MicroRNAs in aged sperm confer psychiatric symptoms to offspring through causing the dysfunction of estradiol signaling in early embryos.
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ABSTRACT:
SUBMITTER: Liang G
PROVIDER: S-EPMC9256735 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Parental age at first pregnancy is increasing worldwide. The offspring of aged father has been associated with higher risk of several neuropsychiatric disorders, such as schizophrenia and autism, but the underlying mechanism remains elusive. Here we report that advanced paternal age in mice alters the profile of transfer RNA-derived small RNAs (tsRNAs). Injection of sperm tsRNAs from aged male mice into zygotes induced anxiety-like behaviors in F1 males. RNA sequencing of the cerebral cortex and hippocampus of those F1 male mice altered the gene expression of dopaminergic synapse and neurotrophin. tsRNAs from aged male mice injection also altered the neuropsychiatry-related gene expression in two-cell and blastocyst stage embryos. More importantly, the sperm tsRNA profile changes significantly during aging in human. The up-regulated sperm tsRNA target genes were involved in neurogenesis and nervous system development. These results suggest that aging-related changes of sperm tsRNA may contribute to the intergenerational transmission of behavioral traits.
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Project description:OBJECTIVE:Maternal infection during pregnancy has been associated with increased risk of offspring psychopathology, including depression. As most infections do not cross the placenta, maternal immune responses to infection have been considered as potentially contributing to this relationship. This study examined whether gestational timing of maternal inflammation during pregnancy is associated with offspring internalizing and/or externalizing symptoms during childhood and, further, whether fetal sex moderated this relationship. METHOD:Participants were 737 pregnant women and their offspring who were continuously followed through late childhood. Archived first and second trimester sera were analyzed for markers of inflammation [interleukin 8 (IL-8), IL-6, IL-1 receptor antagonist (IL-1ra), and soluble tumor necrosis factor receptor-II (sTNF-RII)]. When offspring were aged 9-11, mothers completed a questionnaire assessing psychological symptoms. RESULTS:Multivariate regression analyses indicated that elevated IL-8 in the first trimester was associated with significantly higher levels of externalizing symptoms in offspring. Higher IL-1ra in the second trimester was associated with higher offspring internalizing symptoms. Further, second trimester IL-1ra was associated with increased internalizing symptoms in females only. CONCLUSION:These findings demonstrate that elevated maternal inflammation during pregnancy is associated with the emergence of separate psychological phenotypes and that timing of exposure and fetal sex matter for offspring outcomes. Given that internalizing and externalizing symptoms in childhood increase risk for a variety of mental disorders later in development, these findings potentially have major implications for early intervention and prevention work.
| S-EPMC6644717 | biostudies-literature
Project description:Endocrine disrupting chemicals (EDC) interfere with the natural hormone balance and may induce epigenetic changes through exposure during sensitive periods of development. In this study, the effects of short-term estradiol-17? (E2) exposure on various tissues of pregnant sows (F0) and on day 10 blastocysts (F1) were assessed. Intergenerational effects were investigated in the liver of 1-year old female offspring (F1). During gestation, sows were orally exposed to two low doses and a high dose of E2 (0.05, 10, and 1000?µg/kg body weight/day). In F0, perturbed tissue specific mRNA expression of cell cycle regulation and tumour suppressor genes was found at low and high dose exposure, being most pronounced in the endometrium and corpus luteum. The liver showed the most significant DNA hypomethylation in three target genes; CDKN2D, PSAT1, and RASSF1. For CDKN2D and PSAT1, differential methylation in blastocysts was similar as observed in the F0 liver. Whereas blastocysts showed hypomethylation, the liver of 1-year old offspring showed subtle, but significant hypermethylation. We show that the level of effect of estrogenic EDC, with the periconceptual period as a sensitive time window, is at much lower concentration than currently presumed and propose epigenetics as a sensitive novel risk assessment parameter.
| S-EPMC5945594 | biostudies-literature
Project description:Estradiol (E2) regulates gene expression at the transcriptional level by functioning as a ligand for estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). E2-inducible proteins c-Myc and E2Fs are required for optimal ERalpha activity and secondary estrogen responses, respectively. We show that E2 induces 21 microRNAs and represses seven microRNAs in MCF-7 breast cancer cells; these microRNAs have the potential to control 420 E2-regulated and 757 non-E2-regulated mRNAs at the post-transcriptional level. The serine/threonine kinase, AKT, alters E2-regulated expression of microRNAs. E2 induced the expression of eight Let-7 family members, miR-98 and miR-21 microRNAs; these microRNAs reduced the levels of c-Myc and E2F2 proteins. Dicer, a ribonuclease III enzyme required for microRNA processing, is also an E2-inducible gene. Several E2-regulated microRNA genes are associated with ERalpha-binding sites or located in the intragenic region of estrogen-regulated genes. We propose that the clinical course of ERalpha-positive breast cancers is dependent on the balance between E2-regulated tumor-suppressor microRNAs and oncogenic microRNAs. Additionally, our studies reveal a negative-regulatory loop controlling E2 response through microRNAs as well as differences in E2-induced transcriptome and proteome.
| S-EPMC2724297 | biostudies-literature
Project description:Sperm cryopreservation is routinely used in reproductive medicine, livestock production and wildlife management. Its effect on offspring performance is often assumed to be negligible, but this still remains to be confirmed in well-controlled within-subject experiments. We use a vertebrate model that allows us to experimentally separate parental and environmental effects to test whether sperm cryopreservation influences offspring phenotype under stress and non-stress conditions, and whether such effects are male-specific. Wild brown trout (Salmo trutta) were stripped for their gametes, and a portion of each male's milt was cryopreserved. Then, 960 eggs were simultaneously fertilized with either non-cryopreserved or frozen-thawed semen and raised singly in the presence or absence of a pathogen. We found no significant effects of cryopreservation on fertilization rates, and no effects on growth, survival nor pathogen resistance during the embryo stage. However, fertilization by cryopreserved sperm led to significantly reduced larval growth after hatching. Males varied in genetic quality as determined from offspring performance, but effects of cryopreservation on larval growth were not male-specific. We conclude that cryopreservation causes a reduction in offspring growth that is easily overlooked because it only manifests itself at later developmental stages, when many other factors affect growth and survival too.
| S-EPMC6784727 | biostudies-literature
Project description:Zebrafish are a powerful model system to assess the molecular and cellular effects of exposure to toxic chemicals during embryonic development. To study the effects of environmental endocrine disruptors, embryos and larvae are commonly exposed to supraphysiologic concentrations of these compounds in the water, but their bioavailability in zebrafish is largely unknown. One hypothesis is that supraphysiologic concentrations of estrogens in the water are required to achieve physiologic levels in vivo; however, this has not been directly tested. To test this hypothesis, we developed an assay using radiolabeled estradiol ([3H]E2) to measure uptake from water at multiple concentrations and exposure durations in developing zebrafish from 0 to 5 days postfertilization (dpf). We found that [3H]E2 uptake increased with increasing concentration, duration, and developmental stage. Percent uptake from the total volume of treatment solution increased with increasing exposure duration and developmental stage, but remained constant with increasing concentration. We also found that the chorion, an acellular envelope surrounding embryos through 3 dpf, did not substantially affect [3H]E2 uptake. Finally, we found that at 1 dpf, E2 was preferentially taken up by the yolk at multiple exposure durations, while at 2 dpf E2 was preferentially taken up into the embryonic body. Our results support the hypothesis that exposing zebrafish embryos and larvae to supraphysiologic concentrations of estrogens is required to achieve physiologically relevant doses in vivo. The isotopic assay reported here will provide a foundation for determining the uptake of other compounds for teratogenicity, toxicology and drug discovery studies.
| S-EPMC5837308 | biostudies-literature
Project description:Although psychiatric problems are less prevalent in old age within the general population, it is largely unknown whether this extends to individuals with autism spectrum disorders (ASD). We examined psychiatric symptoms and disorders in young, middle-aged, and older adults with and without ASD (Nmax = 344, age 19-79 years, IQ > 80). Albeit comparable to other psychiatric patients, levels of symptoms and psychological distress were high over the adult lifespan; 79 % met criteria for a psychiatric disorder at least once in their lives. Depression and anxiety were most common. However, older adults less often met criteria for any psychiatric diagnosis and, specifically, social phobia than younger adults. Hence, despite marked psychological distress, psychiatric problems are also less prevalent in older aged individuals with ASD.
| S-EPMC4860203 | biostudies-literature
Project description:BackgroundSleep affects psychiatric health and perceived stress during adolescence.ObjectiveThe first aim of this study was to investigate the prevalence of poor sleep in a sample of Swedish adolescents aged 15 to 19 years. The second aim was to investigate correlations between: a) sleep and psychiatric symptoms and; b) sleep and perceived stress. The third aim was to examine possible sex differences in sleep.MethodIn 2011, a total of 185 Swedish adolescents (aged 15 to 19 years) from two upper secondary schools participated in this cross-sectional study. We used three different psychometric scales: Pittsburgh Sleep Quality Index (PSQI), Symptoms Checklist (SCL-90), and Perceived Stress Scale (PSS) to measure sleep, general psychiatric health and perceived stress.ResultsIn total, 76% of the female students and 71% of the male students had poor overall sleep quality. A large majority, 93%, reported daytime dysfunction and 60% reported problems staying awake during daily activities. The correlation between sleep and general psychiatric health was 0.44 and the correlation between sleep quality and perceived stress was 0.48. Female students reported significantly more sleep disturbances than male students do.ConclusionsThree out of four of the upper secondary school students presented with poor overall sleep that associated with psychiatric symptoms and perceived stress. These findings add to results from earlier studies and imply that interventions to improve sleep in adolescents, individually as well as on a societal level, should be considered as one way of trying to impact the observed rising numbers of psychiatric complaints. Such interventions may improve mental and somatic health in adolescents and prevent the development of psychiatric and stress-related symptoms. Further studies of possible methods, and their implementation, for improving sleep in adolescents should be of high priority.
| S-EPMC7685494 | biostudies-literature
Project description:BackgroundParental history of mood or anxiety disorders is one of the strongest and most consistent risk factors for the development of these disorders in offspring. Gaps remain however in our knowledge of whether maternal or paternal disorders are more strongly associated with offspring disorders, and whether the association exists in non-clinical samples. This study uses a large population-based sample to test if maternal or paternal history of mood and/or anxiety disorders increases the risk of mood and/or anxiety disorders, or symptoms of specific anxiety disorders, in offspring.MethodsData were drawn from the Nicotine Dependence in Teens Study, a prospective cohort investigation of 1293 grade 7 students. Data on mental health outcomes were collected in mailed self-report questionnaires when participants were aged 20.4 (0.7) years on average. Parental data were collected in mailed self-report questionnaires. This current analysis pertains to 564 participants with maternal and/or paternal data. The association between maternal and paternal history and each of diagnosed anxiety disorder, diagnosed mood disorder, and symptoms of specific anxiety disorders in offspring was studied in multivariate logistic regression.ResultsA higher proportion of mothers than fathers had a diagnosed mood/anxiety disorder (23% versus 12%). Similarly, 14% of female offspring had a diagnosed mood/anxiety disorder, compared to 6% of male offspring. The adjusted odds ratio (95% confidence interval) for maternal history was 2.2 (1.1, 4.5) for diagnosed mood disorders, 4.0 (2.1, 7.8) for diagnosed anxiety disorders, and 2.2 (1.2, 4.0) for social phobia symptoms. Paternal history was not associated with any of the mental health outcomes in offspring.ConclusionMaternal, but not paternal mood/anxiety disorders were associated with diagnosed psychiatric disorders, as well as symptoms of specific anxiety disorders, in offspring. Efforts to detect mood and anxiety disorders in offspring with a maternal history should be encouraged.
| S-EPMC3534519 | biostudies-literature
Project description:MicroRNAs (miRNAs), which are non-coding RNAs 18-25 nt in length, regulate a variety of biological processes, including vertebrate development. To identify new species of miRNA and to simultaneously obtain a comprehensive quantitative profile of small RNA expression in mouse embryos, we used the massively parallel signature sequencing technology that potentially identifies virtually all of the small RNAs in a sample. This approach allowed us to detect a total of 390 miRNAs, including 195 known miRNAs covering approximately 80% of previously registered mouse miRNAs as well as 195 new miRNAs, which are so far unknown in mouse. Some of these miRNAs showed temporal expression profiles during prenatal development (E9.5, E10.5 and E11.5). Several miRNAs were positioned in polycistron clusters, including one particular large transcription unit consisting of 16 known and 23 new miRNAs. Our results indicate existence of a significant number of new miRNAs expressed at specific stages of mammalian embryonic development and which were not detected by earlier methods.
| S-EPMC1421506 | biostudies-literature