Transgenerational inheritance of diabetes susceptibility in male offspring with maternal hyperandrogenism [WGBS]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1108291 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28919723_1.fastq.gz | Fastqsanger.gz | |||
| SRR28919723_2.fastq.gz | Fastqsanger.gz | |||
| SRR28919724_1.fastq.gz | Fastqsanger.gz | |||
| SRR28919724_2.fastq.gz | Fastqsanger.gz | |||
| SRR28919725_1.fastq.gz | Fastqsanger.gz |
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Project description:Maternal hyperandrogenism is closely related to metabolic disorders, yet its transgenerational effects on male descendants remain unclear. Here we demonstrate that hyperandrogenism in women predisposes their sons to islet β-cell dysfunction. Male offspring mice with prenatal androgen exposure exhibited hyperglycemia and glucose intolerance due to compromised insulin secretion. Notably, these metabolic disturbances were transmitted across three generations, and exacerbated by aging and a high-fat diet. Altered DNA methylations in F1 sperm and F2 islet contribute to suppressed β-cell functional genes. We identified shared differentially methylated signatures in F1 sperm, type 2 diabetes patients, and sons with maternal hyperandrogenism. Furthermore, caloric restriction and metformin treatments in F1 males corrected hyperglycemic defects and prevented their transmission to offspring. Our findings highlight the transgenerational inheritance of hyperglycemia and β-cell dysfunction in male offspring from maternal hyperandrogenism via DNA methylation changes, providing methylation biomarkers and therapeutic strategies to safeguard future generations’ metabolic health.
2025-02-19 | GSE266699 | GEO
Project description:Maternal hyperandrogenism is closely related to metabolic disorders, yet its transgenerational effects on male descendants remain unclear. Here we demonstrate that hyperandrogenism in women predisposes their sons to islet β-cell dysfunction. Male offspring mice with prenatal androgen exposure exhibited hyperglycemia and glucose intolerance due to compromised insulin secretion. Notably, these metabolic disturbances were transmitted across three generations, and exacerbated by aging and a high-fat diet. Altered DNA methylations in F1 sperm and F2 islet contribute to suppressed β-cell functional genes. We identified shared differentially methylated signatures in F1 sperm, type 2 diabetes patients, and sons with maternal hyperandrogenism. Furthermore, caloric restriction and metformin treatments in F1 males corrected hyperglycemic defects and prevented their transmission to offspring. Our findings highlight the transgenerational inheritance of hyperglycemia and β-cell dysfunction in male offspring from maternal hyperandrogenism via DNA methylation changes, providing methylation biomarkers and therapeutic strategies to safeguard future generations’ metabolic health.
2025-02-19 | GSE266255 | GEO
Project description:Transgenerational inheritance of diabetes susceptibility in male offspring with maternal hyperandrogenism
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Project description:Transgenerational inheritance of diabetes susceptibility in male offspring with maternal hyperandrogenism [RNA-Seq]
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Project description:Transgenerational inheritance of acquired traits/characteristics from ancestors is believed to play important roles in evolution, as well as health problems/symptoms not due to “classical genetic inheritance”. However, the central enigma, such as how the acquired transgenerational characteristics are developed, and how the acquired traits are transmitted from generations to generations of offspring, largely remained veiled. In this study, we used C elegans as a model system and provide evidence that the dynamic of H3K27me3 as a hallmark and regulator for the gut-mediated transgenerational inheritance of acquired traits. Further, we demonstrate that yolk proteins guide the establishment of the acquired epigenetic imprints in soma, as well as determines the transgenerational inheritance of epigenetic imprints and subsequent acquired behavior in offspring by maternal provision. Taken together, our findings support that yolk proteins both function as a systemic “non-nuclear factor” for establishing the somatic epigenetic imprints and as a “cargo” to transmit acquired epigenetic information to the subsequent generations through oocytes.
2022-09-10 | GSE138059 | GEO
Project description:The goals of this study are to compare genome-wide DNA methylation levels in young and aged oocytes,and to investigate the transgenerational inheritance of methylome profiles in oocytes during natural aging. We apply a novel protocol of rapamycin to overcome the DNA methylation drift associated with oocyte aging. 8-week-old female mice were injected intraperitoneally with rapamycin or vehicle for 40 weeks. At the end of the experiment, females (48 weeks, F0) were paired with young adult (~4 mo old) males to produce F1 offspring (OF1 and ORaF1). An F2 generation (OF2 and ORaF2) resulted from mating F1 female at 44~48 weeks of age with young adult males. To generate YF1 and YF2 as normal control (offspring of young mother), we mated females (~8 weeks) with young adult males. Then we collect oocytes (F0,F1 and F2 generations)，sperm ( F1 and F2 generations) and hippocampus (F1 female offspring) from different groups to investigate the transgenerational inheritance of DNA methylome profiles associated with oocyte aging by the single cell whole-genome methylation sequencing (sc-WGBS). We found that oocytes from aged mother exhibited increased DNA methylation levels in CpG sites. Maternal aging related methylome changes can be inherited transgenerationally though oocyte to the germ line of F1 and F2 offspring. The application of rapamycin during the course of oocyte aging could reverse these DNA methylation alterations, and it can ameliorate several neurobehavioral aging trails that were in observed in aged oocyte offspring. WGBS-seq on DNA from hippocampal tissue revealed a number of differentially methylated (P<0.05) genes in OF1 and ORaF1 compared with YF1, and some of the enriched pathways were associated with aging process, such as PI3K-Akt signaling pathway (akin to transcriptional alterations above), MAPK signaling and Ras signaling pathway .
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Project description:The global prevalence of type 2 diabetes (T2D) is increasing, and it is contributing to the susceptibility to diabetes and its related epidemic in offspring. Although the impacts of paternal T2D on metabolism of offspring have been well established, the exact molecular and mechanistic basis that mediates these impacts remains largely unclear. Here we show that paternal T2D increases the susceptibility to diabetes in offspring through the gametic epigenetic alterations. Paternal T2D led to glucose intolerance and insulin resistance in offspring. Relative to controls, offspring of T2D fathers exhibited altered gene expression patterns in the pancreatic islets, with downregulation of several genes involved in glucose metabolism and insulin signaling pathway. Epigenomic profiling of offspring pancreatic islets revealed numerous changes in cytosine methylation depending on paternal T2D, including reproducible changes in methylation over several insulin signaling genes. Paternal T2D altered overall methylome patterns in sperm, with a large portion of differentially methylated genes overlapped with that of pancreatic islets in offspring. Our study revealed, for the first time, that T2D can be inherited transgenerationally through the mammalian germline by an epigenetic manner. Examination of the effect of paternal T2D on the DNA methylation in the pancreatic islets of offspring and in the sperm of father.
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Project description:The current study was designed to use a rodent model to determine if exposure to the chemotherapy drug ifosfamide during puberty can induce altered phenotypes and disease in the grand-offspring of exposed individuals through epigenetic transgenerational inheritance. Numerous toxicant exposures during critical developmental windows can have generational impacts through this non-genetic inheritance mechanism. Pathologies such as delayed pubertal onset, kidney disease and multiple pathologies were observed to be significantly more frequent in the F1 generation offspring of ifosfamide lineage females. The F2 generation grand-offspring ifosfamide lineage males had transgenerational pathology phenotypes of early pubertal onset and reduced testis pathology. Reduced levels of anxiety were observed in both males and females from the exposure lineage in the transgenerational F2 generation grand-offspring. Differential DNA methylated regions (DMRs) were also identified in chemotherapy and control lineages sperm in the F1 and F2 generations. The transgenerational alterations in sperm epigenetics provides a molecular mechanism for the ancestral impacts of chemotherapy. Therefore, chemotherapy exposure can impact pathology and disease susceptibility in subsequent generations.
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Project description:Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Methylated sperm DNA was isolated from rats ancestrally exposed to methoxychlor. Three independent samples from each treatment group were obtained. Differential DNA methylation between treatment groups was determined using Nimblegen microarrays. Treated samples were paired with control samples and hybridized together on arrays, resulting in three arrays for the treatment.
2014-05-30 | E-GEOD-58091 | biostudies-arrayexpress
Project description:Parental environmental exposures can strongly influence descendant risks for adult disease. Metabolic disorders arise from the intersection of environmental and genetic risk factors, with epigenetic inheritance being at the center of the familial cycle of transgenerational disease. How paternal high-fat diet changes the sperm chromatin leading to the acquisition of metabolic disease in offspring remains controversial and ill-defined. Using a genetic model of epigenetic inheritance, we investigated the role of histone H3 lysine 4 methylation (H3K4me3) in the paternal transmission of metabolic dysfunction. We show that obesity-induced alterations in sperm H3K4me3 associated with offspring phenotypes and corresponded to embryonic and placental chromatin profiles and gene expression. Transgenerational susceptibility to metabolic disease was only observed when grandsires had a pre-existing genetic predisposition to metabolic dysfunction that was associated with enhanced alterations to sperm H3K4me3. This non-DNA based knowledge of inheritance has the potential to improve our understanding of how environment shapes heritability and may lead to novel routes for the prevention of disease.
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