Neurotoxic Consequences of Chronic Alcohol Withdrawal: Expression Profiling Reveals Importance of Gender Over Withdrawal Severity

Abstract

While women are more vulnerable than men to many of the medical consequences of alcohol abuse, the role of sex in the response to ethanol is controversial. Neuroadaptive responses that result in the hyperexcitability associated with withdrawal from chronic ethanol likely reflect gene expression changes. We have examined both genders for the effects of withdrawal on brain gene expression using mice with divergent withdrawal severity that have been selectively bred from a genetically heterogeneous population. A total of 295 genes were identified as ethanol regulated from each gender of each selected line by microarray analyses. Hierarchical cluster analysis of the arrays revealed that the transcriptional response correlated with sex rather than with the selected withdrawal phenotype. Consistent with this, gene ontology category over-representation analysis identified cell death and DNA/RNA binding as targeted classes of genes in females, while in males, protein degradation, and calcium ion binding pathways were more altered by alcohol. Examination of ethanolregulated genes and these distinct signaling pathways suggested enhanced neurotoxicity in females. Histopathological analysis of brain damage following ethanol withdrawal confirmed elevated cell death in female but not male mice. The sexually dimorphic response was observed irrespective of withdrawal phenotype. Combined, these results indicate a fundamentally distinct neuroadaptive response in females compared to males during chronic ethanol withdrawal and are consistent with observations that female alcoholics may be more vulnerable than males to ethanol-induced brain damage associated with alcohol abuse.

Voluntary ethanol consumption in 22 inbred mouse strains

“…Female B6 mice had significantly greater intake of 6E, with a trend for an increase in 10E, when compared to their male counterparts. Nonetheless, these findings are consistent with clinical and preclinical studies documenting the existence of sex differences in sensitivity to a number of alcohol-related behaviors associated with neuroadaptation and reinforcement (e.g., Devaud et al, 2003;Finn et al, 2004aFinn et al, , 2004bGreen et al, 1999;Hashimoto and Wiren, 2007;Lancaster, 1995;Middaugh and Kelly, 1999;Rhodes et al, 2007;Vivian et al, 2001;Wiren et al 2006). …”

Astrocyte Dysfunction Induced by Alcohol in Females but Not Males

“…Nevertheless, increased vulnerability to EtOH-induced neurotoxicity in females remains controversial [reviewed in (51)] with additional studies needed to support or refute this hypothesis. This finding is buttressed by the observation that chronic ethanol exposure is associated with a strongly sexually dimorphic transcriptional response (44,118,119). In those studies, significantly regulated transcripts included several genes that are exclusively or predominantly expressed in astrocytes, suggesting that a component of the neuroadapative response in the brain after ethanol exposure reflects changes in astrocyte gene expression that are distinct between males and females.…”

“…Females have higher rates or greater severity of cardiomyopathy, peripheral neuropathy, some types of cancer and liver cirrhosis (5,59). Increased vulnerability to ethanol-induced brain damage in the prefrontal cortex in females has been observed in some studies (44,118). Other studies have not confirmed female vulnerability, but have noted different "brain morphological deficits" between males and females supporting the notion that neurodamage occurs via different mechanisms depending on sex (94).…”

“…We have recently shown that following chronic intoxication in vivo, females exhibit a pro-inflammatory response in the medial prefrontal cortex that includes increased Tnf expression, while males show a pattern consistent with immune suppression (118,119). Associated with this pro-inflammatory tone, females also exhibit increased neurotoxicity (44,118). Combined, our studies suggest the possibility that sexually dimorphic ethanol-induced neurotoxicity in the frontal cortex may be mediated in part by astrocytes both via induction and modulation of inflammatory signaling and through changes in astrocyte function including dysregulation of glutamate homeostasis.…”

The effect of alcohol and nicotine abuse on gene expression in the brain

“…However, the effect of sex was revealed in a recent study on gene expression in male and female rodent brains after 72 h exposure to ethanol vapours followed by 8 h withdrawal (49) .…”