Different Patterns of Regional Purkinje Cell Loss in the Cerebellar Vermis as a Function of the Timing of Prenatal Ethanol Exposure in an Ovine Model.
ABSTRACT Studies in rat models of fetal alcohol spectrum disorders have indicated that the cerebellum is particularly vulnerable to ethanol-induced Purkinje cell loss during the third trimester-equivalent, with striking regional differences in vulnerability in which early-maturing regions in the vermis show significantly more loss than the late-maturing regions. The current study tested the hypothesis that the sheep model will show similar regional differences in fetal cerebellar Purkinje cell loss when prenatal binge ethanol exposure is restricted to the prenatal period of brain development equivalent to the third trimester and also compared the pattern of loss to that produced by exposure during the first trimester-equivalent. Pregnant Suffolk sheep were assigned to four groups: first trimester-equivalent saline control group, first trimester-equivalent ethanol group (1.75g/kg/day), third trimester-equivalent saline control group, and third trimester-equivalent ethanol group (1.75g/kg/day). Ethanol was administered as an intravenous infusion on 3 consecutive days followed by a 4-day ethanol-free interval, to mimic a weekend binge drinking pattern. Animals from all four groups were sacrificed and fetal brains were harvested on gestation day 133. Fetal cerebellar Purkinje cell counts were performed in an early-maturing region (lobules I-X) and a late-maturing region (lobules VIc-VII) from mid-sagittal sections of the cerebellar vermis. As predicted, the third trimester-equivalent ethanol exposure caused a significant reduction in the fetal cerebellar Purkinje cell volume density and Purkinje cell number in the early-maturing region, but not in the late-maturing region. In contrast, the first trimester-equivalent ethanol exposure resulted in significant reductions in both the early and late-maturing regions. These data confirmed the previous findings in rat models that third trimester-equivalent prenatal ethanol exposure resulted in regionally-specific Purkinje cell loss in the early-maturing region of the vermis, and further demonstrated that first trimester ethanol exposure caused more generalized fetal cerebellar Purkinje cell loss, independent of the cerebellar vermal region. These findings support the idea that prenatal ethanol exposure in the first trimester interferes with the genesis of Purkinje cells in an unselective manner, whereas exposure during the third trimester selectively kills post-mitotic Purkinje cells in specific vermal regions during a vulnerable period of differentiation and synaptogenesis.
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ABSTRACT: The first trimester of human development and the equivalent developmental period in animal models is a time when teratogenic ethanol (EtOH) exposure induces the major structural birth defects that fall within fetal alcohol spectrum disorder (FASD). Previous FASD research employing an acute high dose maternal intraperitoneal EtOH treatment paradigm has identified sensitive periods for a number of these defects. Extending this work, this investigation utilized high resolution magnetic resonance microscopy (MRM)-based analyses to examine the dysmorphology resulting from maternal dietary EtOH intake occurring during selected first trimester-equivalent time periods.Alcoholism Clinical and Experimental Research 06/2014; DOI:10.1111/acer.12464 · 3.31 Impact Factor
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ABSTRACT: Abstract Objective: Pre-natal alcohol exposure results in injury to the hippocampus and olfactory bulb, but currently there is no consensus on the critical window of vulnerability. This study tested the hypothesis that pre-natal exposure to a moderate dose of alcohol during all three trimester-equivalents alters development of the hippocampal formation and olfactory bulb in an ovine model, where all brain development occurs pre-natally as it does in humans. Research design and methods: Pregnant sheep were divided into saline control and a binge drinking groups (alcohol dose 1.75 g kg(-1); mean peak blood alcohol concentration 189 + 19 mg dl(-1)). Outcome and results: The density, volume and total cell number were not different between groups for the dentate gyrus, pyramidal cells in the CA1 and CA2/3 fields and mitral cells in the olfactory bulb. Conclusions: A moderate dose of alcohol administered in a binge pattern throughout gestation does not alter cell numbers in the hippocampus or olfactory bulb and exposure during the third trimester-equivalent is required for hippocampal injury, unless very high doses of alcohol are administered. This has important implications in establishing the sensitivity of imaging modalities such as MRI in which volumetric measures are being studied as biomarkers for pre-natal alcohol exposure.Brain Injury 09/2014; 29(1):1-6. DOI:10.3109/02699052.2014.947629 · 1.86 Impact Factor
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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 h 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.Alcohol (Fayetteville, N.Y.) 12/2012; 47(1). DOI:10.1016/j.alcohol.2012.10.004 · 2.04 Impact Factor