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 #
5R01MH091258-02
Application #
8115137
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
2011-03-01
Budget End
2012-02-29
Support Year
2
Fiscal Year
2011
Total Cost
$396,000
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Bronson, Stefanie L; Chan, Jennifer C; Bale, Tracy L (2017) Sex-Specific Neurodevelopmental Programming by Placental Insulin Receptors on Stress Reactivity and Sensorimotor Gating. Biol Psychiatry 82:127-138
Bale, Tracy L; Epperson, C Neill (2017) Sex as a Biological Variable: Who, What, When, Why, and How. Neuropsychopharmacology 42:386-396
Morrison, Kathleen E; Epperson, C Neill; Sammel, Mary D et al. (2017) Preadolescent Adversity Programs a Disrupted Maternal Stress Reactivity in Humans and Mice. Biol Psychiatry 81:693-701
Morrison, Kathleen E; Narasimhan, Sneha; Fein, Ethan et al. (2016) Peripubertal Stress With Social Support Promotes Resilience in the Face of Aging. Endocrinology 157:2002-14
Bale, Tracy L (2016) The placenta and neurodevelopment: sex differences in prenatal vulnerability. Dialogues Clin Neurosci 18:459-464
Bronson, Stefanie L; Bale, Tracy L (2016) The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming. Neuropsychopharmacology 41:207-18
Jašarevi?, Eldin; Morrison, Kathleen E; Bale, Tracy L (2016) Sex differences in the gut microbiome-brain axis across the lifespan. Philos Trans R Soc Lond B Biol Sci 371:20150122
Bale, Tracy L; Epperson, C Neill (2015) Sex differences and stress across the lifespan. Nat Neurosci 18:1413-20
Jašarevi?, Eldin; Howerton, Christopher L; Howard, Christopher D et al. (2015) Alterations in the Vaginal Microbiome by Maternal Stress Are Associated With Metabolic Reprogramming of the Offspring Gut and Brain. Endocrinology 156:3265-76
Jašarevi?, Eldin; Rodgers, Ali B; Bale, Tracy L (2015) A novel role for maternal stress and microbial transmission in early life programming and neurodevelopment. Neurobiol Stress 1:81-88

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