Fetal Alcohol Exposure and Temporal Vulnerability: Regional Differences in Cell Loss as a Function of the Timing of Binge‐Like Alcohol Exposure During Brain Development

Abstract

This study was conducted to determine the temporal and regional vulnerability of the brain as a function of exposure to alcohol during brain development. Our goal was to manipulate the timing of alcohol exposure and assess the relative risk of cell loss in two different brain regions. Groups of timed pregnant Sprague-Dawley rats received binge-like alcohol exposure during either the first 10 days (first-trimester equivalent) or second 10 days of gestation (second-trimester equivalent), or the combination of first- and second-trimester equivalents for prenatal treatments. Offspring from some of the animals exposed to alcohol during the combined first- and second-trimester equivalent were reared artificially from postnatal days (P) 4 through 9 (part of the third-trimester equivalent) and also received binge-like alcohol during this period, producing animals that were exposed to alcohol during all three trimesters equivalent. Offspring from untreated dams were also reared artificially and received alcohol from only P4-9, thus creating animals that were exposed to alcohol only during part of the third-trimester equivalent. All pups were perfused on P10. Appropriate controls (nutritional and normally reared) were matched to every alcohol treatment combination. Peak blood alcohol concentrations were not different among the treatment groups for a given sampling time. Total cell numbers in the cerebellum (Purkinje and granule cells) and the olfactory bulb (mitral and granule cells) were estimated by the unbiased stereological technique, the optical disector. In terms of temporal vulnerability, alcohol exposure during the equivalent of all three trimesters resulted in a greater reduction in cerebellar Purkinje cell numbers compared with exposure to alcohol during the third-trimester equivalent, whereas both groups had a significant reduction in cell number compared with all other timing groups. Cerebellar granule cell number was reduced after alcohol exposure during all three trimesters equivalent, compared with all other timing groups. Alcohol exposure during the third-trimester equivalent resulted in a decrement in the number of olfactory bulb mitral cell numbers compared with all other groups, but there were no differences among the timing groups in numbers of olfactory bulb granule cells. When the cell loss in the two regions was compared within each alcohol treatment group to determine the relative regional vulnerability, the primary salient finding was that cerebellar Purkinje cells were more vulnerable to alcohol-induced loss subsequent to exposure during all three trimesters equivalent. No other regional differences were detected. These results extend earlier findings by showing that alcohol exposure during different periods of brain development results in regional differences in cell loss as a function of the timing of alcohol exposure during brain development and illustrate the variability of alcohol-induced neuronal loss.

Prenatal exposure to ethanol causes partial diabetes insipidus in adult rats

“…In the rat, this diet produces blood alcohol levels of ϳ130 mg/dl 1 h into the dark cycle (17). When 5.1 g of ethanol/kg were administered as a bolus, peak blood alcohol levels reached ϳ300 mg/dl (20). These levels of blood alcohol are commonly achieved in humans (National Institute on Alcohol Abuse and Alcoholism, http:// www.niaaa.nih.gov/extramural/impasp.htm).…”

“…The diets were continued until gestational day 21 when the dams were returned to their normal rat chow. The pups were fed by their biological lactating mothers (20) and weaned at 21 days.…”

Early postnatal alcohol exposure reduced the size of vibrissal barrel field in rat somatosensory cortex (SI) but did not disrupt barrel field organization

“…Taken together, the findings in the present and previous studies provide evidence that the early postnatal period, which is the period of brain growth spurt that is analogous to the third trimester of pregnancy in humans, is a critical period of vulnerability to alcohol neurotoxicity in cerebral cortex, as it appears to be for many other brain regions. (Livy et al, 2001;Livy et al, 2003;Maier et al, 1999;Maier and West, 2003;Tran and Kelly, 2003). Interestingly, PAE also reduced the size of the PMBSF and sizes of individual barrels in neonatal pups (Margret et al, 2005b), however in postnatal alcohol exposed pups, averaged PMBSF and individual barrel sizes were approximately 8% smaller than in PAE pups suggesting that both pre-and-postnatal periods are important for barrel field development.…”

“…In rodents, prenatal exposure to alcohol disrupted the distribution of callosal projection neurons in first somatosensory cortex (SI) (Miller, 1997), significantly decreased somatosensory cortical volume, total neuron and glial cell numbers (Miller and Potempa, 1990), and resulted in significant structural and metabolic alterations in rat cerebral cortex (Miller and Dow-Edwards, 1988;Miller and Dow-Edwards, 1993). Similarly, early postnatal alcohol exposure decreased brain weight (Bonthius and West, 1991;Maier et al, 1999), reduced neocortical volume (Mooney and Napper, 2005), and reduced the size of neocortex (Miller, 1996) in rats.…”

Ethanol exposure of neonatal rats does not increase biomarkers of oxidative stress in isolated cerebellar granule neurons

“…The pathology of Fetal Alcohol Syndrome includes significant malformation and dysfunction in the brain including learning, behavioral, social, and psychiatric disorders that persist into adulthood (Sowell et al, 2002;Warren and Bast, 1988). Animal models (Bonthius and West, 1991;Driscoll et al, 1990;Green et al, 2002;Kane et al, 1997;Klintsova et al, 2002;Light et al, 2002b;Light et al, 1998) demonstrate that ethanol exposure during brain development causes significant neuronal loss (Hamre and West, 1993;Maier et al, 1999;Pierce et al, 1989;Pierce et al, 1997;Pierce et al, 1993;Pierce and West, 1987;Pierce et al, 1999). The neonatal rodent model of maternal drinking in the third trimester demonstrates striking Purkinje cell and granule neuron loss in the cerebellum (Goodlett et al, 1990;Light et al, 2002a;Pierce et al, 1999).…”