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.
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.
| Nugent, Bridget M; O'Donnell, Carly M; Epperson, C Neill et al. (2018) Placental H3K27me3 establishes female resilience to prenatal insults. Nat Commun 9:2555 |
| 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 |
| 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 |
| 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; 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 |
| 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 |
| Bale, Tracy L; Epperson, C Neill (2015) Sex differences and stress across the lifespan. Nat Neurosci 18:1413-20 |
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