Elevated zygotic let-7f-5p alters developmental trajectories and sex-specific somatic growth [Blastocyst]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE314398 | GEO | 2026/05/26
REPOSITORIES: GEO
Similar Datasets
Project description:Paternal preconception experiences shape offspring development and longitudinal health outcomes, including disease risk. Small non-coding RNA (sncRNA) are potential causal agents in the germline transmission of paternal exposures at conception. In a previous repeated sampling human cohort, we identified that sperm microRNA (miRNA), let-7f-5p (let-7f), was significantly increased in response to elevated prior perceived stress. To understand the potential role of sperm let-7f in the transmission of stress and its impact on development, we investigated outcomes produced by increasing zygote levels of this miRNA. We found alterations in gene expression at the blastocyst stage and at mid-gestation following zygotic microinjections. These changes were male-specific, and functional enrichment analyses revealed significant shifts in cellular developmental processes, metabolic functioning, neurodevelopment, and bone development. These sex-specific developmental differences persisted until adulthood, with let-7f males having greater somatic growth. Together, our findings demonstrate a clear role for sperm let-7f in shaping offspring trajectory.
2026-05-26 | GSE314713 | GEO
Project description:Paternal preconception experiences shape offspring development and longitudinal health outcomes, including disease risk. Small non-coding RNA (sncRNA) are potential causal agents in the germline transmission of paternal exposures at conception. In a previous repeated sampling human cohort, we identified that sperm microRNA (miRNA), let-7f-5p (let-7f), was significantly increased in response to elevated prior perceived stress. To understand the potential role of sperm let-7f in the transmission of stress and its impact on development, we investigated outcomes produced by increasing zygote levels of this miRNA. We found alterations in gene expression at the blastocyst stage and at mid-gestation following zygotic microinjections. These changes were male-specific, and functional enrichment analyses revealed significant shifts in cellular developmental processes, metabolic functioning, neurodevelopment, and bone development. These sex-specific developmental differences persisted until adulthood, with let-7f males having greater somatic growth. Together, our findings demonstrate a clear role for sperm let-7f in shaping offspring trajectory.
2026-05-26 | GSE314710 | GEO
Project description:Paternal preconception experiences shape offspring development and longitudinal health outcomes, including disease risk. Small non-coding RNA (sncRNA) are potential causal agents in the germline transmission of paternal exposures at conception. In a previous repeated sampling human cohort, we identified that sperm microRNA (miRNA), let-7f-5p (let-7f), was significantly increased in response to elevated prior perceived stress. To understand the potential role of sperm let-7f in the transmission of stress and its impact on development, we investigated outcomes produced by increasing zygote levels of this miRNA. We found alterations in gene expression at the blastocyst stage and at mid-gestation following zygotic microinjections. These changes were male-specific, and functional enrichment analyses revealed significant shifts in cellular developmental processes, metabolic functioning, neurodevelopment, and bone development. These sex-specific developmental differences persisted until adulthood, with let-7f males having greater somatic growth. Together, our findings demonstrate a clear role for sperm let-7f in shaping offspring trajectory.
2026-05-26 | GSE314467 | GEO
Project description:Prenatal development is influenced by various paternal factors, including environmental exposures, lifestyle, and epigenetic modifications. This dissertation investigates the impact of chronic paternal alcohol (EtOH) consumption on offspring development, with a particular focus on placental function, mitochondrial health, and microRNA (miRNA) mediated epigenetic inheritance. Using a previously established mouse model, we explored how preconception paternal alcohol exposure alters sperm-inherited small RNA population and its downstream consequences on placental structure and function. Our findings demonstrate that chronic paternal EtOH consumption induces significant changes in sperm small RNA populations, particularly miRNAs known to regulate early embryonic development. These alterations correlate with disruptions in fetal growth and placental histology, suggesting an intergenerational transmission of stress-induced epigenetic modifications. Furthermore, we identified sex-specific differences in fetoplacental development, where male offspring exhibited pronounced placental inefficiencies and metabolic disruptions. A key aspect of this research involves the role of nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of oxidative stress. We show that paternal NRF2 loss-of-function phenocopies the effects of chronic alcohol exposure, reinforcing the hypothesis that oxidative stress-induced epigenetic alterations mediate the observed developmental outcomes. Placental mitochondrial function, a vital determinant of fetal energy supply, was also significantly impaired in alcohol-exposed offspring. Notably, these defects persisted into adulthood, implicating long-term metabolic consequences. To assess the genetic and epigenetic basis of these outcomes, we conducted proteomic and transcriptomic analyses, revealing dysregulated pathways involved in mitochondrial bioenergetics, redox balance, and cellular metabolism. Our results highlight that paternal alcohol exposure not only disrupts placental architecture but also modifies the epigenetic landscape of the developing embryo, leading to systemic physiological alterations. These findings underscore the importance of considering paternal contributions to reproductive health and fetal development. By elucidating the mechanisms underlying alcohol-induced epigenetic inheritance, this research provides novel insights into the role of paternal environmental exposures in shaping offspring health trajectories. Ultimately, this work advocates for broader perspectives on preconception health, emphasizing the need for preventive strategies to mitigate paternal influences on developmental disorders.
2026-01-01 | GSE303374 | GEO
Project description:Offspring health outcomes are often linked with epigenetic alterations triggered by maternal nutrition and intrauterine environment. Strong experimental data also link paternal preconception nutrition with pathophysiology in the offspring, but the mechanism(s) routing effects of paternal exposures remain elusive. Animal experimental models have highlighted small non-coding RNAs (sncRNAs) as potential regulators of these effects. This study characterised the baseline sncRNA landscape of human sperm and the effect of a 6 week dietary intervention on their expression profile. 5’tRFs, miRNA and piRNAs were the most abundant sncRNA subtypes identified; their expression was associated with age, BMI and sperm quality. Nutritional intervention with vitamin D and omega-3 fatty acids altered expression of 3 tRFs, 15 miRNAs and 112 piRNAs, targeting genes involved in fatty acid metabolism and transposable elements in the sperm genome.
2021-10-31 | GSE159752 | GEO
Project description:<p>The gut microbiota operates at the interface of host-environment interactions to influence human homeostasis and metabolic networks. Environmental factors that unbalance gut microbial ecosystems can therefore elicit physiological and disease-associated responses across somatic tissues. However, the systemic impact of the gut microbiome on the germline - and consequently on the F1 offspring it gives rise to - is unexplored. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory ‘gut-germline axis’ in males, which is sensitive to environmental exposures and programs offspring fitness through impacting placental function.</p>
2024-02-12 | MTBLS1629 | MetaboLights
Project description:Preconception parental environment can reproducibly program offspring phenotype without altering the DNA sequence, yet the mechanisms underpinning this ‘epigenetic inheritance’ remains elusive. Here, we demonstrate the existence of an intact piRNA-pathway in mature Drosophila sperm and show that pathway modulation alters offspring gene transcription in a sequence-specific manner. We map a dynamic small RNA content in developing sperm and find that the mature sperm carry a highly distinct small RNA cargo. By biochemical pulldown, we identify a small RNA subset bound directly to piwi protein. And, we show that piRNA-pathway controlled sperm small RNAs are linked to target gene repression in offspring. Critically, we find that full piRNA-pathway dosage is necessary for the intergenerational metabolic and transcriptional reprogramming events triggered by high paternal dietary sugar. These data provide a direct link between regulation of endogenous mature sperm small RNAs and transcriptional programming of complementary sequences in offspring. Thus, we identify a novel mediator of paternal intergenerational epigenetic inheritance.
2022-01-01 | GSE172107 | GEO
Project description:Spermatozoa deliver a complex and environment sensitive pool of small non-coding RNAs (sncRNA) to the oocyte at fertilisation [ref], which influences offspring development and adult phenotypic trajectories [refs]. Whether mature spermatozoa in the epididymis can directly sense the environment is still not fully understood [ref]. Here, we used two distinct paradigms of preconception acute High Fat Diet challenge to dissect epididymal vs spermatogenic contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNA fragments as sperm-born sensors. In human spermatozoa, we found mt-tsRNAs in linear association with BMI and showed that paternal overweight at conception is sufficient to double offspring obesity risk and compromise metabolic health. Using mouse genetics and metabolic phenotypic data, we show that alterations of mt-tsRNAs are downstream of mitochondrial dysfunction in mice. Most importantly, single embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tsRNAs at fertilisation and implied them in the control of early embryo metabolism. Our study supports the importance of paternal health at conception for offspring metabolism, propose mt-tsRNAs as sperm-born environmental effectors of paternal inheritance and demonstrate, for the first time in a physiological and unperturbed setting, father-to-offspring transfer of sperm mt-tsRNAs at fertilisation.
2024-04-03 | GSE239814 | GEO
Project description:Spermatozoa deliver a complex and environment sensitive pool of small non-coding RNAs (sncRNA) to the oocyte at fertilisation, which influences offspring development and adult phenotypic trajectories. Whether mature spermatozoa in the epididymis can directly sense the environment is still not fully understood. Here, we used two distinct paradigms of preconception acute High Fat Diet challenge to dissect epididymal vs spermatogenic contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNA fragments as sperm-born sensors. In human spermatozoa, we found mt-tsRNAs in linear association with BMI and showed that paternal overweight at conception is sufficient to double offspring obesity risk and compromise metabolic health. Using mouse genetics and metabolic phenotypic data, we show that alterations of mt-tsRNAs are downstream of mitochondrial dysfunction in mice. Most importantly, single embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tsRNAs at fertilisation and implied them in the control of early embryo metabolism. Our study supports the importance of paternal health at conception for offspring metabolism, propose mt-tsRNAs as sperm-born environmental effectors of paternal inheritance and demonstrate, for the first time in a physiological and unperturbed setting, father-to-offspring transfer of sperm mt-tsRNAs at fertilisation.
2024-04-03 | GSE239810 | GEO
Project description:Spermatozoa deliver a complex and environment sensitive pool of small non-coding RNAs (sncRNA) to the oocyte at fertilisation, which influences offspring development and adult phenotypic trajectories. Whether mature spermatozoa in the epididymis can directly sense the environment is still not fully understood. Here, we used two distinct paradigms of preconception acute High Fat Diet challenge to dissect epididymal vs spermatogenic contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNA fragments as sperm-born sensors. In human spermatozoa, we found mt-tsRNAs in linear association with BMI and showed that paternal overweight at conception is sufficient to double offspring obesity risk and compromise metabolic health. Using mouse genetics and metabolic phenotypic data, we show that alterations of mt-tsRNAs are downstream of mitochondrial dysfunction in mice. Most importantly, single embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tsRNAs at fertilisation and implied them in the control of early embryo metabolism. Our study supports the importance of paternal health at conception for offspring metabolism, propose mt-tsRNAs as sperm-born environmental effectors of paternal inheritance and demonstrate, for the first time in a physiological and unperturbed setting, father-to-offspring transfer of sperm mt-tsRNAs at fertilisation.
2024-04-03 | GSE239807 | GEO