The mechanism through which fetal antecedents contribute to disease development is not understood, though likely involves a complex interaction between maternal environment, placental changes, embryo sex and epigenetic programming. As most neurodevelopmental disorders exhibit a sex bias in presentation, elucidation of the mechanisms by which sex-specific susceptibility arises is likely to provide critical insight into disease etiology. We have recently identified a sensitive period of early gestation where stress has sex-specific long- term programming effects on offspring stress pathway neurodevelopment. Mechanistically, we have detected sex-specific effects of maternal stress on placental inflammatory cytokines, growth factors and epigenetic machinery. From these studies, we hypothesize that early pregnancy is a highly sensitive period for the long- term sex-specific consequences of maternal stress through effects on placental inflammation, epigenetic machinery and nutrient transport altering programming of the developing embryo. Therefore, our studies will examine: 1) how early prenatal stress (EPS) alters the long-term programming of stress pathway neurodevelopment through sex-specific placental and embryonic inflammation, nutrient transport and changes in epigenetic machinery during a highly sensitive period of early gestation, 2) the possible rescue of the sex- specific programming effects of EPS by maternal treatment with an anti-inflammatory or a specific inhibitor of NFkB activation, NBD, and 3) genomic and proteomic technology including ChIP-Sequencing and pathway focused PCR Arrays to analyze placental and embryonic brain tissues and proteomic analysis of amniotic fluid across gestation to identify potential translatable biomarkers and genes important in the programming of stress dysregulation predictive of neurodevelopmental disorders in EPS offspring.

Public Health Relevance

The mechanism through which fetal antecedents contribute to disease development is not understood, though likely involves a complex interaction between maternal environment, placental changes, embryo sex and epigenetic programming. We have recently identified a sensitive period of early gestation where stress has sex-specific long-term programming effects on offspring stress pathway neurodevelopment. We hypothesize that early pregnancy is a highly sensitive period for the long-term sex-specific consequences of maternal stress through effects on placental inflammation, epigenetic machinery and nutrient transport altering programming of the developing embryo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH091258-05
Application #
8619658
Study Section
Special Emphasis Panel (ZMH1-ERB-L (02))
Program Officer
Desmond, Nancy L
Project Start
2010-07-21
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$396,000
Indirect Cost
$148,500
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Epperson, C Neill; Kim, Deborah R; Bale, Tracy L (2014) Estradiol modulation of monoamine metabolism: one possible mechanism underlying sex differences in risk for depression and dementia. JAMA Psychiatry 71:869-70
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Howerton, Christopher L; Morgan, Christopher P; Fischer, David B et al. (2013) O-GlcNAc transferase (OGT) as a placental biomarker of maternal stress and reprogramming of CNS gene transcription in development. Proc Natl Acad Sci U S A 110:5169-74
Rodgers, Ali B; Morgan, Christopher P; Bronson, Stefanie L et al. (2013) Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J Neurosci 33:9003-12
Bale, Tracy L; Chen, Alon (2012) Minireview: CRF and Wylie Vale: a story of 41 amino acids and a Texan with grit. Endocrinology 153:2556-61
Morgan, Christopher P; Bale, Tracy L (2011) Early prenatal stress epigenetically programs dysmasculinization in second-generation offspring via the paternal lineage. J Neurosci 31:11748-55
Bale, Tracy L (2011) Sex differences in prenatal epigenetic programming of stress pathways. Stress 14:348-56