Prenatal alcohol exposure increases TNFalpha-induced cytotoxicity in primary astrocytes.
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.
De Vito
W J
WJ
Division of Endocrinology, University of Massachusetts Medical Center, Worcester, MA 01655, USA. william.devito@umassmed.edu
Xhaja
K
K
Stone
S
S
D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000097:blood / Q000494:pharmacology*; D002518:Ceramides / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D005260:Female; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D013107:Sphingolipids / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002492:Central Nervous System Depressants; D002518:Ceramides; D013107:Sphingolipids; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol