Parental lifetime exposures to perturbations such as stress, infection, malnutrition, and to advanced age have been linked with an increased risk for neurodevelopmental disorders in their children. While maternal insults during pregnancy can directly impact fetal development, the mechanisms by which paternal lifelong experiences can alter germ cell programming and affect offspring neurodevelopment are not known. However, transmission of these epigenetic marks to the next generation can significantly elevate disease risk, and if programmed into the germline can affect future generations as well. Using male stress experience as a model in which we can examine mechanisms involved in offspring neurodevelopmental programming, we found that paternal stress significantly altered offspring HPA stress axis regulation and reprogrammed the hypothalamus. Mechanistically, we identified 9 specific miRNAs in the mature sperm from stressed males that contributed to the offspring phenotype. Further, we were able to completely recapitulate the offspring phenotype by microinjection of these 9 miRNAs into fertilized zygotes. Using single-cell amplification technology, we were identified a novel role for these miRNAs to significantly affect post-fertilization embryo development, providing substantial evidence that sperm miRNAs are programmable by the environment and are able to transmit this information allowing for paternally directed embryo development. Therefore, our proposal will utilize our mouse model of paternal stress to examine: 1) the mechanisms whereby stress alters paternal germ cell miRNA that affect neurodevelopment and give rise to the offspring phenotype, 2) the transgenerational transmission of stress dysregulation to a second generation programmed by paternal stress and sperm miRNAs, and 3) the mechanism within the offspring brain that promotes the paternal stress phenotype through increased BBB permeability and repressive histone epigenetic programming.

Public Health Relevance

Parental lifetime exposures to perturbations such as stress, infection, malnutrition, and to advanced age have been linked with an increased risk for neurodevelopmental disorders in their children. Using male stress experience as a model in which we can examine mechanisms involved in offspring neurodevelopmental programming, we found that paternal stress significantly altered offspring HPA stress axis regulation and reprogrammed the hypothalamus as a result of changes in parental sperm miRNAs. Therefore, our proposal will utilize our mouse model of paternal stress to examine mechanisms by which germ cell miRNA programming through epididymal exosomes affect neurodevelopment and may become transgenerational.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH108286-05
Application #
9487303
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Winsky, Lois M
Project Start
2015-08-01
Project End
2020-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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