Neurochemical, epigenetic, and structural brain changes associated with prenatal stress exposure, and the mitigating effects of DHA
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The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that in utero stress exposure can modify developmental trajectories, influencing adult health. Research indicates that maternal stress can negatively impact neurodevelopment, especially in individuals genetically predisposed to stress. Such stress has been linked to various neurodevelopmental disorders, including autism spectrum disorder (ASD). Our previous research showed that stress-sensitive polymorphisms in the serotonin transporter (SERT) gene may interact with environmental stress during pregnancy, increasing ASD risk. Offspring of stress-exposed mice with one SERT gene copy missing (SERT-het) exhibited autism-related behaviors, indicating heightened stress susceptibility. This dissertation's first study examines if prenatal docosahexaenoic acid (DHA) supplementation mitigates autism-related behaviors in stress-exposed SERT-het mice and how it affects lipid peroxidation and brain structure. DHA, an abundant omega-3 fatty acid in mammalian brains, influences brain development and maintenance. DHA supplementation in stress-exposed SERT-het (SERT-het/stress) mice reduced autismxi related behaviors due to prenatal stress, although lipid peroxidation remained unchanged. The second study investigates microRNA (miRNA) as a potential maternal biomarker for neurodevelopmental changes linked to gene-environment (G x E) interactions. We previously identified differentially expressed (DE) miRNAs in blood samples from prenatally stress-exposed mothers with short SERT alleles (S-allele) and ASD-affected children, suggesting a possible blood molecular signature for ASD-related G x E interactions. Therefore, in the second study, we assessed maternal DE miRNA profiles in the SERT-het/stress mouse model at embryonic day 21 (E21) and postnatal day 60 (PD60). The SERT-het/stress group exhibited differential expression of 3 miRNAs at E21 and 13 miRNAs at PD60, which correlated with behavioral findings. In the specific population of S-allele carriers with prenatal stress, these miRNAs could potentially act as indicators for G x E interactions in ASD and demonstrate temporal variability. These studies provide evidence for beneficial effect of DHA and epigenetic alterations associated with the G x E interaction which we hope will lead to better understanding of the mechanisms and eventually treatments of ASD, resulting from prenatal stress exposure in genetically stress susceptible individuals.
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Ph. D.