Sperm miRNAs as Potential Mediators of the Transgenerational Effects of Stress.
Dickson, David.
2019
-
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, ... read moremicroRNAs 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.
Thesis (Ph.D.)--Tufts University, 2021.
Submitted to the Dept. of Neuroscience.
Advisor: Larry Feig.
Committee: Peter Juo, Michele Jacob, Yongjie Yang, and John Christianson.
Keywords: Neurosciences, Developmental biology, and Developmental psychology.read less - ID:
- qz20t591g
- To Cite:
- TARC Citation Guide EndNote
