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CB1‐receptor knockout neonatal mice are protected against ethanol‐induced impairments of DNMT1, DNMT3A,and DNA methylation
Authors:Nagaraja N Nagre  Shivakumar Subbanna  Madhu Shivakumar  Delphine Psychoyos  Balapal S Basavarajappa
Institution:1. Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA;2. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA;3. New York State Psychiatric Institute, Columbia University, New York City, New York, USA;4. Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York City, New York, USA
Abstract:The significant consequences of ethanol use during pregnancy are neurobehavioral abnormalities involving hippocampal and neocortex malfunctions that cause learning and memory deficits collectively named fetal alcohol spectrum disorder. However, the molecular mechanisms underlying these abnormalities are still poorly understood and therefore warrant systematic research. Here, we document novel epigenetic abnormalities in the mouse model of fetal alcohol spectrum disorder. Ethanol treatment of P7 mice, which induces activation of caspase 3, impaired DNA methylation through reduced DNA methyltransferases (DNMT1 and DNMT3A) levels. Inhibition of caspase 3 activity, before ethanol treatment, rescued DNMT1, DNMT3A proteins as well as DNA methylation levels. Blockade of histone methyltransferase (G9a) activity or cannabinoid receptor type‐1 (CB1R), prior to ethanol treatment, which, respectively, inhibits or prevents activation of caspase 3, rescued the DNMT1 and DNMT3A proteins and DNA methylation. No reduction of DNMT1 and DNMT3A proteins and DNA methylation was found in P7 CB1R null mice, which exhibit no ethanol‐induced activation of caspase 3. Together, these data demonstrate that ethanol‐induced activation of caspase 3 impairs DNA methylation through DNMT1 and DNMT3A in the neonatal mouse brain, and such impairments are absent in CB1R null mice. Epigenetic events mediated by DNA methylation may be one of the essential mechanisms of ethanol teratogenesis.
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Keywords:caspase 3  CB1R  epigenetics  fetal alcohol spectrum disorder  methyltransferase  neuronal loss
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