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Paternal nicotine enhances fear memory, reduces nicotine administration and alters hippocampal genetic and neural function in offspring [Bisulfite-seq]

ABSTRACT: We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on hippocampal DNA methylation in F1 offspring.

ORGANISM(S): Mus musculus

PROVIDER: GSE140904 | GEO | 2019/11/25

REPOSITORIES: GEO

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Paternal nicotine enhances fear memory, reduces nicotine administration and alters hippocampal genetic and neural function in offspring [RNA-seq]

Project description:We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on hippocampal RNA expression in F1 offspring.

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Paternal nicotine enhances fear memory, reduces nicotine administration and alters hippocampal genetic and neural function in offspring

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Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring

Project description:Although it is increasingly accepted that some paternal environmental conditions can influence phenotypes in future generations, it remains unclear whether phenotypes induced in offspring represent specific responses to particular aspects of the paternal exposure history, or whether they represent a more generic response to paternal “quality of life”. To establish a paternal effect model based on a specific ligand-receptor interaction and thereby enable pharmacological interrogation of the offspring phenotype, we explored the effects of paternal nicotine administration on offspring phenotype in mouse. We show that paternal exposure to chronic nicotine induced a broad protective response to xenobiotic exposure in the next generation. This effect manifested as increased survival following an injection of toxic levels of nicotine, was specific to male offspring, and was only observed after these offspring were first acclimated to low levels of nicotine for a week. Importantly, offspring xenobiotic resistance was documented not only for toxic nicotine challenge, but also for toxic cocaine challenge, indicating that paternal nicotine exposure reprograms offspring to become broadly resistant to environmental toxins. Mechanistically, the reprogrammed state was characterized by enhanced clearance of nicotine in drug-acclimated animals, and we found that isolated hepatocytes displayed upregulation of enzymes that metabolize xenobiotics. Taken together, our data show that paternal nicotine exposure induces a protective phenotype in offspring by enhancing metabolic tolerance to xenobiotics in the environment.

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Paternal nicotine enhances fear memory, reduces nicotine administration and alters hippocampal genetic and neural function in offspring [Bisulfite-seq]

Project description:Paternal nicotine enhances fear memory, reduces nicotine administration and alters hippocampal genetic and neural function in offspring [Bisulfite-seq]

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Paternal nicotine enhances fear memory, reduces nicotine administration and alters hippocampal genetic and neural function in offspring [RNA-seq]

Project description:Paternal nicotine enhances fear memory, reduces nicotine administration and alters hippocampal genetic and neural function in offspring [RNA-seq]

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Paternal nicotine enhances fear memory, reduces nicotine administration, and alters hippocampal genetic and neural function in offspring.

Project description:Nicotine use remains highly prevalent with tobacco and e-cigarette products consumed worldwide. However, increasing evidence of transgenerational epigenetic inheritance suggests that nicotine use may alter behavior and neurobiology in subsequent generations. We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on fear conditioning in F1 and F2 offspring, as well as conditioned fear extinction and spontaneous recovery, nicotine self-administration, hippocampal cholinergic functioning, RNA expression, and DNA methylation in F1 offspring. Paternal nicotine exposure was associated with enhanced contextual and cued fear conditioning and spontaneous recovery of extinguished fear memories. Further, nicotine reinforcement was reduced in nicotine-sired mice, as assessed in a self-administration paradigm. These behavioral phenotypes were coupled with altered response to nicotine, upregulated hippocampal nicotinic acetylcholine receptor binding, reduced evoked hippocampal cholinergic currents, and altered methylation and expression of hippocampal genes related to neural development and plasticity. Gene expression analysis suggests multigenerational effects on broader gene networks potentially involved in neuroplasticity and mental disorders. The changes in fear conditioning similarly suggest phenotypes analogous to anxiety disorders similar to post-traumatic stress.

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Paternal nicotine enhances fear memory, reduces nicotine administration and alters hippocampal genetic and neural function in offspring

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-11-25 | GSE140905 | GEO

Effects of paternal nicotine taking on gene expression in dorsal hippocampus of drug naïve male offspring

Project description:Nicotine intake, whether through tobacco smoking or e-cigarettes, remains a global health concern. An emerging preclinical literature indicates that parental nicotine exposure produces behavioral, physiological, and molecular changes in subsequent generations. However, the heritable effects of voluntary parental nicotine taking are unknown. Here, we show increased acquisition of nicotine taking in male and female offspring of sires that self-administered nicotine. In contrast, self-administration of sucrose and cocaine were unaltered in male and female offspring suggesting that the intergenerational effects of paternal nicotine taking may be reinforcer specific. Further characterization revealed memory deficits and increased anxiety-like behaviors in drug-naïve male, but not female, offspring of nicotine-experienced sires. Using an unbiased, genome-wide approach, we discovered that these phenotypes were associated with decreased expression of Satb2, a transcription factor known to play important roles in synaptic plasticity and memory formation, in the hippocampus of nicotine-sired male offspring. This effect was sex-specific as no changes in Satb2 expression were found in nicotine-sired female offspring. Finally, increasing Satb2 levels in the hippocampus prevented the escalation of nicotine intake and rescued the memory deficits associated with paternal nicotine taking in male offspring. Collectively, these findings indicate that paternal nicotine taking produces heritable sex-specific molecular changes that promote addiction-like phenotypes and memory impairments in male offspring. To characterize the molecular changes associated with the heritable effects of paternal nicotine taking, an unbiased, whole-genome analysis was used to characterize the hippocampal transcriptome of drug-naïve F1 males

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Paternal nicotine exposure promotes hepatic fibrosis in offspring

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