Temporal vulnerability of fetal cerebellar Purkinje cells to chronic binge alcohol exposure: ovine model.
BACKGROUND
Human magnetic resonance imaging (MRI) and autopsy studies reveal abnormal cerebellar development in children who had been exposed to alcohol prenatally, independent of the exposure period. Animal studies conducted utilizing the rat model similarly demonstrate a broad period of vulnerability, albeit the third trimester-equivalent of human brain development is reported to be the most vulnerable period, and the first trimester-equivalent exposure produces cerebellar Purkinje cell loss only at high doses of alcohol. However, in the rat model, all 3 trimester-equivalents do not occur prenatally, requiring the assumption that intrauterine environment, placenta, maternal interactions, and parturition do not play an important role in mediating the damage. In this study, we utilized the ovine model, where all 3 trimester-equivalents occur in utero, to determine the critical window of vulnerability of fetal cerebellar Purkinje cells.


METHODS
Four groups of pregnant sheep were used: first trimester-equivalent pair-fed saline control group, first trimester-equivalent alcohol group (1.75 g/kg), third trimester-equivalent pair-fed saline control group, and third trimester-equivalent alcohol group (1.75 g/kg). The alcohol exposure regimen was designed to mimic a human binge pattern. Alcohol was administered intravenously on 3 consecutive days beginning on day 4 and day 109 of gestation in the first and third trimester-equivalent groups, respectively, and the alcohol treatment was followed by a 4-day inter-treatment interval when the animals were not exposed to alcohol. Such treatment episodes were replicated until gestational day 41 and 132 in the first and third trimester-equivalent groups, respectively. All fetal brains were harvested on day 133 and processed for stereological cerebellar Purkinje cell counting.


RESULTS
Significant deficits were found in the fetal cerebellar Purkinje cell number and density in the first and third trimester-equivalent alcohol exposed fetuses compared with those in the saline controls. However, there was no difference between the first and third trimester-equivalent alcohol administered groups. When comparing the present findings to those from a previous study where the duration of alcohol exposure was all 3 trimester-equivalents of gestation, we did not detect a difference in fetal cerebellar Purkinje cell number.


CONCLUSIONS
We conclude that the fetal cerebellar Purkinje cells are sensitive to alcohol exposure at any time during gestation and that women who engage in binge drinking during the first trimester are at a high risk of giving birth to children with cerebellar damage even if drinking ceases after the first trimester. Our findings also support the hypothesis that only a certain population of Purkinje cells are vulnerable to alcohol-induced depletion irrespective of the timing or duration of alcohol exposure.
Department of Veterinary Physiology and Pharmacology and Michael E. DeBakey Institute, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas 77843-4466, USA.
Jayanth
J
Ramadoss
Emilie R
ER
Lunde
Wei-Jung A
WJ
Chen
James R
JR
West
Timothy A
TA
Cudd
D000428:Alcohol Drinking / Q000009:adverse effects*; D000437:Alcoholism / Q000503:physiopathology; D000818:Animals; D002452:Cell Count; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002531:Cerebellum / Q000196:embryology* / Q000473:pathology; D004195:Disease Models, Animal; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D005260:Female; D008431:Maternal-Fetal Exchange / Q000502:physiology; D011247:Pregnancy; D011689:Purkinje Cells / Q000187:drug effects* / Q000473:pathology; D012756:Sheep
D002492:Central Nervous System Depressants; D000431:Ethanol