Elsevier

Alcohol

Volume 41, Issue 8, December 2007, Pages 577-586
Alcohol

Effects of maternal administration of vitamins C and E on ethanol neurobehavioral teratogenicity in the guinea pig

https://doi.org/10.1016/j.alcohol.2007.08.005Get rights and content

Abstract

Consumption of ethanol during human pregnancy can produce a wide spectrum of teratogenic effects, including neurobehavioral dysfunction. This study, in the guinea pig, tested the hypothesis that chronic maternal administration of antioxidant vitamins C plus E, together with ethanol, mitigates ethanol neurobehavioral teratogenicity. Pregnant guinea pigs received one of the following four chronic oral regimens: ethanol and vitamins C plus E; ethanol and vitamin vehicle; isocaloric-sucrose/pair-feeding and vitamins C plus E; or isocaloric-sucrose/pair-feeding and vehicle. Vitamins C (250 mg) plus E (100 mg) or vehicle were given daily, and ethanol (4 g/kg maternal body weight/day) (E) or isocaloric-sucrose/pair-feeding was given for 5 consecutive days followed by 2 days of no treatment each week throughout gestation. One neonate from selected litters was studied on postnatal day (PD) 0. Neurobehavioral function was determined by measuring task acquisition and task retention using an 8-day moving-platform version of the Morris water-maze task, starting on PD 45. Thereafter, in vivo electrophysiologic assessment of changes in hippocampal synaptic plasticity was conducted. There was an ethanol-induced decrease in neonatal brain weight compared with sucrose. The vitamins C plus E regimen protected hippocampal weight relative to brain weight in ethanol offspring, and mitigated the ethanol-induced deficit in the task-retention component of the water-maze task. However, in the sucrose group, this Vit regimen produced deficits in both task acquisition and task retention. The vitamins C plus E regimen did not mitigate the ethanol-induced impairment of hippocampal long-term potentiation. These results indicate that maternal administration of this high-dose vitamins C plus E regimen throughout gestation has limited efficacy and potential adverse effects as a therapeutic intervention for E neurobehavioral teratogenicity.

Introduction

The term, fetal alcohol spectrum disorders, is all-encompassing and describes the full spectrum of teratogenic effects that have been observed in the offspring of women who consumed excessive amounts of alcoholic beverages during pregnancy (Hoyme et al., 2005). At the most severe end of the spectrum is fetal alcohol syndrome (FAS), characterized by three principal features: craniofacial dysmorphology, pre-/postnatal growth deficiency, and central nervous system (CNS) dysfunction and dysmorphology (Jones and Smith, 1973, Jones et al., 1973). The CNS dysfunction and dysmorphology persist throughout postnatal life and are considered to be the most debilitating to the individual as a consequence of chronic prenatal ethanol exposure (CPEE). Laboratory animal studies have demonstrated that the hippocampus is one of the target sites of ethanol CNS teratogenicity (Kimura et al., 2000), which can manifest as hyperactivity (Catlin et al., 1993, Driscoll et al., 1990), deficits in spatial learning and memory (Driscoll et al., 1990, Iqbal et al., 2004, Richardson et al., 2002, Savage et al., 2002), and impaired synaptic plasticity (Richardson et al., 2002, Sutherland et al., 1997).

Many mechanisms have been proposed for ethanol neurobehavioral teratogenicity, including oxidative stress (OS) (see reviews by Abel and Hannigan, 1995, Goodlett et al., 2005). In several organ systems, including the brain, excessive ethanol exposure can result in increased production of reactive oxygen species (ROS), including superoxide radical anion, hydroxyl radical and hydrogen peroxide, and/or suppression of antioxidant defense mechanisms that normally inactivate ROS, including superoxide dismutase, glutathione and glutathione peroxidase, thereby resulting in OS (see review by Cohen-Kerem and Koren, 2003).

Several studies have evaluated the ability of antioxidants to mitigate ethanol-induced OS. Daily administration of ascorbic acid (vitamin C), a hydrophilic antioxidant, in a dose of 250 mg/kg body weight, to chronic ethanol-treated adult guinea pigs prevents OS in the brain (Suresh et al., 1999). Daily administration of α-tocopherol (vitamin E), a lipophilic antioxidant, in a dose of 150 mg/kg diet, to adult guinea pigs decreases nonenzymatic lipid peroxidation in the liver (Barja et al., 1996). In the frog embryo, vitamin C inhibits ethanol-induced ROS generation, and decreases ethanol-induced growth restriction and microencephaly (Peng et al., 2005). Trolox, a vitamin E analog, protects cultured rat neurons against cell death induced by 6-day in vitro exposure to ethanol (Lamarche et al., 2004). Notably, this cellular neuroprotection is associated with preservation by trolox of the intracellular glutathione content that is decreased by exposure to ethanol alone. Vitamin E attenuates both ethanol-induced brain growth restriction and increased lipid peroxidation in the chick embryo (Miller et al., 2000).

Whereas antioxidants have been shown to decrease some of the biochemical measures of ethanol-induced OS, relatively few studies have evaluated the efficacy of antioxidants to protect against ethanol neurobehavioral teratogenicity. In the rat, concurrent administration of vitamin E (2 g/kg body weight) with high-dose ethanol exposure over a 3-day neonatal period protects against ethanol-induced hippocampal OS-mediated biochemical changes and CA1 pyramidal cell loss, but not against impaired spatial-learning performance in the Morris water-maze (Marino et al., 2004). Given the strong evidence that maternal ethanol administration induces OS in the developing brain, further studies appeared to be warranted to test the idea that maternal treatment with hydrophilic plus lipophilic antioxidant compounds mitigates the brain injury induced by CPEE.

In the present study, the following research hypothesis was tested: maternal administration of vitamins C plus E mitigates ethanol neurobehavioral teratogenicity in postnatal life, manifesting as decreased hippocampal weight, deficits in spatial learning and memory, and impaired hippocampal synaptic plasticity. The guinea pig was selected as the animal model for this study, as it has a trimester-equivalent type of gestation, is well developed morphologically, metabolically, and functionally at birth, and has extensive prenatal brain development, including the brain growth spurt, which is more similar to the human situation compared with the rat or mouse (Dobbing and Sands, 1970).

Section snippets

Chemicals

l-Ascorbic acid (vitamin C) and dl-α-tocopherol (vitamin E) were purchased from Sigma Chemical (Oakville, ON). All other chemicals were at least reagent-grade quality and were obtained from Sigma Chemical (Oakville, ON) or Fisher Scientific (Unionville, ON).

Experimental animals

The animals used in this study were cared for according to the principles and guidelines established by the Canadian Council on Animal Care. The experimental protocol for this study was approved by the Queen's University Animal Care

Pregnancy outcome

The pregnancy outcome data are presented in Table 1. There was no difference in total food consumption during pregnancy, litter size, offspring birth weight, or distribution of male and female offspring among the four experimental groups. The incidence of perinatal death appeared to be higher in the ethanol plus vitamins (E + Vit) group compared with the ethanol plus vehicle (E), sucrose plus vitamins (S + Vit), and sucrose plus vehicle (S) groups. Two-way ANOVA of the length-of-gestation data

Discussion

This study in the guinea pig tested the hypothesis that maternal administration of vitamins C plus E mitigates ethanol neurobehavioral teratogenicity in postnatal life, manifesting as decreased hippocampal weight, deficits in task acquisition and retention in the Morris water-maze, and impaired hippocampal synaptic plasticity. Vitamin C, a hydrophilic antioxidant, is a potent scavenger of oxygen free radicals, including superoxide radical anion and hydroxyl radical (Suresh et al., 1999; review

Acknowledgments

This research was supported by a grant from the Canadian Institutes of Health Research (NET-54014).

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