cortisol from chronic binge alcohol are responsible at least in part for fetal neuronal deficits. Animals were divided into four treatment groups: normal control, pair-fed saline control, alcohol and cortisol. The magnitude of elevation in cortisol in response to alcohol was mimicked in the cortisol group by infusing pregnant ewes with hydrocortisone for 6 hours on each day of the experiment, and administering saline during the first hour in lieu of alcohol. The experiment was conducted on three consecutive days followed by four days without treatment beginning on gestational day (GD) 109 until GD 132. Peak maternal blood alcohol concentration in the alcohol group was 239 ± 7 mg/dl. The fetal brains were collected and processed for stereological cell counting on GD 133. The estimated total number of fetal cerebellar Purkinje cells, the reference volume and the Purkinje cell density were not altered in response to glucocorticoid infusion in the absence of alcohol. These results suggest that glucocorticoids independently during the third trimester equivalent may not produce fetal cerebellar Purkinje cell loss. However, the elevations in cortisol along with other changes induced by alcohol could together lead to brain injury seen in the fetal alcohol spectrum disorders.

Effects of all three trimester moderate binge alcohol exposure on the foetal hippocampal formation and olfactory bulb

“…The total number of foetal hippocampal pyramidal cells in the CA1 and CA2/3 fields, granule cells in the dentate gyrus and mitral cells in the olfactory bulb were estimated using unbiased stereological cell counting techniques as described in previous publications [15,30,31]. The term CA2/3 refers to the summed CA2 and CA3 fields, which were combined due to the difficulty in differentiating these two fields accurately at this developmental stage.…”

“…The placement of the disector frames was determined by the GRID ® software in a random manner. The estimated total number of cells in the olfactory bulb, dentate gyrus, CA1 and CA2/3 fields were then calculated by multiplying the reference volume of the respective regions and the numerical density of cells within this reference volume as described before [15,30,31]. …”

Interactive effects of in vitro binge-like alcohol and ATP on umbilical endothelial nitric oxide synthase post-translational modifications and redox modulation

“…Many alcohol studies on eNOS have been performed in adult non-pregnant human or animal tissues; for instance, in vitro acute treatment of alcohol (0.1%, 3h) increased bovine aortic endothelial NO [7], whereas alcohol at 4 g/kg for 12 weeks decreased rat aortic eNOS expression, NO levels, and impaired vasorelaxation [8]. Intravenous infusion of alcohol in male and non-pregnant female rabbits [9] as well as in healthy human volunteers [10] dose-dependently decreased levels of exhaled NO.…”

The Role of Acidemia in Maternal Binge Alcohol-Induced Alterations in Fetal Bone Functional Properties

“…in rats, maternal alcohol consumption (36% alcohol derived calories) throughout gestation increases maternal bone resorption (Keiver and Weinberg, 2003; Sawant et al, 2012; Washburn et al, 2012), decreases the fetal tibial diaphysis length, disrupts organization of the histological zones within the fetal tibial ephiphyses, decreases the length of the resting zone, and increases the length of the hypertropic zone (Snow and Keiver, 2007). Further, alcohol exposure throughout gestation decreases ovine fetal but not maternal bone strength (Ramadoss et al, 2006), and hampers rat fetal skeletal ossification independent of overall fetal growth restriction (Simpson et al, 2005).…”