Prenatal alcohol exposure increases TNFalpha-induced cytotoxicity in primary astrocytes

• Published in: Alcohol (Fayetteville, N.Y.) Vol. 21; no. 1; pp. 63 - 71
• Main Authors: De Vito, W J, Xhaja, K, Stone, S
• Format: Journal Article
• Language: English
• Published: United States 01.05.2000
• Subjects: Animals; Astrocytes - chemistry; Astrocytes - drug effects; Cell Death - drug effects; Cell Death - physiology; Cells, Cultured; Central Nervous System Depressants - blood; Central Nervous System Depressants - pharmacology; Ceramides - metabolism; DNA Fragmentation - drug effects; DNA Fragmentation - physiology; Ethanol - blood; Ethanol - pharmacology; Female; Male; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Sphingolipids - metabolism; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0741-8329

We examined the effect of prenatal alcohol exposure (PAE) on tumor necrosis factor-alpha-(TNFalpha) induced cell death in primary astrocyte cultures. Flow cytometry revealed that PAE increased the sensitivity of astrocytes to the cytotoxic effects of TNFalpha when compared to astrocytes prepared from pair-fed and chow-fed controls. In a number of cell types, TNFalpha regulates cell growth or death, in part, by the hydrolysis of sphingomyelin to ceramide and sphingosine-1-phosphate (SPP). Using a 3-(4. 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxic assay we found that PAE increased the sensitivity of astrocytes to the cytotoxic effects of TNFalpha, sphingomyelinase (SMase), and C(2)- and C(6)-ceramide. The increasing cellular concentrations of SPP, a sphingolipid metabolic that induces cell growth, protected the cells from TNFalpha-induced cell death. N, N-dimethylsphingosine (DMS), which inhibits SPP production, and N-oleoylethanolamine, which inhibits acid ceramidases, increased TNFalpha-induced cytotoxicity in astrocytes prepared from PAE rats. These studies suggest that PAE shifts the balance of sphingolipid metabolism in favor of a pathway that increases the susceptibility of astrocytes to the cytotoxic effect of TNFalpha.