Characterization of the intergenerational impact of in utero and postnatal oxycodone exposure
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE157348 | GEO | 2020/09/03
REPOSITORIES: GEO
Similar Datasets
Project description:The development of physical dependence and addiction disorders due to misuse of opioid analgesics is a major concern with pain therapeutics. In this study, we developed a mouse model of oxycodone exposure to gain insight into genes and molecular pathways in reward-related brain regions that are affected by prolonged exposure to oxycodone and subsequent withdrawal in the presence or absence of chronic neuropathic pain. RNA-Sequencing (RNA-Seq) and bioinformatic analyses revealed that oxycodone withdrawal alone triggers robust gene expression adaptations in the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and ventral tegmental area (VTA), with numerous genes and pathways selectively affected by oxycodone withdrawal under peripheral nerve injury states. Our pathway analysis predicted that histone deacetylase 1 (HDAC1), an epigenetic modifier with a prominent role in striatal plasticity, is a top upstream regulator in opioid withdrawal in both the NAc and mPFC. Indeed, treatment with the novel HDAC1/2 inhibitor RBC1HI (Regenacy Brain Class 1 HDAC Inhibitor) attenuated behavioral manifestations of oxycodone withdrawal, with the drug being more efficacious under states of neuropathic pain. Since RBC1HI displays antiallodynic actions in models of neuropathic pain, inhibition of HDAC1/2 may provide an avenue for chronic pain patients dependent on opioids to transition to non-opioid analgesics. Overall, our study highlights transcriptomic events in components of the reward circuitry associated with oxycodone withdrawal under pain-free and prolonged neuropathic pain states, thereby providing information on possible new targets for the treatment of physical dependence to opioids and transitioning individuals to non-opioid medications for chronic pain management.
2023-01-23 | GSE223541 | GEO
Project description:In the present study, zebrafish were exposed to permethrin during early-life, and F1 and F2 generations were bred unexposed. Permethrin exposed F0 fish showed a hypoactive phenotype at adulthood, whereas males from the F1 and F2 generations showed a decrease in anxiety-like behavior. Thus, we performed transcriptomic changes to identify underlying molecular mechanisms. They showed limited overlap between sex and generations. In F0, genes and pathways related to glutamatergic synapse activity (Gene Ontology and Reactome databases) were significantly enriched and may explain the behavioral effects. In F1 and F2 generations, mechanisms are less clear as limited changes which could correlate with behavior were observed in the F1 generation.
2021-07-01 | GSE154020 | GEO
Project description:Characterization of the intergenerational impact of in utero and postnatal oxycodone exposure
| PRJNA661036 | ENA
Project description:Prescription opioid abuse during and after pregnancy is a rising public health concern. While earlier studies have documented that offspring exposed to opioids in utero have impaired neurodevelopment, a significant knowledge gap remains in comparing the overall development between offspring exposed in utero and postnatally. Adding a layer of complexity is the role of heredity in the overall development of these exposed offspring. To fill in these important knowledge gaps, the current study uses a preclinical rat model mimicking oxycodone (oxy) exposure in utero (IUO) and postnatally (PNO) to investigate comparative and intergenerational effects in the two different treatment groups. While significant phenotypic attributes were observed with the two treatments and across the two generations, RNA sequencing revealed alterations in the expression of key synaptic genes in the two exposed groups in both generations. RNA sequencing and post validation of genes using RT-PCR highlighted the differential expression of several neuropeptides associated with the hypocretin system, a system recently implicated in addiction. Further, behavior studies revealed anxiety-like behaviors and social deficits that persisted even in the subsequent generations in the two treatment groups. To summarize, our study for the first time reveals a new line of investigation on the potential risks associated with oxy use during and after pregnancy, specifically the disruption of neurodevelopment and intergenerational impact on behavior.
| S-EPMC7511347 | biostudies-literature
Project description:Analyse of gene expression modification after chronic analgesic treatment. The hypothesis tested in the present study was that oxycodone and morphine induced gene expression modification. Results provide important information to understand the analgesic effects of oxycodone as compared to morphine in a neuropathic pain model Total RNA obtained from DRG of neuropathic or control animals after oxycodone or morphine treatment
2014-01-09 | E-GEOD-53897 | biostudies-arrayexpress
Project description:To determine whether paternal methamphetamine exposure alters the development, behavior and gene expression of first (F1) and second (F2) generations. We administrated methamphetamine (5 mg/kg) or saline (10 ml/kg) to sire (F0) and performed gene expression profiling analysis using data obtained from RNA-seq of striatum of 7-week-old male F1 mice. Male F1 mice were mated with untreated female mice to obtain F2 mice. Male F1 mice were mated with female mice to obtain F2 mice. RNA-seq of striatum of 7-week-old male F2 mice was also analyzed in the same way.
2024-08-08 | GSE248542 | GEO
Project description:The pre and postnatal environment can affect both an individual’s risk of adult onset metabolic disease and that of subsequent generations. Although animal models and epidemiological data implicate epigenetic inheritance, little is known of the mechanisms involved. In a robust intergenerational model of developmental programming we demonstrate that the nutritional environment experienced in utero by F1 generation embryos alters the DNA methylome of the F1 adult male germ line in a locus-specific manner, without affecting overall methylation levels. Differentially methylated regions are mostly hypomethylated and are enriched in nucleosome retaining regions in adult sperm. A substantial fraction is resistant to early embryo methylation reprogramming, and thus have the potential to alter F2 generation development. Altered expression of transcripts neighbouring differentially methylated regions are evident in tissues of F2 offspring despite lack of persistence of differential methylation. Transmitted methylation variation in the germline at key regulatory loci may therefore contribute to the development of metabolic disease in the subsequent generation.
2014-07-16 | GSE58747 | GEO
Project description:Atmospheric pollution is a rising concern in urban areas and a major contributor to people’s mortality, with potential intergenerational consequences. Our aim was to evaluate the effects of exposure of pregnant F0 females to diluted diesel exhaust (DE) on feto-placental development in the second generation (F2). These rabbits were exposed to diluted and filtered DE (E: exposed group) or clean air (C: Control group) for 2h/day, 5days/week by nose-only exposure from 3rd to 27th days post-conception (dpc). Not exposed anymore after birth, female offspring (F1) were mated with control males at adulthood. F2 feto-placental units were collected at 28dpc. Fatty acid profiles were determined from fetal and maternal plasma, maternal liver and placenta by gas chromatography. Placental structure was explored by stereology while placental gene expression was analyzed using a dedicated microarray. At 28dpc, maternal F1 biochemistry was not different between groups, although F1 E females exhibited increased content of hepatic neutral lipid. Similarly the content of lipid was higher in F2 E placentas, mostly by monounsaturated fatty acids while arachidonic acid was reduced. The proportion of n-3 polyunsaturated fatty acids (n-3 PUFA) was increased whereas AA decreased in F2 E fetal plasma compared to Controls. No structural change was observed in placentas between groups. GSEA analysis of transcriptomic data revealed that gene involved in proteasome complex and ubiquitin pathways were up-regulated in E placentas when compared to C placentas, whereas those involved in ion channel or inflammation regulations were down-regulated. In conclusion, in utero exposure of F1 females to DE can affect both placental function and fetal metabolism in the second generation (F2). Placental FA profiles suggest adaptive protective mechanisms against inflammation, through placental storage of non-essential FA and the favored transplacental transfer of n-3 PUFA. The fetal physiological consequences of observed alterations in placental genes involved in protein metabolism and intracellular signaling remain to be determined. In order to evaluate the intergenerational effects to the F2 generation of in utero F1 exposure to DE, we chose the rabbit model because of its hemochorial placenta closer to the human one (Fischer et al 2012; Furukawa, 2014) than those of rodents. The present study follows our recent publication related to the effects of diesel exhaust exposure of rabbit female F0 during gestation on feto-placental development in F1 and F2 generations (Valentino et al., 2016) where we have shown that F2 feto-placental biometry was not disturbed consecutively to the in utero exposure of the F1 generation (Valentino et al., 2016). Nevertheless, these macroscopically normal fetuses had reduced plasma total cholesterol (-25.9%) and non-HDL cholesterol (-26%) associated with an increase in plasma triglycerides concentrations (+25.9%) compared to F2 control group (Valentino et al., 2016). In the present study, placental function in the second generation was explored at a biochemical and molecular levels in order to understand how the placenta contributed to the fetal dyslipidemia without affecting the biometry.
2019-07-25 | GSE109831 | GEO
Project description:The pre and postnatal environment can affect both an individual’s risk of adult onset metabolic disease and that of subsequent generations. Although animal models and epidemiological data implicate epigenetic inheritance, little is known of the mechanisms involved. In a robust intergenerational model of developmental programming we demonstrate that the nutritional environment experienced in utero by F1 generation embryos alters the DNA methylome of the F1 adult male germ line in a locus-specific manner, without affecting overall methylation levels. Differentially methylated regions are mostly hypomethylated and are enriched in nucleosome retaining regions in adult sperm. A substantial fraction is resistant to early embryo methylation reprogramming, and thus have the potential to alter F2 generation development. Altered expression of transcripts neighbouring differentially methylated regions are evident in tissues of F2 offspring despite lack of persistence of differential methylation. Transmitted methylation variation in the germline at key regulatory loci may therefore contribute to the development of metabolic disease in the subsequent generation. 2 biological replicates of pooled sperm samples for each control (C) or undernutrition (UN) model
2014-07-16 | E-GEOD-58747 | biostudies-arrayexpress
Project description:Hypoxia is amongst the most widespread and pressing problems in aquatic environments. Here we demonstrate that fish (Oryzias melastigma) exposed to hypoxia show reproductive impairments (retarded gonad development, decrease in sperm count and sperm motility) in F1 and F2 generations despite these progenies (and their germ cells) having never been exposed to hypoxia. We further show that the observed transgenerational reproductive impairments are associated with a differential methylation pattern of specific genes in sperm of both F0 and F2 coupled with relevant transcriptomic and proteomic alterations, which may impair spermatogenesis.
2021-05-25 | PXD026257 | Pride