Cited by 230Stress Responses and CortisolSperm and Testicular FunctionGenetic Syndromes and Imprinting

Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring

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Short, A K, Fennell, K A, Perreau, V M, Fox, A, O’Bryan, M K, Kim, J H, Bredy, T W, Pang, T Y +1 more·2016·Translational Psychiatry

Abstract

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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  1. Wheatley D. Stress, anxiety and depression. Stress Med 1997; 13: 173–177.
  2. Gourley SL, Kiraly DD, Howell JL, Olausson P, Taylor JR. Acute hippocampal BDNF restores motivational and forced swim performance after corticosterone. Biol Psychiatry 2008; 64: 884–890. 18675955 PMC2633780

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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)
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
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

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