Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice
Open accessAbstract
Small non-coding RNAs (sncRNAs) are potential vectors at the interface between genes and environment. We found that traumatic stress in early life altered mouse microRNA (miRNA) expression, and behavioral and metabolic responses in the progeny. Injection of sperm RNAs from traumatized males into fertilized wild-type oocytes reproduced the behavioral and metabolic alterations in the resulting offspring.
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Childhood maltreatment, including abuse and neglect, represents a sustained early-life stressor associated with long-term biological and behavioral changes across generations.
“Childhood maltreatment, including abuse and neglect, represents a sustained early-life stressor associated with long-term biological and behavioral changes across generations.”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [116]
The Abstract reports that early-life traumatic stress altered biological measures and behavioral responses across generations in mice. The study used unpredictable maternal separation and maternal stress; it does not establish that human childhood maltreatment, including abuse and neglect, has those cross-generational effects. No page number is available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEvidence suggests involvement of stress-response regulation, neurodevelopmental and emotional processing pathways, and epigenetic remodeling processes in shaping intergenerational outcomes.
“Evidence suggests involvement of stress-response regulation, neurodevelopmental and emotional processing pathways, and epigenetic remodeling processes in shaping intergenerational outcomes (116–124).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [116]
The paper’s account of the mouse experiments (indexed under Abstract; page not given) reports stress-related miRNA regulation and inherited changes in fear, aversion, and depressive-like behavior. It also supports a role for sperm RNAs in transmission, but does not establish neurodevelopmental pathways or epigenetic remodeling as mechanisms shaping those outcomes. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn animal studies using the maternal separation with unpredictable stress (MSUS) paradigm, exposed males demonstrated alterations in sperm small and long noncoding RNAs.
“In animal studies using the maternal separation with unpredictable stress (MSUS) paradigm, exposed males demonstrated alterations in sperm small and long noncoding RNAs (116, 117).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [116]
The paper reports that F1 males exposed to MSUS had altered sperm small noncoding RNAs, including miRNAs and piRNAs (passage [3], section labeled Abstract; page unavailable). It does not report alterations in sperm long noncoding RNAs, so that part of the claim is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAnimal models have demonstrated epigenetic remodeling of stress-related genes and histone acetylation patterns in brain regions involved in emotional regulation following early-life stress.
“Animal models have also demonstrated epigenetic remodeling of stress-related genes and histone acetylation patterns in brain regions involved in emotional regulation following early-life stress (116, 117).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [116]
The indexed passage labeled Abstract (page not provided) reports altered miRNA expression after early-life trauma and decreased expression of a stress-pathway protein in the hippocampus of offspring. This supports stress-related molecular changes in a brain region, but the paper does not report histone acetylation patterns or establish the broader claim of epigenetic remodeling of stress-related genes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA few studies have shown environmentally driven changes in the epigenetic landscape via histone modifications and long noncoding RNAs.
“Nonetheless, a few studies have shown environmentally driven changes of the epigenetic landscape in other ways, such as via histone modifications and long noncoding RNAs.”
From Epigenetics and depression (2019) · cites this paper as [63]
The Abstract (page not provided) reports that early-life traumatic stress in mice altered microRNA expression, supporting an environmentally driven change involving noncoding RNAs. It identifies these as small noncoding RNAs, not long noncoding RNAs, and does not report an environmentally driven histone modification; histones appear only in the References. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Studies of environmentally driven histone modifications and long noncoding RNAs have almost exclusively been done in animal models, with a few exceptions in human cohorts.
“This has almost exclusively been done in animal models, 63 , 64 , 65 , 66 with a few exceptions of studies in human cohorts. 67”
From Epigenetics and depression (2019) · cites this paper as [63]
The Abstract (page not supplied) describes a mouse study in which early-life traumatic stress altered small non-coding RNAs, so this paper supports its use as an example of animal-model research on environmentally driven RNA changes. It does not study long noncoding RNAs or environmentally driven histone modifications, and it does not establish that such studies have been conducted almost exclusively in animals. The human-cohort exception is attached to a different citation in the citing sentence. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAmong epigenetic mechanisms implicated in paternal transmission of stress effects via sperm are DNA methylation, oxidative damage to sperm DNA, histone modifications, and changes in small noncoding RNA including microRNA.
“Among the epigenetic mechanisms that have been implicated in paternal transmission of stress effects via sperm are DNA methylation, oxidative damage to sperm DNA, histone modifications, and changes in small noncoding RNA [175][176][177][178][179] , including microRNA 180,181”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [176]
The paper’s Abstract reports altered sperm small noncoding RNAs, including microRNAs, after early-life trauma in mice, and sperm-RNA injection reproduced effects in offspring. It mentions DNA methylation and histone modifications only as possible later mechanisms, not as demonstrated mechanisms in this study. Our copy does not support the attributed role of oxidative damage to sperm DNA. (LLM, conf=0.88)
Experimental — accuracy not yet measuredF3 offspring of these animals continued to show phenotypic differences, indicating conservation of stress effects through sperm.
“Furthermore, F3 offspring of these animals continued to show phenotypic differences, indicating conservation of stress effects through sperm.”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [176]
The paper states that F3 MSUS mice had behavioral symptoms similar to F1 and F2 mice (passage [3], section labeled Abstract; page unavailable). It does not establish that sperm carried the effects into F3: it reports normal sperm miRNA levels in F2 males and proposes other epigenetic marks as a possible means of further transmission. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSuch studies have produced very compelling data suggesting that exposure to extreme stress in males can affect brain, behavior and sperm in the next generation.
“Such studies have produced very compelling data suggesting that exposure to extreme stress in males can affect brain, behavior and sperm in the next generation 176,179”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [176]
The paper reports altered behavior and hippocampal miRNAs in F2 offspring of mice exposed to early-life traumatic stress. It also reports altered sperm miRNAs in the stressed F1 males, but says miRNAs were not altered in F2 sperm; thus it does not support the claim that sperm was affected in the next generation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWhen altered microRNAs from sperm of stressed males were injected into fertilized wild-type oocytes, comparable behavioral, metabolic and molecular outcomes were observed in the F2 offspring, indicating transmission of epigenetic marks.
“When altered microRNAs from sperm of the stressed males were injected into fertilized wild-type oocytes, comparable behavioral, metabolic and molecular outcomes were observed in the F2 offspring, indicating transmission of epigenetic marks.”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [176]
The injection-results passage (labeled Abstract in our copy) reports comparable behavioral, metabolic and molecular effects in animals produced by injecting sperm RNAs from stressed males into fertilized wild-type oocytes. The Methods specify that the injected material was total sperm RNA, not isolated altered microRNAs. The passage reports depressive-like behavior in the injected animals’ offspring, but does not report the full set of comparable outcomes in those offspring; it also does not identify the injected animals as F2. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAn independent research team demonstrated that small non-coding RNAs (sncRNAs), common in sperm, can mediate inheritance of environmentally acquired traits or phenotypes in mice.
“An independent research team also demonstrated that small non-coding RNAs (sncRNAs), common in sperm, can mediate inheritance of environmentally acquired traits or phenotypes in mice 176”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [176]
The Abstract reports that sperm RNAs from mice exposed to early-life trauma reproduced behavioral and metabolic changes when injected into fertilized oocytes, and says the results strongly suggest sncRNAs contribute to inheritance. But the Methods (RNAs injection in fertilized oocytes; page not provided) specify that the injected material was total sperm RNA, not isolated sncRNAs. The claim therefore overstates direct demonstration of sncRNA mediation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredEarly life stress, modeled by unpredictable maternal separation and maternal stress, led to depressive-like behavioral patterns upon exposure to novel environments and changes in sncRNAs in F1 sperm.
“early life stress, modeled by unpredictable maternal separation and maternal stress, led to depressive-like behavioral patterns upon exposure to novel environments and changes in sncRNAs in F1 sperm.”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [176]
The paper reports that F1 mice exposed to unpredictable maternal separation and maternal stress showed depressive-like behavior on the forced swim test, and that several sncRNAs changed in F1 sperm. It does not describe the response to an unfamiliar space on the elevated plus maze as depressive-like; it interprets that result as reduced avoidance and fear (behavioral-results passage [1]; sperm-RNA passage [3], both labeled Abstract in our copy). (LLM, conf=0.83)
Experimental — accuracy not yet measuredSimilar RNA changes were detected in offspring tissues, including brain and serum.
“Similar RNA changes were detected in offspring tissues, including brain and serum (116).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [116]
Behavioral and metabolic phenotypes were observed in subsequent generations, and injection of sperm RNA from exposed males into naive zygotes reproduced several of these features.
“Behavioral and metabolic phenotypes were observed in subsequent generations, and injection of sperm RNA from exposed males into naive zygotes reproduced several of these features (116, 117).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [116]
Injection of sperm RNAs from traumatized males into fertilized wild-type oocytes reproduced the alterations in the resulting offspring.
“Gapp et al.9 found that traumatic stress in early life altered behavioral and metabolic processes in the progeny and that injection of sperm RNAs from traumatized males into fertilized wild-type oocytes reproduced the alterations in the resulting offspring.”
From A critical view on transgenerational epigenetic inheritance in humans (2018) · cites this paper as [9]
Gapp et al. found that traumatic stress in early life altered behavioral and metabolic processes in the progeny.
“Gapp et al.9 found that traumatic stress in early life altered behavioral and metabolic processes in the progeny and that injection of sperm RNAs from traumatized males into fertilized wild-type oocytes reproduced the alterations in the resulting offspring.”
From A critical view on transgenerational epigenetic inheritance in humans (2018) · cites this paper as [9]
Research on possible intergenerational transmission of stress effects through epigenetic marks in sperm has been conducted in rodents, and includes preconception exposures at various developmental stages to stressful and adverse social experiences.
“Research on possible intergenerational transmission of stress effects through epigenetic marks in sperm has been conducted in rodents, and includes preconception exposures at various developmental stages to stressful and adverse social experiences 149,175,176,179,181,203,204”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [176]
F0 exposed to several unpredictable maternal stressors and separation demonstrated changes that could be observed across two generations.
“F0 exposed to several unpredictable maternal stressors and separation demonstrated changes that could be observed across two generations 176”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [176]
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“Similar RNA changes were detected in offspring tissues, including brain and serum (116).”
Influential
- Authors
- Gapp, K., Jawaid, A., Sarkies, P., Bohacek, J., Pelczar, P., Prados, J., Farinelli, L., Miska, E., & Mansuy, I. M.
- Affiliations
- University of Zurich (CH)
- The Gurdon Institute (GB)
- Corresponding author
- Mansuy, Isabelle M
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2014-04-13
- Volume
- 17
- Issue
- 5
- Pages
- 667-669
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4333222
- OpenAlex
- W1976684529
- Cited by
- 1,306
- References
- 31
- Citations by year
- 2026: 59 · 2025: 83 · 2024: 80 · 2023: 99 · 2022: 128 · 2021: 104 · 2020: 155 · 2019: 102 · 2018: 140 · 2017: 102 · 2016: 106 · 2015: 90 · 2014: 55
- FWCI
- 48.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Apollo (University of Cambridge) (acceptedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Wellcome Trust (092096)
- Cancer Research UK (11832)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- sperm RNA, transgenerational inheritance, early life stress, microRNA, small RNA, epigenetic inheritance, behavior change, metabolic changes, oocyte injection, mice
- MeSH terms
- Animals, Animals, Newborn, Energy Intake, Dark Adaptation, Disease Models, Animal, Female, Gene Expression Regulation, Male, Maternal Deprivation, Mice, Inbred C57BL, Oocytes, Reaction Time, Spermatozoa, Stress, Psychological, Maze Learning, RNA, Small Interfering, MicroRNAs, Cell Line, Tumor, Mice, RNA, Small Untranslated
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