Paternal Stress Exposure Alters Sperm MicroRNA Content and Reprograms Offspring HPA Stress Axis Regulation
Open accessAbstract
Neuropsychiatric disease frequently presents with an underlying hyporeactivity or hyperreactivity of the HPA stress axis, suggesting an exceptional vulnerability of this circuitry to external perturbations. Parental lifetime exposures to environmental challenges are associated with increased offspring neuropsychiatric disease risk, and likely contribute to stress dysregulation. While maternal influences have been extensively examined, much less is known regarding the specific role of paternal factors. To investigate the potential mechanisms by which paternal stress may contribute to offspring hypothalamic–pituitary–adrenal (HPA) axis dysregulation, we exposed mice to 6 weeks of chronic stress before breeding. As epidemiological studies support variation in paternal germ cell susceptibility to reprogramming across the lifespan, male stress exposure occurred either throughout puberty or in adulthood. Remarkably, offspring of sires from both paternal stress groups displayed significantly reduced HPA stress axis responsivity. Gene set enrichment analyses in offspring stress regulating brain regions, the paraventricular nucleus (PVN) and the bed nucleus of stria terminalis, revealed global pattern changes in transcription suggestive of epigenetic reprogramming and consistent with altered offspring stress responsivity, including increased expression of glucocorticoid-responsive genes in the PVN. In examining potential epigenetic mechanisms of germ cell transmission, we found robust changes in sperm microRNA (miR) content, where nine specific miRs were significantly increased in both paternal stress groups. Overall, these results demonstrate that paternal experience across the lifespan can induce germ cell epigenetic reprogramming and impact offspring HPA stress axis regulation, and may therefore offer novel insight into factors influencing neuropsychiatric disease risk.
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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.
“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 [179]
The Discussion (page unavailable) reports that stress in male mice altered paternal germ cells and offspring HPA-axis regulation, supporting an effect on offspring stress circuitry. But it calls the exposure mild, not extreme; the sperm changes were measured in fathers, not offspring. The Results, “Analysis of offspring physiology & behavior” (page unavailable), found no paternal-stress effect on the behavioral tests reported. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThese mice (F0) demonstrated behavioral changes in response to the stressor, and also changes in several specific sperm microRNA.
“These mice (F0) demon-strated behavioral changes in response to the stressor, and also changes in several specific sperm microRNA.”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [179]
The Results section, “Analysis of sperm miR environment” (page unavailable), reports significant increases in nine specific sperm microRNAs in stressed males. The paper does not report behavioral changes in those F0 males in response to the stressors; its behavioral tests concern their offspring. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMales bred with naïve females produced offspring with blunted HPA axis responsivity as well as changes in transcription of GR genes in the paraventricular nucleus.
“Males were bred with naïve females and produced offspring with blunted HPA axis responsivity as well as changes in transcription of GR genes in the paraventricular nucleus 179”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [179]
The Breeding Scheme (Materials & Methods) says the males were bred with naïve females, and the Abstract reports reduced HPA stress responsivity in their offspring. The Discussion reports enriched expression of glucocorticoid receptor (GR)-responsive genes in the paraventricular nucleus, not a demonstrated change in transcription of GR genes themselves; the Brain Gene Expression Analysis (Results) says no single gene met its significance criteria. (LLM, conf=0.85)
Experimental — accuracy not yet measuredEnduring behavioral responses to stress and epigenetic alterations in adult offspring have been demonstrated to be mediated by changes in gametes, in utero effects, variations in early postnatal care, and/or other early life experiences influenced by parental exposure.
“Enduring behavioral responses to stress and epigenetic alterations in adult offspring have been demonstrated to be mediated by changes in gametes (10)(11)(12)(13), in utero effects (14), variations in early postnatal care (15,16), and/or other early life experiences (17) that are influenced by parental exposure (18).”
From Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation (2016) · cites this paper as [13]
Epigenetic effects in maternal or paternal gametes are a potential explanation for epigenetic effects in offspring, but blood samples will not permit ascertainment of gamete-dependent transmission.
“Epigenetic effects in maternal or paternal gametes are a potential explanation for epigenetic effects in offspring (10-13), but blood samples will not permit ascertainment of gamete-dependent transmission.”
From Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation (2016) · cites this paper as [13]
Among 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 [179]
The compelling data demonstrating heritable epigenetic alterations come from animal models.
“Still, the compelling data demonstrating heritable epigenetic alterations come from animal models 179,181”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [179]
In a different paradigm, two groups of male mice were exposed to a wide range of stressors over 42 days at puberty or adulthood.
“two groups of male mice were exposed to a wide range of stressors over 42 days at puberty or adulthood 179”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [179]
In this study, although significant sex differences were noted in endocrine and behavioral measures, there was no interaction between sex and paternal stress in the offspring of those exposed at puberty or adulthood.
“Although significant sex differences were noted in endocrine and behavioral measures, there was no interaction between sex and paternal stress in the offspring of those exposed at puberty or adulthood.”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [179]
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- Authors
- Rodgers, A. B., Morgan, C. P., Bronson, S. L., Revello, S., & Bale, T. L.
- Affiliations
- University of Pennsylvania (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-05-22
- Volume
- 33
- Issue
- 21
- Pages
- 9003-9012
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3712504
- OpenAlex
- W1986062308
- Cited by
- 814
- References
- 69
- Citations by year
- 2026: 39 · 2025: 34 · 2024: 45 · 2023: 58 · 2022: 48 · 2021: 67 · 2020: 107 · 2019: 66 · 2018: 77 · 2017: 71 · 2016: 74 · 2015: 71 · 2014: 40 · 2013: 15
- FWCI
- 29.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01mh091258-05, MH099910, MH091258)
- National Institute of Mental Health (P50MH099910, R37MH108286, MH087597, MH 091258, MH099910, R01 MH-091258, R01MH087597)
- National Institute of General Medical Sciences (T32GM007517)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- sperm microRNA, hypothalamic-pituitary-adrenal axis, chronic stress, paraventricular nucleus, bed nucleus of the stria terminalis, glucocorticoid-responsive genes
- MeSH terms
- Acoustic Stimulation, Adaptation, Ocular, Analysis of Variance, Animals, Animals, Newborn, Disease Models, Animal, Female, Gene Expression Regulation, Hypothalamo-Hypophyseal System, Male, Mice, Inbred C57BL, Pituitary-Adrenal System, Pregnancy, Prenatal Exposure Delayed Effects, Sex Factors, Spermatozoa, Reflex, Startle, Stress, Psychological, Citalopram, Selective Serotonin Reuptake Inhibitors, Maze Learning, Hindlimb Suspension, MicroRNAs, Mice
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