Effects Of Postnatal Ethanol Exposure Research Articles

Effects of genetics and sex on adolescent behaviors following neonatal ethanol exposure in BXD recombinant inbred strains.

Fetal alcohol spectrum disorders (FASD) are the leading preventable neurodevelopmental disorders and two hallmark symptoms of FASD are abnormal behavior, and cognitive and learning deficits. The severity of alcohol's teratogenic effects on the developing brain is influenced by genetics and sex. We previously identified recombinant inbred BXD mouse strains that show differential vulnerability to ethanol-induced cell death in the developing hippocampus, a brain region important in learning and memory. The present study aimed to test the hypothesis that strains with increased vulnerability to ethanol-induced cell death in the hippocampus have concomitant deficits in multiple hippocampal-related behaviors during adolescence. The current study evaluated the effects of developmental ethanol exposure on adolescent behavior in two BXD strains that show high cell death (BXD48a, BXD100), two that show low cell death (BXD60, BXD71), and the two parental strains (C57BL/6 J (B6), DBA/2 J (D2)). On postnatal day 7, male and female neonatal pups were treated with ethanol (5.0 g/kg) or saline given in two equal doses 2 h apart. Adolescent behavior was assessed across multiple behavioral paradigms including the elevated plus maze, open field, Y-maze, and T-maze. Our results demonstrate that the effects of developmental ethanol exposure on adolescent behavioral responses are highly dependent on strain. The low cell death strains, BXD60 and BXD71, showed minimal effect of ethanol exposure on all behavioral measures but did present sex differences. The parental -B6 and D2-strains and high cell death strains, BXD48a and BXD100, showed ethanol-induced effects on activity-related or anxiety-like behaviors. Interestingly, the high cell death strains were the only strains that showed a significant effect of postnatal ethanol exposure on hippocampal-dependent spatial learning and memory behaviors. Overall, we identified effects of ethanol exposure, strain, and/or sex on multiple behavioral measures. Interestingly, the strains that showed the most effects of postnatal ethanol exposure on adolescent behavior were the BXD strains that show high ethanol-induced cell death in the neonatal hippocampus, consistent with our hypothesis. Additionally, we found evidence for interactions among strain and sex, demonstrating that these factors have a complex effect on alcohol responses and that both are important considerations.

Effects of postnatal ethanol exposure and maternal separation on mood, cognition and hippocampal arborization in adolescent rats

Ethanol exposure and early life stress during brain development are associated with an increased risk of developing psychiatric disorders. We used a third-trimester equivalent model of fetal alcohol spectrum disorders combined with a maternal separation (MS) protocol to evaluate whether these stressors cause sexually dimorphic behavioral and hippocampal dendritic arborization responses in adolescent rats. Wistar rat pups were divided into four experimental groups: 1) Control; 2) MS (MS, for 3 h/day from postnatal (PND) 2 to PND14); 3) EtOH (EtOH, 5 g/kg/day, i.p., PND2, 4, 6, 8, and 10); 4) EtOH + MS. All animals were divided into two cohorts and subjected to a battery of behavioral tests when they reached adolescence (PND37−44). Animals from cohort 1 were submitted to: 1) the open field test; 2) self-cleaning behavior (PND38); and 3) the motivation test (PND39−41). Animals from cohort 2 were submitted to: 1) the novel object recognition (PND37−39); 2) social investigation test (PND40); and 3) Morris water maze test (PND41−44). At PND45, the animals were euthanized, and the brains were collected for subsequent dendritic analysis. Postnatal ethanol exposure (PEE) caused anxiety-like behavior in females and reduced motivation, and increased hippocampal dendritic arborization in both sexes. MS reduced body weight, increased locomotor activity in females, and increased motivation, and hippocampal dendritic arborization in both sexes. We found that males from the EtOH + MS groups are more socially engaged than females, who were more interested in sweets than males. Altogether, these data suggest that early life adverse conditions may alter behavior in a sex-dependent manner in adolescent rats.

Effects of postnatal ethanol exposure at different developmental phases on neurotrophic factors and phosphorylated proteins on signal transductions in rat brain

Exposure to ethanol during development induces severe brain damage resulting in a number of CNS dysfunctions including microencephaly and mental retardation in humans and in laboratory animals. The most vulnerable period to ethanol neurotoxicity coincides with the peak of brain growth spurt. Recently, neurotrophic factors and/or their signal transduction pathways have been reported as a potential relevant target for the developmental neurotoxicity of ethanol. The present studies were designed to investigate the effects of ethanol given in various developmental phases during the brain growth spurt in rats. Rat pups were assigned to the three treatment groups and treated with 5 g/kg of ethanol for three days, on postnatal days (PND) 2–4, 6–8 or 13–15. Whole brain weights were reduced only in the PND 6–8 group concurrently with the reduction of GDNF mRNA in cortex in this group. BDNF mRNA expression was reduced in both the PND 6–8 and 13–15 groups, while mRNA expressions of NT-3 and NGF were unchanged in all three groups. Phospho-Akt level was mostly reduced in the PND 6–8 group. Both phospho-MAPK and p-70S6 kinase levels were decreased in all groups whereas no changes were observed in either phospho-PKCζ or CREB level. The phosphorylation of Akt was immediately inhibited after single administration of ethanol, and its inhibition was correlated with variations in blood ethanol concentration.These findings suggest that GDNF and the phosphorylation of Akt play a possible key role in the ethanol-induced developmental neurotoxicity.

Effects of postnatal ethanol exposure on neurotrophic factors and signal transduction pathways in rat brain

Exposure to ethanol during development induces severe brain damage, resulting in a number of CNS dysfunctions including microencephaly and mental retardation. Potential targets of ethanol-induced neurotoxicity include neurotrophic factors and their signal transduction pathways. In the present study, rat pups were given ethanol at the dose of 5 g kg(-1) via gavage from postnatal day (PND) 5 to 8, and mRNA expression of nerve growth-factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophic factor-3 (NT-3) in the cerebral cortex was examined, with attention to signal transduction, on PND 8. The mRNA level of BDNF was decreased by ethanol while those of NGF or NT-3 were not changed. Brain weights were decreased and the levels of phospho-MAPK, phospho-p70S6K and phospho Akt were decreased while phosphor-PKCzeta and phospho-CREB remained unchanged. These results suggest that BDNF and its related signal pathways involving Akt, MAPK and p70S6K are potential targets of ethanol-induced developmental neurotoxicity.

Effects of postnatal ethanol exposure on brain growth and lipid composition in n-3 fatty acid-deficient and -adequate rats.

The artificial rearing model was used to investigate the effects of short-term exposure to ethanol on growth and fatty acid composition of forebrain (FB) and cerebellum (CB) during the brain growth spurt in either n-3 fatty acid-adequate (AD) or n-3 deficient (DEF) rat pups. On postnatal day 5, offspring of female rats that had been fed AD or DEF diets from day 5 of life were assigned to three groups: members of two groups were gastrostomized and artificially fed formulas appropriate for their maternal history, and the third group (suckled control) was fostered to lactating dams of a similar dietary history. Half of the artificially reared pups in each dietary condition were fed ethanol in their formula (7% vol/vol) in one-quarter of their daily feedings, while the others received maltose-dextrin substituted isocalorically for ethanol. Blood alcohol concentrations did not differ between the dietary groups. FB weight on postnatal day 9 was lower in ethanol-exposed offspring in both dietary conditions. Brain fatty acid composition reflected dietary history in that, compared with AD pups, DEF pups had lower percentages of docosahexaenoic acid, higher percentages of 22:5n-6, and a higher n-6/n-3 fatty acid ratio. However, the effects of ethanol exposure were inconsistent, lowering the n-6/n-3 ratio in the phosphatidylethanolamine (PE) fraction in FB but not in CB, while increasing this ratio in the phosphatidylcholine (PC) fraction in FB of the DEF pups only. Thus, while ethanol had some effects on lipid composition, there was no difference between the dietary groups in their vulnerability to the effects of early short-term ethanol exposure on brain growth.

Effect of Postnatal Ethanol Exposure on Expression of Differentiation Antigens of Murine Splenic Lymphocytes

Ethanol is a recognized immunosuppressive agent in the chronic alcoholic. However, the effects of ethanol exposure on the developing immune system have not been extensively investigated. This study evaluated the effects of early postnatal ethanol exposure, via breast milk, on splenic lymphocyte differentiation antigen expression in offspring reared by ethanol-fed mice. Maternal mice were fed a liquid diet containing 20% ethanol-derived calories during pregnancy (E-P), pregnancy and lactation (E-PL), or lactation (E-L). Ad libitum-fed (C) and pair-fed (PF) control groups, fed a control liquid diet, were included. Expression of differentiation antigens on splenic lymphocytes from 21-day-old offspring reared by females in 1 of the 3 ethanol exposure conditions was evaluated by flow cytometry. Offspring reared by E-P females had similar numbers of splenic lymphocytes as offspring reared by C and pair-fed during pregnancy (PF-P) females. In contrast, offspring reared by E-PL and E-L females had fewer splenic lymphocytes than both PF-PL and PF-L (respectively), and C offspring. The number of Thy 1.2+, CD4+, CD8+, and IgG+ (B-cell) splenic lymphocytes was reduced in E-PL and E-L offspring compared with PF and C offspring. E-P offspring had fewer CD4+ and IgG+ splenic lymphocytes than C, but not PF-P, offspring. The percentage of Thy 1.2+ splenic lymphocytes was significantly reduced among E-PL and E-L offspring compared with PF-PL and PF-L (respectively), and C offspring.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of postnatal ethanol exposure on glial cell development in rat optic nerve

This study morphologically evaluated the effects of limited postnatal alcohol exposure on the development of glial cells in the rat optic nerve. Rat pups were artificially reared on Days 5–18 with a supplemented milk diet fed via a chronic gastrostomy tube. Experimental animals received 4% ethanol in their diet on Days 5–9, otherwise the experimental and control animals received identical diets. Optic nerve tissues were prepared for electron microscopy on Days 10, 16, 22, 29, and 90. There were fewer glial cells per cross section and the cross-sectional areas of optic nerves were smaller on Days 10 and 16 in the ethanol-exposed animals. The alcohol caused a delay in the maturation of oligodendroglial cells at 10 days as evidenced by decreases in the total number of oligodendroglia present and by a delay in the appearance of immature cells within the oligodendroglial lineage. All of these effects were compensated for at later ages. There was no evidence of alcohol-induced degeneration of glial cells or their organelles. Thus, postnatal alcohol exposure causes a delay in oligodendrocyte maturation but appears to have no long-term effects on the glial cell population of rat optic nerve.