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Sperm miRNAs as Potential Mediators ...

Dickson, David Alec.

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Sperm miRNAs as Potential Mediators of the Transgenerational Effects of Stress.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Sperm miRNAs as Potential Mediators of the Transgenerational Effects of Stress./
Author:	Dickson, David Alec.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	141 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
Contained By:	Dissertations Abstracts International81-04B.
Subject:	Neurosciences. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13862639
ISBN:	9781687911209

Sperm miRNAs as Potential Mediators of the Transgenerational Effects of Stress.
Dickson, David Alec.

Sperm miRNAs as Potential Mediators of the Transgenerational Effects of Stress. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 141 p.

Source: Dissertations Abstracts International, Volume: 81-04, Section: B.

Thesis (Ph.D.)--Tufts University-Graduate School of Biomedical Sciences, 2021.

This item must not be sold to any third party vendors.

Recent studies in rodents suggest that epigenetic inheritance of the effect of paternal life experiences is a factor to consider in understanding susceptibility to psychological disorders. Many epigenetic mechanisms involved in this process have been proposed, and the most convincing evidence implicates small non-coding RNA molecules, such as microRNAs, in this process. According to this model, microRNAs are delivered by sperm to zygotes upon fertilization, where they are required for normal mouse embryonic development, and stress-induced increases in sperm miRNAs have been shown to promote altered behaviors in their future offspring, sometimes in a sex-dependent manner. Our studies use a mouse model of Chronic Social Instability (CSI) stress, where mating stressed male mice to control females results in anxiety and defective social interactions specifically in female offspring across at least three generations.My thesis has implicated specific sperm miRNAs, miR-409-3p, miR-34c, and miR-449a, in the transmission of the effects of stress across generations. miR-409-3p was first implicated because its levels are significantly increased not only in the sperm of CSI stressed F0 males, but also their F1 and F2 male offspring that transmit stress phenotypes to their female offspring. Moreover, manipulations of miR-409-3p levels in early embryos implicate it in establishing baseline anxiety levels in adult females, but not males. In contrast, both miR-34c and miR-449a levels are significantly decreased in the sperm of stressed males and their sons. Strikingly they are also reduced in the sperm of men exposed to high levels of adverse childhood experiences (ACEs) that correlate with elevated risk for future psychiatric disorders. In our mouse model, the decreased expression of miR-34c and miR-449a is maintained into early embryos from stressed fathers, where knockouts of both miRNAs, but not individually, are known to alter brain development and spermatogenesis in mice. RNA sequencing of early mouse embryos derived from stressed fathers revealed possible mediators of these phenotypes, some of which may be attributed to these implicated miRNAs.This work is the first to demonstrate altered sperm miRNA profiles in men exposed to early life stress, and has begun to elucidate the mechanisms underlying the inheritance of stress, helping to further understand mental health risk. Considering that women are at an increased risk for many psychiatric disorders, these studies may have begun uncovering a novel sex-specific mechanism leading to the development of mental health disorders in adults.

ISBN: 9781687911209Subjects--Topical Terms:

588700
Neurosciences.
Subjects--Index Terms:

Epigenetics

Sperm miRNAs as Potential Mediators of the Transgenerational Effects of Stress.
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245 1 0 $a Sperm miRNAs as Potential Mediators of the Transgenerational Effects of Stress.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2021
300 $a 141 p.
500 $a Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
500 $a Advisor: Feig, Larry A.
502 $a Thesis (Ph.D.)--Tufts University-Graduate School of Biomedical Sciences, 2021.
506 $a This item must not be sold to any third party vendors.
520 $a Recent studies in rodents suggest that epigenetic inheritance of the effect of paternal life experiences is a factor to consider in understanding susceptibility to psychological disorders. Many epigenetic mechanisms involved in this process have been proposed, and the most convincing evidence implicates small non-coding RNA molecules, such as microRNAs, in this process. According to this model, microRNAs are delivered by sperm to zygotes upon fertilization, where they are required for normal mouse embryonic development, and stress-induced increases in sperm miRNAs have been shown to promote altered behaviors in their future offspring, sometimes in a sex-dependent manner. Our studies use a mouse model of Chronic Social Instability (CSI) stress, where mating stressed male mice to control females results in anxiety and defective social interactions specifically in female offspring across at least three generations.My thesis has implicated specific sperm miRNAs, miR-409-3p, miR-34c, and miR-449a, in the transmission of the effects of stress across generations. miR-409-3p was first implicated because its levels are significantly increased not only in the sperm of CSI stressed F0 males, but also their F1 and F2 male offspring that transmit stress phenotypes to their female offspring. Moreover, manipulations of miR-409-3p levels in early embryos implicate it in establishing baseline anxiety levels in adult females, but not males. In contrast, both miR-34c and miR-449a levels are significantly decreased in the sperm of stressed males and their sons. Strikingly they are also reduced in the sperm of men exposed to high levels of adverse childhood experiences (ACEs) that correlate with elevated risk for future psychiatric disorders. In our mouse model, the decreased expression of miR-34c and miR-449a is maintained into early embryos from stressed fathers, where knockouts of both miRNAs, but not individually, are known to alter brain development and spermatogenesis in mice. RNA sequencing of early mouse embryos derived from stressed fathers revealed possible mediators of these phenotypes, some of which may be attributed to these implicated miRNAs.This work is the first to demonstrate altered sperm miRNA profiles in men exposed to early life stress, and has begun to elucidate the mechanisms underlying the inheritance of stress, helping to further understand mental health risk. Considering that women are at an increased risk for many psychiatric disorders, these studies may have begun uncovering a novel sex-specific mechanism leading to the development of mental health disorders in adults.
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653 $a Chronic social instability
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