Rompala, Gregory R
(2018)
ROLE OF PATERNAL PRECONCEPTION ENVIRONMENT
IN ETHANOL- AND STRESS-RELATED PHENOTYPES.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
While the importance of maternal health during pregnancy for proper offspring development is
well-acknowledged, a potential role for preconception health -- especially that of the father -- is
rarely considered. However, a recent surge of studies strongly implicates paternal experiences and
environmental exposures prior to conception as causal drivers of complex neurobehavioral
offspring phenotypes. Considering this work, my dissertation laboratory previously discovered
that paternal chronic ethanol exposure increased ethanol sensitivity and decreased ethanol drinking
preference selectively in male offspring. This dissertation builds off those preliminary studies with
the hypothesis that paternal preconception environment alters ethanol- and stress-related
phenotypes via epigenetic mechanisms in sperm. Initial experiments revealed that paternal chronic
ethanol blunted the corticosterone response to acute stress, prevented stress-induced polydipsia,
and altered genetic and epigenetic regulation of corticotropin-releasing factor in the hypothalamus
in male offspring. In addition, paternal chronic stress reduced ethanol drinking behavior in male
offspring and this phenotype was dependent on the vendor/shipping history of the sire. Subsequent
experiments examined the effects of chronic ethanol on small noncoding RNA in sperm, an
epigenetic mechanism causally implicated in the cross-generational effects of paternal
preconception environment. The unique small noncoding RNA signature of sperm is shaped during
epididymal transit by extracellular vesicles (i.e., epididymosomes). Small RNA sequencing
revealed several ethanol-responsive small noncoding RNAs in sperm and some species were
similarly affected in epididymosomes. Finally, the effects of epididymosomes on intergenerational
ROLE OF PATERNAL PRECONCEPTION ENVIRONMENT
IN ETHANOL- AND STRESS-RELATED PHENOTYPES
Gregory R. Rompala, Ph.D.
University of Pittsburgh, 2018
v
ethanol- and stress-related behaviors were directly tested. Normal sperm was incubated with
epididymal extracellular vesicles from chronic ethanol (Ethanol EV-donor) or control-treated
(Control EV-donor) mice prior to in vitro fertilization (IVF) and embryo transfer to produce adult
progeny. While Ethanol EV-donor treatment did not recapitulate the ethanol- or stress-related
intergenerational effects of paternal ethanol, Ethanol EV-donors did impart increased anxiety-like
behavior to IVF-derived females and modestly increased limited access ethanol intake in IVF-derived
males. In summary, paternal preconception environment impacts ethanol- and stressrelated
behavior in offspring, possibly via small noncoding RNAs in the germline and epididymal
extracellular vesicles.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Committee Chair | McClung, Colleen | mcclungca@upmc.edu | | | | Committee Member | Torregrossa, Mary | | | | | Committee Member | Hill, Shirley | | | | | Committee Member | DeFranco, Don | | | | | Committee Member | Pierce, Robert C | | | | | Thesis Advisor | Homanics, Gregg | homanicsge@anes.upmc.edu | | |
|
| Date: |
19 February 2018 |
| Date Type: |
Publication |
| Defense Date: |
29 January 2018 |
| Approval Date: |
19 February 2018 |
| Submission Date: |
17 February 2018 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
231 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
alcohol, stress, epigenetics |
| Date Deposited: |
19 Feb 2018 20:36 |
| Last Modified: |
19 Feb 2018 20:36 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33797 |
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