Teenage binge drinking is a major health concern in the United States, with 21% of teenagers reporting binge-pattern drinking behavior in the last 30 days. Recently, our lab showed that alcohol-naïve offspring of rats exposed to alcohol during adolescence exhibited altered gene expression profiles in the hypothalamus, a brain region involved in stress regulation. We employed Enhanced Reduced Representation Bisulfite Sequencing as an unbiased approach to test the hypothesis that parental exposure to binge-pattern alcohol during adolescence alters DNA methylation profiles in their alcohol-naïve offspring. Wistar rats were administered a repeated binge-ethanol exposure paradigm during early (postnatal day (PND) 37-44) and late (PND 67-74) adolescent development. Animals were mated 24h after the last ethanol dose and subsequent offspring were produced. Analysis of male PND7 offspring revealed that offspring of alcohol-exposed parents exhibited differential DNA methylation patterns in the hypothalamus. The differentially methylated cytosines (DMCs) were distinct between offspring depending on which parent was exposed to ethanol. Moreover, novel DMCs were observed when both parents were exposed to ethanol and many DMCs from single parent ethanol exposure were not recapitulated with dual parent exposure. We also measured mRNA expression of several differentially methylated genes and some, but not all, showed correlative changes in expression. Importantly, methylation was not a direct predictor of expression levels, underscoring the complexity of transcriptional regulation. Overall, we demonstrate that adolescent binge ethanol exposure causes altered genome-wide DNA methylation patterns in the hypothalamus of alcohol-naïve offspring.
Teenage binge drinking is a common practice that has been shown to increase the risk for developing mood disorders in adulthood. The hypothalamo-pituitary-adrenal (HPA) axis is often dysfunctional in mood disorder patients, and animal models of adolescent binge alcohol exposure similarly show disordered HPA axis function, even after long periods of alcohol abstinence. Here, we sought to investigate the anxiety-like behavioral consequences of binge alcohol exposure in a Wistar rat model. Male rats were administered alcohol in a binge pattern during peri-puberty, and one month later, anxiety-like behaviors were measured using the elevated plus maze. A subset of the rats then underwent 30 minutes of restraint stress, and the anxiety-like behaviors were measured again. We observed an increase in risk assessment behaviors due to both adolescent binge alcohol exposure and restraint stress, but no differences in canonical anxiety-like behaviors. We also repeated the observation that adolescent binge alcohol induces long-term changes in HPA axis sensitivity. Therefore, we concluded that a history of peri-pubertal binge alcohol exposure subtly alters the behavioral response to subsequent acute psychological stress during adulthood, which may over time contribute to the development of mood disorders. This relatively pragmatic animal model represents a more clinically relevant tool in understanding the molecular mechanisms underlying the long-term effects of adolescent binge drinking.
Preconception behaviors and experiences of mothers and fathers can affect future offspring. Recently, our laboratory showed that alcohol-naive offspring of parents who were exposed to repeated binge alcohol during adolescence showed altered DNA methylation patterns in the hypothalamus, a brain region involved in regulation of pubertal development, stress, and behavior. These observations have potentially far-reaching consequences for human health, as more than 4.6 million Americans under the age of 21 years report engaging in the rapid intoxication behavior of binge-pattern alcohol (EtOH) drinking. Therefore, we tested the hypothesis that offspring of binge EtOH‒exposed parents would have altered hypothalamic function manifested phenotypically as improper pubertal development, impaired socialization, and dysregulated stress response. In addition, we tested the hypothesis that parental EtOH exposure would confer adaptive protection from the negative effects of EtOH when offspring were themselves exposed to EtOH. Rats received EtOH via oral gavage once daily for 6 days at both early [postnatal day (PND) 37] and late puberty (PND 67). Animals were paired (EtOH-EtOH, vehicle-vehicle) for mating 24 hours after the last EtOH dose. After weaning, offspring were randomized to vehicle treatment to assess changes in normal development or to EtOH treatment to assess the effect of parental EtOH exposure on offspring response to this treatment. We found that offspring had smaller body weights and displayed fewer play behaviors when parents had been exposed to EtOH before conception. In addition, offspring showed a reduction in pubertal development markers that could indicate that parental preconception EtOH exposure confers maladaptive epigenetic traits in first-generation offspring.
Adolescence is hallmarked by two parallel processes of sexual maturation and adult patterning of the brain. Therefore, adolescence represents a vulnerable postnatal period for neurodevelopment where exogenous factors can negatively impact adult brain function. For example, alcohol exposure during pubertal development can lead to long-term and widespread neurobiological dysfunction and these effects have been shown to persist even in the absence of future alcohol exposure. However, the molecular mechanisms mediating the persistent effects of alcohol are unclear. We propose that dysregulation of microRNAs (miR) could be a unifying epigenetic mechanism underlying these widespread long-term changes. We tested the hypothesis that repeated alcohol exposure during pubertal development would cause disruption of normal miR expression profiles during puberty and, subsequently, their downstream mRNA target genes in the ventral hippocampus using an established rat model of adolescent binge drinking. We found 6 alcohol-sensitive miRs that were all downregulated following alcohol exposure and we also investigated the normal age-dependent changes in those miRs throughout the pubertal period. Interestingly, these miRs were normally decreased throughout the process of puberty, but alcohol prematurely exacerbated the normal decline in miR expression levels. The work presented herein provides foundational knowledge about the expression patterns of miRs during this critical period of neurodevelopment. Further, this regulation of miR and mRNA expression by alcohol exposure presents a complex regulatory mechanism by which perturbation in this time-sensitive period could lead to long-term neurological consequences.
Oestrogen receptor (ER)β is a multifunctional nuclear receptor that mediates the actions of oestrogenic compounds. Despite its well defined role in mediating the actions of oestrogens, a substantial body of evidence demonstrates that ERβ has a broad range of physiological functions independent of those normally attributed to oestrogen signalling. These functions can partly be achieved by the activity of several alternatively spliced isoforms that have been identified for ERβ. This short review describes structural differences between the ERβ splice variants that are known to be translated into proteins. Moreover, we discuss how these alternative structures contribute to functional differences in the context of both healthy and pathological conditions. Our review also describes the principal factors that regulate alternative RNA splicing. The alternatively spliced isoforms of ERβ are differentially expressed according to brain region, age and hormonal milieu, emphasising the likelihood that there are precise cellspecific mechanisms regulating ERβ alternative splicing. However, despite these correlative data, the molecular factors regulating alternative ERβ splicing in the brain remain unknown. We also review the basic mechanisms that regulate alternative RNA splicing and use that framework to make logical predictions about ERβ alternative splicing in the brain. K E Y W O R D Salternative splicing, brain, oestrogen receptor β, splice variants | INTRODUCTIONAgeing represents a continuous spectrum of phenotypic and behavioural changes that are ultimately driven by an inefficient cellular functioning, thus contributing to increased cell damage over time.Detrimental changes in cellular function include telomere shortening, increased missense/nonsense mutations, translational errors and organelle dysfunction, all of which can result in protein dysfunction and the accumulation of cytotoxic protein aggregates. Concurrent with these age-related abnormalities is an increased incidence of global alternative RNA splicing.1 Alternative RNA splicing is heralded as a means of expanding the cellular proteome beyond the constraints of strict genetic coding. As such, it is widely considered to be both beneficial and detrimental depending on the structural and functional aspects of the alternatively expressed isoforms. In young healthy tissues, it is likely that one dominant isoform is expressed, 2 despite the availability of the molecular machinery required to achieve the expression of multiple isoforms. However, human studies demonstrate that ageing increases the incidence of alternative splicing independent of disease, thereby increasing the abundance of alternatively spliced isoforms that are expressed in a variety of tissues. One of the highest rates of alternative splicing events occurs in the brain, and an increased expression of alternatively spliced isoforms can contribute to age-related deficits in many neurobiological processes. 1,3-5Menopause is a unique biological process in women that is concurrent with ageing. A phys...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.