Dataset Information

Paternal Preconception Chronic Variable Stress Confers Attenuated Ethanol Drinking Behavior Selectively to Male Offspring in a Pre-Stress Environment Dependent Manner.

ABSTRACT: Stress-related psychiatric disorders such as major depression are strongly associated with alcohol abuse and alcohol use disorder. Recently, many epidemiological and preclinical studies suggest that chronic stress prior to conception has cross-generational effects on the behavior and physiological response to stress in subsequent generations. Thus, we hypothesized that chronic stress may also affect ethanol drinking behaviors in the next generation. In the first cohort of mice, we found that paternal preconception chronic variable stress significantly reduced both two-bottle choice and binge-like ethanol drinking selectively in male offspring. However, these results were not replicated in a second cohort that were tested under experimental conditions that were nearly identical, except for one notable difference. Cohort 1 offspring were derived from in-house C57BL/6J sires that were born in the animal vivarium at the University of Pittsburgh whereas cohort 2 offspring were derived from C57BL/6J sires shipped directly from the vendor. Therefore, a third cohort that included both in-house and vendor born sires was analyzed. Consistent with the first two cohorts, we observed a significant interaction between chronic stress and sire-source with only stressed sires that were born in-house able to impart reduced ethanol drinking behaviors to male offspring. Overall, these results demonstrate that paternal preconception stress can impact ethanol drinking behavior in males of the next generation. These studies provide additional support for a recently recognized role of the paternal preconception environment in shaping ethanol drinking behavior.

SUBMITTER: Rompala GR

PROVIDER: S-EPMC6225737 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Paternal Preconception Chronic Variable Stress Confers Attenuated Ethanol Drinking Behavior Selectively to Male Offspring in a Pre-Stress Environment Dependent Manner.

Rompala Gregory R GR Simons Alison A Kihle Brooke B Homanics Gregg E GE

Frontiers in behavioral neuroscience 20181102

Stress-related psychiatric disorders such as major depression are strongly associated with alcohol abuse and alcohol use disorder. Recently, many epidemiological and preclinical studies suggest that chronic stress prior to conception has cross-generational effects on the behavior and physiological response to stress in subsequent generations. Thus, we hypothesized that chronic stress may also affect ethanol drinking behaviors in the next generation. In the first cohort of mice, we found that pat ...[more]

PMID: 30450042

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Project description:BACKGROUND:Although clinical data support an association between paternal alcohol use and deficits in child neurocognitive development, the relationship between paternal drinking and alcohol-induced growth phenotypes remains challenging to define. Using an established mouse model of chronic exposure, previous work by our group has linked preconception paternal alcohol use to sex-specific patterns of fetal growth restriction and placental dysfunction. The aim of the present study was to investigate the long-term impact of chronic preconception paternal alcohol use on offspring growth and metabolic programming. RESULTS:Preconception paternal alcohol exposure induced a prolonged period of fetal gestation and an increased incidence of intrauterine growth restriction, which affected the male offspring to a greater extent than the females. While the female offspring of ethanol-exposed males were able to match the body weights of the controls within the first 2 weeks of postnatal life, male offspring continued to display an 11% reduction in weight at 5 weeks of age and a 6% reduction at 8 weeks of age. The observed growth deficits associated with insulin hypersensitivity in the male offspring, while in contrast, females displayed a modest lag in their glucose tolerance test. These metabolic defects were associated with an up-regulation of genes within the pro-fibrotic TGF-? signaling pathway and increased levels of cellular hydroxyproline within the livers of the male offspring. We observed suppressed cytokine profiles within the liver and pancreas of both the male and female offspring, which correlated with the up-regulation of genes in the LiverX/RetinoidX/FarnesoidX receptor pathways. However, patterns of gene expression were highly variable between the offspring of alcohol-exposed sires. In the adult offspring of alcohol-exposed males, we did not observe any differences in the allelic expression of Igf2 or any other imprinted genes. CONCLUSIONS:The impact of paternal alcohol use on child development is poorly explored and represents a significant gap in our understanding of the teratogenic effects of ethanol. Our studies implicate paternal exposure history as an additional and important modifier of alcohol-induced growth phenotypes and challenge the current maternal-centric exposure paradigm.

Project description:Alcohol use disorder (AUD) is a devastating psychiatric disorder that has significant wide-reaching effects on individuals and society. Selectively bred mouse lines are an effective means of exploring the genetic and neuronal mechanisms underlying AUD and such studies are translationally important for identifying treatment options. Here, we report on behavioral characterization of two replicate lines of mice that drink to intoxication, the High Drinking in the Dark (HDID)-1 and -2 mice, which have been selectively bred (20+ generations) for the primary phenotype of reaching high blood alcohol levels (BALs) during the drinking in the dark (DID) task, a binge-like drinking assay. Along with their genetically heterogenous progenitor line, Hs/Npt, we tested these mice on: DID and drinking in the light (DIL); temporal drinking patterns; ethanol sensitivity, through loss of righting reflex (LORR); and operant self-administration, including fixed ratio (FR1), fixed ratio 3:1 (FR3), extinction/reinstatement, and progressive ratio (PR). All mice consumed more ethanol during the dark than the light and both HDID lines consumed more ethanol than Hs/Npt during DIL and DID. In the dark, we found that the HDID lines achieved high blood alcohol levels early into a drinking session, suggesting that they exhibit front loading like drinking behavior in the absence of the chronicity usually required for such behavior. Surprisingly, HDID-1 (female and male) and HDID-2 (male) mice were more sensitive to the intoxicating effects of ethanol during the dark (as determined by LORR), while Hs/Npt (female and male) and HDID-2 (female) mice appeared less sensitive. We observed lower HDID-1 ethanol intake compared to either HDID-2 or Hs/Npt during operant ethanol self-administration. There were no genotype differences for either progressive ratio responding, or cue-induced ethanol reinstatement, though the latter is complicated by a lack of extinguished responding behavior. Taken together, these findings suggest that genes affecting one AUD-related behavior do not necessarily affect other AUD-related behaviors. Moreover, these findings highlight that alcohol-related behaviors can also differ between lines selectively bred for the same phenotype, and even between sexes within those same line.

Dataset Information

Paternal Preconception Chronic Variable Stress Confers Attenuated Ethanol Drinking Behavior Selectively to Male Offspring in a Pre-Stress Environment Dependent Manner.

Publications

Paternal Preconception Chronic Variable Stress Confers Attenuated Ethanol Drinking Behavior Selectively to Male Offspring in a Pre-Stress Environment Dependent Manner.

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