Strain-specific programming of prenatal ethanol exposure across generations

Abstract

Behavioral consequences of prenatal alcohol exposure (PAE) can be transmitted from in utero-exposed F1 generation to their F2 offspring. This type of transmission is modulated by genetic and epigenetic mechanism. This study investigated the intergenerational consequences of prenatal exposure to low ethanol dose (1g/kg) during gestational days 17–20, on ethanol-induced hypnosis in adolescent male F1 and F2 generations, in two strains of rats. Adolescent Long Evans and Sprague Dawley male rats were tested for sensitivity to ethanol-induced hypnosis at 3.5g/kg or 4.5g/kg ethanol dose using the loss of righting reflex (LORR) paradigm. We hypothesized that PAE would attenuate sensitivity to ethanol-induced hypnosis in the ethanol-exposed animals in these two strains and in both generations. Interestingly, we only found this effect in Sprague Dawley rats. Lastly, we investigated PAE related changes in expression of GABAA receptor α1, α4, and δ subunits in the cerebral cortex of the PAE sensitive Sprague Dawley strain. We hypothesized a reduction in the cerebral cortex GABAA receptor subunits’ expression in the F1 and F2 PAE groups compared to control animals. GABAA receptor α1, α4, and δ subunits protein expressions were quantified in the cerebral cortex of F1 and F2 male adolescents by western blotting. PAE didn’t alter cerebral cortical GABAA receptor subunit expressions in the F1 generation, but it decreased GABAA receptor α4 and δ subunits’ expressions in the F2 generation, and had a tendency to decrease α1 subunit expression. We also found correlations between some of the subunits in both generations. These strain-dependent vulnerabilities to ethanol sensitivity, and intergenerational PAE-mediated changes in sensitivity to alcohol indicate that genetic and epigenetic factors interact to determine the outcomes of PAE animals and their offspring.

Maternal care‐related differences in males and females rats’ sensitivity to ethanol and the associations between the GABAergic system and steroids in males

“…This finding is consistent with previous reports of brain region-specific associations between maternal care and GABA A receptor subunit expression (Caldji, Diorio, Anisman, & Meaney, 2004;Caldji et al, 2003). This finding also corroborates our recently reported association between increased cortical GABA A α1 and δ subunit expressions and increased sensitivity to ethanol-induced hypnosis (Popoola, Nizhnikov, & Cameron, 2017). In addition, we revealed the first reported evidence of associations between variations in maternal care and GABA A receptor subunit expressions in brain regions that are associated with the execution and coordination of motor activity (Hanchar, Dodson, Olsen, Otis, & Wallner, 2005;Saeed, 2006).…”

Responding to the Unique Complexities of Fetal Alcohol Spectrum Disorder

“…Researchers have recently begun to explore the multi-generational contributors to FASD. Although the specific mechanisms underlying the intergenerational aspects of FASD are not fully understood, possible genetic and epigenetic contributors have been examined ( Govorko et al, 2012 ; Harper et al, 2014 ; Mead and Sarkar, 2014 ; Popoola et al, 2017 ). PAE is an early life stressor that can damage the developing brain and cause neurological alterations leading to a heightened vulnerability to stress, mental health problems, and substance use ( Weinberg et al, 2008 ; Hellemans et al, 2010 ; Ciafrè et al, 2020 ).…”

Intergenerational Effects of Alcohol: A Review of Paternal Preconception Ethanol Exposure Studies and Epigenetic Mechanisms in the Male Germline

“…Another study examining cross‐generational alcohol drinking behaviors found that paternal binge‐alcohol exposure over 8 days increased alcohol intake by intraoral infusion in postnatal offspring (Hollander et al., ). Finally, female mice exposed to alcohol during postnatal development exhibited reduced sensitivity to alcohol‐induced loss of righting reflex and passed this phenotype to male and female offspring (Popoola et al., ). Intriguingly, in 3 of these studies, the cross‐generational alcohol‐related phenotypes coincided with altered BDNF signaling in reward‐related brain regions (Ceccanti et al., ; Finegersh and Homanics, ; Rompala et al., ).…”