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.

Long-term effects of preterm birth on behavior and neurosteroid sensitivity in the guinea pig

“…The deficiencies in the markers of neurodevelopment and neurosteroid-sensitive receptors were associated with increased activity in the open field and environment exploration tests, with the preterm males more active than the control term males. Similar results are seen in mice expressing an attention deficit hyperactivity disorder-like phenotype, where the distance travelled and time spent travelling is markedly higher for the affected mice compared to the controls (35). This hyperactive type behavior has parallels with clinical studies on expremature male children that show an increased incidence of disorders that to some extent involve hyperactivity (7,8).…”

Ethanol deregulates Mecp2/MeCP2 in differentiating neural stem cells via interplay between 5-methylcytosine and 5-hydroxymethylcytosine at the Mecp2 regulatory elements

“…The discrepancies in these studies regarding the effect of ethanol on MeCP2 expression could be attributed to multiple factors such as the model of study (in vivo animal models or in vitro cultured cells), stage of embryonic development, specific brain region or cell type within a brain region, concentration and duration of ethanol treatment (Bekdash et al, 2013;Chen et al, 2013;Gangisetty et al, 2014;Guo et al, 2012;Kim et al, 2013Kim et al, , 2014Perkins et al, 2013;Subbanna et al, 2014;Tunc-Ozcan et al, 2013). Further supporting the role of MeCP2 in alcoholism, a recent study demonstrated the regulatory effect of MeCP2 on sensitivity to ethanol and drinking ethanol (Repunte-Canonigo et al, 2014).…”

“…Recent studies also implicate the potential of preconception paternal alcohol consumption, which can lead to FASD (Kim et al, 2014;Knezovich and Ramsay, 2012). Previous studies have shown the importance of both alcohol exposure and withdrawal (termination of alcohol consumption) in FASD pathogenesis (Carlson et al, 2012), emphasizing the necessity to study the effect of both ethanol exposure and withdrawal on the central nervous system development (Pierog et al, 1977;Thomas and Riley, 1998).…”

Could ethanol-induced alterations in the expression of glutamate transporters in testes contribute to the effect of paternal drinking on the risk of abnormalities in the offspring?

“…In contrast, results of other studies, using male mice exposed to ethanol, implied that an increased methylation of specific DNA loci, e.g. cytosine-rich sequences ("CpG islands") in the promoter region of the DAT gene encoding a dopamine transporter, could be at fault [3]. Disturbed expression of DAT has, indeed, been causally linked to an attentiondeficit/hyperactivity disorder (ADHD)-like behaviour similar to that observed in the offspring of the ethanol-exposed male mice [3]; (cf.…”

“…cytosine-rich sequences ("CpG islands") in the promoter region of the DAT gene encoding a dopamine transporter, could be at fault [3]. Disturbed expression of DAT has, indeed, been causally linked to an attentiondeficit/hyperactivity disorder (ADHD)-like behaviour similar to that observed in the offspring of the ethanol-exposed male mice [3]; (cf. review of animal models of ADHD [4] and altered expression of DAT1/SLC6A3 in human ADHD [5]).…”