Chronic exposure to ethanol of male mice before mating produces attention deficit hyperactivity disorder‐like phenotype along with epigenetic dysregulation of dopamine transporter expression in mouse offspring

作者：Pitna Kim, Chang Soon Choi, Jin Hee Park, So Hyun Joo, Soo Young Kim, Hyun Myung Ko, Ki Chan Kim, Se Jin Jeon, Seung Hwa Park, Seol‐Heui Han, Jong Hoon Ryu, Jae Hoon Cheong, Jung Yeol Han, Ki Narm Ko, Chan Young Shin · 发表于：Journal of Neuroscience Research · 年份：2014 · DOI：10.1002/jnr.23275 · 被引用次数：101 · 研究领域：Prenatal Substance Exposure Effects、Epigenetics and DNA Methylation、Child Welfare and Adoption

Preconception exposure to EtOH through the paternal route may affect neurobehavioral and developmental features of offspring. This study investigates the effects of paternal exposure to EtOH before conception on the hyperactivity, inattention, and impulsivity behavior of male offspring in mice. Sire mice were treated with EtOH in a concentration range approximating human binge drinking (0-4 g/kg/day EtOH) for 7 weeks and mated with untreated females mice to produce offspring. EtOH exposure to sire mice induced attention deficit hyperactivity disorder (ADHD)-like hyperactive, inattentive, and impulsive behaviors in offspring. As a mechanistic link, both protein and mRNA expression of dopamine transporter (DAT), a key determinant of ADHD-like phenotypes in experimental animals and humans, were significantly decreased by paternal EtOH exposure in cerebral cortex and striatum of offspring mice along with increased methylation of a CpG region of the DAT gene promoter. The increase in methylation of DAT gene promoter was also observed in the sperm of sire mice, suggesting germline changes in the epigenetic methylation signature of DAT gene by EtOH exposure. In addition, the expression of two key regulators of methylation-dependent epigenetic regulation of functional gene expression, namely, MeCP2 and DNMT1, was markedly decreased in offspring cortex and striatum sired by EtOH-exposed mice. These results suggest that preconceptional exposure to EtOH through the paternal route induce...