Ethanol disrupts cell cycle regulation in developing rat cortex interaction with transforming growth factor beta1.
Ethanol is a potent teratogenic agent that disrupts several aspects of neuronogenesis, including the proliferation rate of cortical precursors. With regard to corticogenesis, possible targets of ethanol toxicity include soluble factors, like transforming growth factor beta1 (TGFbeta1), that regulate cortical growth and cell cycle proteins that control the kinetics of the cell cycle. The effect of ethanol on normal cell proliferation and TGFbeta1-regulated cell proliferation in the developing cortex was assessed using an organotypic slice culture model. Ethanol elongated the cell cycle, possibly through a decrease in the expression of G1 cell cycle protein cyclin D1. Further, ethanol exposure antagonized the anti-proliferative action of TGFbeta1 and blocked TGFbeta1-dependent increases in cell cycle inhibitor p21. Collectively, this evidence suggests that disruption of appropriate cell cycle protein expression and inhibition of TGFbeta1 activity are potential mechanisms underlying the effect of ethanol on cortical development.
Siegenthaler
Julie A
JA
Department of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, New York 13210, USA.
Miller
Michael W
MW
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000633:toxicity*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000196:embryology*; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D019394:Ki-67 Antigen / Q000378:metabolism; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D016196:S Phase / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D000963:Antimetabolites; C493962:Cdkn1b protein, rat; D002492:Central Nervous System Depressants; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019394:Ki-67 Antigen; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000431:Ethanol; D001973:Bromodeoxyuridine