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Opposing Actions of Ethanol and Nicotine on Micro RNA s are Mediated by Nicotinic Acetylcholine Receptors in Fetal Cerebral Cortical–Derived Neural Progenitor Cells
Author(s) -
Balaraman Sridevi,
WinzerSerhan Ursula H.,
Miranda Rajesh C.
Publication year - 2012
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2012.01793.x
Subject(s) - mecamylamine , methyllycaconitine , nicotinic acetylcholine receptor , nicotine , nicotinic agonist , acetylcholine receptor , neurogenesis , chemistry , pharmacology , messenger rna , rna , medicine , endocrinology , receptor , biology , microbiology and biotechnology , biochemistry , gene
Background Ethanol ( EtOH ) and nicotine are often co‐abused. However, their combined effects on fetal neural development, particularly on fetal neural stem cells ( NSC s), which generate most neurons of the adult brain during the second trimester of pregnancy, are poorly understood. We previously showed that EtOH influenced NSC maturation in part, by suppressing the expression of specific micro RNA s (mi RNA s). Here, we tested in fetal NSC s the extent to which EtOH and nicotine coregulated known EtOH ‐sensitive (mi R ‐9, mi R ‐21, mi R ‐153, and mi R ‐335), a nicotine‐sensitive mi RNA (mi R ‐140‐3p), and mRNA s for nicotinic acetylcholine receptor ( nAChR ) subunits. Additionally, we tested the extent to which these effects were nAChR dependent. Methods Gestational day 12.5 mouse fetal murine cerebral cortical–derived neurosphere cultures were exposed to EtOH , nicotine, and mecamylamine, a noncompetitive nAChR antagonist, individually or in combination, for short (24 hour) and long (5 day) periods, to mimic exposure during the in vivo period of neurogenesis. Levels of mi RNA s, mi RNA ‐regulated transcripts, and nAChR subunit mRNA s were assessed by quantitative reverse transcription polymerase chain reaction. Results EtOH suppressed the expression of known EtOH ‐sensitive mi RNA s and miR‐140‐3p, while nicotine at concentrations attained by cigarette smokers induced a dose‐related increase in these mi RNA s. Nicotine's effect was blocked by EtOH and by mecamylamine. Finally, EtOH decreased the expression of nAChR subunit mRNA s and, like mecamylamine, prevented the nicotine‐associated increase in α4 and β2 nAChR transcripts. Conclusions EtOH and nicotine exert mutually antagonistic, nAChR ‐mediated effects on teratogen‐sensitive mi RNA s in fetal NSC s. These data suggest that concurrent exposure to EtOH and nicotine disrupts mi RNA regulatory networks that are important for NSC maturation.