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Cited by 212Sperm and Testicular FunctionMicroRNA in disease regulationEpigenetics and DNA Methylation

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Reduced levels of miRNAs 449 and 34 in sperm of mice and men exposed to early life stress

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Dickson, David A., Paulus, Jessica K., Mensah, Virginia, Lem, Janis, Saavedra-Rodriguez, Lorena, Gentry, Adrienne, Pagidas, Kelly, Feig, Larry A.·2018·Translational Psychiatry
DOI 10.1038/s41398-018-0146-2PMC PMC5966454
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Abstract

Exposure of male mice to early life stress alters the levels of specific sperm miRNAs that promote stress-associated behaviors in their offspring. To begin to evaluate whether similar phenomena occur in men, we searched for sperm miRNA changes that occur in both mice and men exposed to early life stressors that have long-lasting effects. For men, we used the Adverse Childhood Experience (ACE) questionnaire. It reveals the degree of abusive and/or dysfunctional family experiences when young, which increases risks of developing future psychological and physical disorders. For male mice, we used adolescent chronic social instability (CSI) stress, which not only enhances sociability defects for >1 year, but also anxiety and defective sociability in female offspring for multiple generations through the male lineage. Here we found a statistically significant inverse correlation between levels of multiple miRNAs of the miR-449/34 family and ACE scores of Caucasian males. Remarkably, we found members of the same sperm miRNA family are also reduced in mice exposed to CSI stress. Thus, future studies should be designed to directly test whether reduced levels of these miRNAs could be used as unbiased indicators of current and/or early life exposure to severe stress. Moreover, after mating stressed male mice, these sperm miRNA reductions persist in both early embryos through at least the morula stage and in sperm of males derived from them, suggesting these miRNA changes contribute to transmission of stress phenotypes across generations. Since offspring of men exposed to early life trauma have elevated risks for psychological disorders, these findings raise the possibility that a portion of this risk may be derived from epigenetic regulation of these sperm miRNAs.

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Fig. 1 Decreased sperm miRNA expression in men with extensive adverse childhood experiences. a qPCR analysis of miR-449a, miR-449b-5p, miR-34b-3p, miR-34c-5p, miR-152-3p, and miR-375-3p in sperm RNA from low ACE group (score 0–1, n = 5) vs. high ACE group (score >4, n = 5). Wilcoxon rank-sum test *P < 0.05, **P < 0.01. Data represented as mean ± SEM. b–c Correlation plot comparing relative expression of miR-449a to miR-449b (b) and miR-34b to miR-34c (c) for individual samples fitted with single-variable linear regression. n = 10, r = Spearman’s coefficient with exact p value listed. Each point represents an individual sample
Fig. 1 Decreased sperm miRNA expression in men with extensive adverse childhood experiences. a qPCR analysis of miR-449a, miR-449b-5p, miR-34b-3p, miR-34c-5p, miR-152-3p, and miR-375-3p in sperm RNA from low ACE group (score 0–1, n = 5) vs. high ACE group (score >4, n = 5). Wilcoxon rank-sum test *P < 0.05, **P < 0.01. Data represented as mean ± SEM. b–c Correlation plot comparing relative expression of miR-449a to miR-449b (b) and miR-34b to miR-34c (c) for individual samples fitted with single-variable linear regression. n = 10, r = Spearman’s coefficient with exact p value listed. Each point represents an individual sampleCC BY · PubMed Central
Fig. 2 ACE score negatively correlates with expression of miR-449a and miR-34c in 28 human sperm samples. a–b qPCR analysis of miR-449a, miR-34c-5p, miR-152-3p, and miR-375-3p in all samples, normalized to the overall average expression to generate a relative expression value. Trend lines represent single-variable linear regression. n = 28, r = Spearman’s coefficient, with p values listed. Each point represents an individual sample. c Correlation plot comparing miR-449a expression to miR-34c expression in individual samples fitted with single-variable linear regression. r = Spearman’s coefficient, with exact p value listed. d–e qPCR analysis of miR-152-3p and miR-375-3p, data analyzed as in a, b
Fig. 2 ACE score negatively correlates with expression of miR-449a and miR-34c in 28 human sperm samples. a–b qPCR analysis of miR-449a, miR-34c-5p, miR-152-3p, and miR-375-3p in all samples, normalized to the overall average expression to generate a relative expression value. Trend lines represent single-variable linear regression. n = 28, r = Spearman’s coefficient, with p values listed. Each point represents an individual sample. c Correlation plot comparing miR-449a expression to miR-34c expression in individual samples fitted with single-variable linear regression. r = Spearman’s coefficient, with exact p value listed. d–e qPCR analysis of miR-152-3p and miR-375-3p, data analyzed as in a, bCC BY · PubMed Central
Fig. 3 miR-449a and miR-34c are downregulated in sperm across generations and in early embryos derived from them in a mouse model of early life stress. a qPCR analysis of miR-449a, miR-34c-5p, miR-152-3p, and miR-375-3p in pooled mature motile sperm isolated from stressed or control mice, n = 4–6 males per pool, 1 pool per group. b–c qPCR analysis of miR-449a (b), miR-34c-5p (c) in pooled F1 embryos derived from mating control females with stressed or unstressed males. Embryos for each group of fathers and cell stage were pooled prior to analysis (n = 30–60 embryos per pool), 1 pool per group. d Same analysis as (a) performed on sperm from offspring of control and stressed fathers. All samples were pooled before triplicate qPCR analysis, presented as fold change (mean ± experimental error) normalized to a F0 control, b 2-cell control, c 2-cell control, d F0 control
Fig. 3 miR-449a and miR-34c are downregulated in sperm across generations and in early embryos derived from them in a mouse model of early life stress. a qPCR analysis of miR-449a, miR-34c-5p, miR-152-3p, and miR-375-3p in pooled mature motile sperm isolated from stressed or control mice, n = 4–6 males per pool, 1 pool per group. b–c qPCR analysis of miR-449a (b), miR-34c-5p (c) in pooled F1 embryos derived from mating control females with stressed or unstressed males. Embryos for each group of fathers and cell stage were pooled prior to analysis (n = 30–60 embryos per pool), 1 pool per group. d Same analysis as (a) performed on sperm from offspring of control and stressed fathers. All samples were pooled before triplicate qPCR analysis, presented as fold change (mean ± experimental error) normalized to a F0 control, b 2-cell control, c 2-cell control, d F0 controlCC BY · PubMed Central

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Metadata

Authors
Dickson, D. A., Paulus, J. K., Mensah, V., Lem, J., Saavedra-Rodriguez, L., Gentry, A., Pagidas, K., & Feig, L. A.
Affiliations
  • Tufts University (US)
  • Brown University (US)
  • Tufts Medical Center (US)
  • University of Louisville (US)
Corresponding author
Feig, Larry A.
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2018-05-23
Volume
8
Issue
1
Pages
101-101
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-018-0146-2
PMC
PMC5966454
OpenAlex
W2803802792
Cited by
208
References
41
Citations by year
2026: 11 · 2025: 20 · 2024: 16 · 2023: 61 · 2022: 16 · 2021: 25 · 2020: 27 · 2019: 28 · 2018: 4
FWCI
22.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institutes of Health
  • Center for Neuroscience Research (P30 NS047243)
  • National Institute of Mental Health (R01MH107536)
  • National Institute of Neurological Disorders and Stroke (P30NS047243)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
sperm microRNA, miR-449, miR-34, early life stress, adverse childhood experiences, epigenetic regulation, sociability, anxiety, male fertility, embryonic development, stress biomarkers
MeSH terms
Adult Survivors of Child Adverse Events, Adult, Animals, Humans, Male, Spermatozoa, Stress, Psychological, MicroRNAs, White People, Mice

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