Transgenerational Transmission of the Effect of Gestational Ethanol Exposure on Ethanol Use-Related Behavior

Abstract

Background Prenatal alcohol exposure (PAE) enhances the risk for alcoholism by increasing the propensity to consume alcohol and altering neurophysiological response to alcohol challenge. Transgenerationally transmittable genetic alterations have been implicated in these behavioral changes. To date, transgenerational transmission of PAE-induced behavioral responses to alcohol has never been experimentally investigated. Therefore, we explored the transgenerational transmission of PAE-induced behavioral effects across 3 generations. Methods Pregnant Sprague Dawley dams received 1 g/kg ethanol (EtOH) or water daily on gestational days 17 through 20 via gavage, or remained untreated in their home cages. To produce second filial (F2) or F3 generations, similarly treated adult F1 or F2 offspring were mated and left undisturbed through gestation. On postnatal day (PND) 14, male and female F1, F2, and F3 offspring were tested for consumption of 5% (w/v) EtOH (in water), or water. Using the loss of righting reflex (LORR) paradigm on PND 42, F1 and F2 adolescent male offspring were tested for sensitivity to acute EtOH-induced sedation–hypnosis at 3.5 or 4.5 g/kg dose. F3 male adolescents were similarly tested at 3.5 g/kg dose. Blood EtOH concentration (BEC) was measured at waking. Results EtOH exposure increased EtOH consumption compared to both water and untreated control groups in all generations. EtOH-treated group F1 and F2 adolescents displayed attenuated LORR duration compared to the water group. No attenuated LORR was observed in the F3 generation. BEC at waking corroborated with the significant LORR duration differences while also revealing differences between untreated control and water groups in F1 and F2 generations. Conclusions Our results provide novel behavioral evidence attesting that late gestational moderate EtOH exposure increases EtOH intake across 3 generations and may alter sensitivity to EtOH-induced sedation–hypnosis across 2 generations.

Strain-specific programming of prenatal ethanol exposure across generations

“…PAE can induce various psychological outcomes, including an increased risk for problematic alcohol use. Interestingly, certain behavioral consequences of PAE can be transmitted from in utero -exposed F1 generation to their F2 and F3 offspring, as our laboratory recently demonstrated (Nizhnikov et al, 2016). Indeed, following prenatal exposure in F1, we found an increase in ethanol intake in F1 through F3 generation infant Sprague Dawley rats, and attenuated sensitivity to ethanol-induced hypnosis in the F1 and F2 generation adolescent male offspring.…”

“…The prenatal developmental process of the cerebral cortex is susceptible to PAE-induced disruptions that can last long into adulthood, especially when exposure occurs during late gestation (Miller, 1996, Skorput and Yeh, 2016, Miller, 1986). Therefore, assessing PAE-induced changes in the cerebral cortex may provide valuable insight into changes in motor coordination under the influence of ethanol, such as those previously reported in Sprague Dawley rats (Nizhnikov et al, 2016). …”

“…Most of GABA A α4 and δ subunits are located on the extrasynaptic membrane area and are also involved in modulation of sensitivity to ethanol-induced intoxication via mediation of tonic currents (Jia et al, 2007, Kumar et al, 2009, Orser, 2006). Based on the roles of these subunits, variations in their expressions may contribute to PAE-related transgenerational changes in sensitivity to ethanol-induced hypnosis (Nizhnikov et al, 2016). …”

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

“…Prenatal exposure to low-to-moderate levels of alcohol leads to elevated alcohol drinking in adolescent and adult rodents and even zebrafish (Fabio, Macchione, Nizhnikov, & Pautassi, 2015; Nizhnikov, Popoola, & Cameron, 2016; Sterling, Chang, Karatayev, Chang, & Leibowitz, 2016). Notably, this exposure to alcohol also stimulates the proliferation of OX neurons, subsequently leading to their increase in gene expression and density (Chang, Karatayev, Liang, Barson, & Leibowitz, 2012; Sterling et al, 2016).…”

Epigenetic mediators and consequences of excessive alcohol consumption

“…Work on the proopiomelanocortin ( POMC ) gene has shown that not only is gene expression downregulated in rats which were prenatally exposed to alcohol, but that the effect of lowered POMC expression can be transmitted through the paternal line to the F2 and F3 generations (Govorko, Bekdash, Zhang, & Sarkar, 2012). Studies have found additional genes with altered expression across generations (Asimes et al, this issue; Popoola, Nizhnikov, & Cameron, this issue; Przybycien-Szymanska, Rao, Prins, & Pak, 2014), as well as altered alcohol drinking-associated behaviors (Finegersh & Homanics, 2014; Nizhnikov, Popoola, & Cameron, 2016), and methylation programming (Asimes et al, this issue; Finegersh & Homanics, 2014). The cross-generational effects on behavior can be dependent on genetic background, as Popoola et al show using rat strains, or conserved across strains, as Rompala, Finegersh, Slater, and Homanics show in mouse models (both in this issue).…”