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.

Abstract

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 induces behavioral changes in offspring, possibly via epigenetic changes in gene expression, which is essential for the regulation of ADHD-like behaviors.

• Authors: 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
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 92 Issue 5 Pg. 658-70 (May 2014) ISSN: 1097-4547 [Electronic] United States
• PMID: 24510599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Central Nervous System Depressants
• Dopamine Plasma Membrane Transport Proteins
• Methyl-CpG-Binding Protein 2
• Ethanol

Topics

• Animals
• Attention Deficit Disorder with Hyperactivity (chemically induced)
• Avoidance Learning (physiology)
• Central Nervous System Depressants (toxicity)
• Disease Models, Animal
• Dopamine Plasma Membrane Transport Proteins (genetics, metabolism)
• Drinking Behavior
• Epigenesis, Genetic (drug effects)
• Ethanol (toxicity)
• Exploratory Behavior (physiology)
• Female
• Gene Expression Regulation (drug effects)
• Male
• Maze Learning (physiology)
• Methyl-CpG-Binding Protein 2 (genetics, metabolism)
• Mice
• Mice, Inbred ICR
• Phenotype
• Pregnancy
• Prenatal Exposure Delayed Effects (chemically induced, physiopathology)