Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring
Open accessAbstract
Recent studies have suggested that physiological and behavioral traits may be transgenerationally inherited through the paternal lineage, possibly via non-genomic signals derived from the sperm. To investigate how paternal stress might influence offspring behavioral phenotypes, a model of hypothalamic–pituitary–adrenal (HPA) axis dysregulation was used. Male breeders were administered water supplemented with corticosterone (CORT) for 4 weeks before mating with untreated female mice. Female, but not male, F1 offspring of CORT-treated fathers displayed altered fear extinction at 2 weeks of age. Only male F1 offspring exhibited altered patterns of ultrasonic vocalization at postnatal day 3 and, as adults, showed decreased time in open on the elevated-plus maze and time in light on the light–dark apparatus, suggesting a hyperanxiety-like behavioral phenotype due to paternal CORT treatment. Interestingly, expression of the paternally imprinted gene Igf2 was increased in the hippocampus of F1 male offspring but downregulated in female offspring. Male and female F2 offspring displayed increased time spent in the open arm of the elevated-plus maze, suggesting lower levels of anxiety compared with control animals. Only male F2 offspring showed increased immobility time on the forced-swim test and increased latency to feed on the novelty-supressed feeding test, suggesting a depression-like phenotype in these animals. Collectively, these data provide evidence that paternal CORT treatment alters anxiety and depression-related behaviors across multiple generations. Analysis of the small RNA profile in sperm from CORT-treated males revealed marked effects on the expression of small noncoding RNAs. Sperm from CORT-treated males contained elevated levels of three microRNAs, miR-98, miR-144 and miR-190b, which are predicted to interact with multiple growth factors, including Igf2 and Bdnf. Sustained elevation of glucocorticoids is therefore involved in the transmission of paternal stress-induced traits across generations in a process involving small noncoding RNA signals transmitted by the male germline.
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Subsequent progeny (F2) of corticosterone-exposed male mice had reduced anxiety but an increase in depressive behaviors.
“This also resulted in subsequent progeny (F2) with reduced anxiety but an increase in depressive behaviors [77,78,79,81].”
From Biological Embedding of Early-Life Adversity and a Scoping Review of the Evidence for Intergenerational Epigenetic Transmission of Stress and Trauma in Humans (2023) · cites this paper as [81]
The F2 Results report increased open-arm time in both female and male offspring, consistent with reduced anxiety. Increased forced-swim immobility and latency to feed were found only in F2 males; F2 females showed no significant differences on those measures. The claim omits that sex-specific limit on the depressive behaviors. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCorticosterone administration in adult male mice resulted in male pups (F1) displaying a hyper-anxiety phenotype.
“A similar study investigated corticosterone administration in adult male mice, and male pups (F1) displayed a hyper-anxiety phenotype [81].”
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- Authors
- Short, A. K., Fennell, K. A., Perreau, V. M., Fox, A., O’Bryan, M. K., Kim, J. H., Bredy, T. W., Pang, T. Y., & Hannan, A. J.
- Affiliations
- The University of Melbourne (AU)
- Monash University (AU)
- The University of Queensland (AU)
- Corresponding author
- Pang, T Y
- Venue
- Translational Psychiatry
- Published
- 2016-06-14
- Volume
- 6
- Issue
- 6
- Pages
- e837-e837
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC4931607
- OpenAlex
- W2443212980
- Cited by
- 230
- References
- 89
- Citations by year
- 2026: 15 · 2025: 13 · 2024: 29 · 2023: 37 · 2022: 24 · 2021: 27 · 2020: 23 · 2019: 23 · 2018: 19 · 2017: 17 · 2016: 2
- FWCI
- 12.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Funders
- State Government of Victoria
- National Health and Medical Research Council (FT100100835, 1083468)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- corticosterone, transgenerational epigenetic inheritance, microRNA, miR-98, miR-144, insulin-like growth factor II, brain-derived neurotrophic factor, anxiety-like behavior, depression-like behavior, fear extinction, ultrasonic vocalizations, HPA axis dysregulation, paternal stress, germline transmission, hippocampus
- MeSH terms
- Animals, Anxiety, Corticosterone, Depression, Exons, Fear, Female, Hypothalamo-Hypophyseal System, Insulin-Like Growth Factor II, Male, Mice, Inbred C57BL, Phenotype, Pituitary-Adrenal System, Pregnancy, Sex Factors, Spermatozoa, Gene Expression, Maze Learning, Paternal Exposure, Brain-Derived Neurotrophic Factor, MicroRNAs, RNA, Small Untranslated
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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