Transgenerational Effects of Nicotine via Maternal Smoking Associated with ADHD in Offspring Resulting in Decreased Dopamine in the Prefrontal Cortex
Introduction. Prenatal nicotine exposure (PNE) via maternal smoking during pregnancy causes multiple neurological disorders in the fetus, including Attention Deficiency Hyperactivity Disorder (ADHD). ADHD is the most prevalent neurodevelopment disorder among children in the United States.1 ADHD is characterized by hyperactivity, inattention and impulsivity from decreased dopamine in the prefrontal cortex (PFC).2 PNE mice models are associated with lower dopamine in the PFC and the development of ADHD through several mechanisms: dopaminergic neuronal loss, reduced tyrosine hydrolase and increased monoamine oxidase.2,3,4,5 Studies have shown genetic predisposition to ADHD in PNE offspring via dopamine transporter (DAT) polymorphism.6 Currently, a major concern of maternal tobacco smoking during pregnancy is the development of ADHD in future generations unexposed to direct prenatal nicotine via DNA methylation.2 Understanding the effects of nicotine on the developing fetal brain is necessary for prevention of ADHD in PNE offspring and future generations. Methods. Mouse models were treated with water, water+saccharin, or 100 mg/ml nicotine+saccharin throughout pregnancy and the behavior of PNE offspring was analyzed using Y-maze, object-based attention test, and cliff avoidance.3 Dopamine and tyrosine hydrolase were measured in PFC of PNE mice immunohistochemically.4 DNA methylation of PFC tissue in PNE mice was quantified using ELISA.2 Additionally, blood sample was obtained from 161 children to analyze DAT gene using PCR and diagnosis of ADHD was made using DSM-5 criteria.6 Results. PNE mice showed statically significant (p<0.05) decrease in spatial working memory, object based attention and cliff avoidance compared to control group.3 Statically significant (p<0.05) decrease in dopamine and tyrosine hydrolase was observed in PFC of PNE mice.4 PNE mice of F1 and F2 had reduced DNA methylation in PFC (p=0.0020 and p=0.0020, respectively) compared to control group.2 DNA hypomethylation may alter the dopaminergic neuronal development, dopamine synthesis, dopamine degradation or a combination of all.2,4 Similar level of DNA hypomethylation in F1 and F2 mice implies that nicotine may have transgenerational effects in unexposed generations.2 Children who were exposed to prenatal nicotine and are homozygous for high risk repeat DAT gene (DAT +/+) had significantly higher hyperactive-impulsive scores (p<0.01) compared to children with no PNE and DAT+/- or DAT -/- .6 DAT polymorphism may increase the risk of ADHD in PNE children.6 Conclusions. Studies have shown an association between maternal smoking during pregnancy and ADHD in offspring with transgenerational effects via DNA hypomethylation in PFC.2,4 Genetic factors such as DAT polymorphism may contribute to the increased risk of ADHD.6
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