Abstract
BackgroundWomen are more vulnerable than men to the neurotoxicity and severe brain damage caused by chronic heavy alcohol use. In addition, brain damage due to chronic heavy alcohol use may be associated with sex-dependent epigenetic modifications. This study aimed to identify microRNAs (miRNAs) and their target genes that are differentially expressed in the hippocampi of male and female animal models in response to alcohol.MethodsAfter chronic alcohol administration (3~3.5 g/kg/day) in male (control, n = 10; alcohol, n = 12) or female (control, n = 10; alcohol, n = 12) Sprague-Dawley rats for 6 weeks, we measured body weights and doublecortin (DCX; a neurogenesis marker) concentrations and analyzed up- or downregulated miRNAs using GeneChip miRNA 4.0 arrays. The differentially expressed miRNAs and their putative target genes were validated by RT-qPCR.ResultsAlcohol attenuated body weight gain only in the male group. On the other hand, alcohol led to increased serum AST in female rats and decreased serum total cholesterol concentrations in male rats. The expression of DCX was significantly reduced in the hippocampi of male alcohol-treated rats. Nine miRNAs were significantly up- or downregulated in male alcohol-treated rats, including upregulation of miR-125a-3p, let-7a-5p, and miR-3541, and downregulation of their target genes (Prdm5, Suv39h1, Ptprz1, Mapk9, Ing4, Wt1, Nkx3-1, Dab2ip, Rnf152, Ripk1, Lin28a, Apbb3, Nras, and Acvr1c). On the other hand, 7 miRNAs were significantly up- or downregulated in alcohol-treated female rats, including downregulation of miR-881-3p and miR-504 and upregulation of their target genes (Naa50, Clock, Cbfb, Arih1, Ube2g1, and Gng7).ConclusionsThese results suggest that chronic heavy alcohol use produces sex-dependent effects on neurogenesis and miRNA expression in the hippocampus and that sex differences should be considered when developing miRNA biomarkers to diagnose or treat alcoholics.
Highlights
Women are more vulnerable than men to the neurotoxicity and severe brain damage caused by chronic heavy alcohol use
A two-way repeated measures ANOVA revealed a significant treatment × sex × weight interaction [F(df = 1.976) = 7.026, p = 0.002]. These results suggest that chronic alcohol exposure affected body weight gain differently in males and females
Alterations in biochemical parameters and lipid expression after chronic alcohol administration To identify the effects of alcohol in the MC, MA, FC, and FA groups, we measured the serum concentrations of factors related to toxicity and lipid metabolism as described previously [29, 32]
Summary
Women are more vulnerable than men to the neurotoxicity and severe brain damage caused by chronic heavy alcohol use. The incidence of alcohol use disorders (AUDs) has increased in women as well as men, and AUDs have increased rapidly in young women worldwide, especially in South Korea [1]. This increase is thought to be due to the fact that the perception of women’s traditional roles is gradually changing, and as women participate more broadly in society, their opportunities to drink alcohol have increased [2]. Previous studies have indicated that women’s AUDs have become increasingly important; to date, treatment of AUDs in most countries including South Korea and the USA has mainly focused on men, and laboratory studies on the negative effects of alcohol have typically used only male animals
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