Neurochemical, epigenetic, and structural brain changes associated with prenatal stress exposure, and the mitigating effects of DHA

[EMBARGOED UNTIL 5/1/2024] 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.Includes bibliographical references

Solution processed SiNxCyOz thin films thermally transformed from silicon oxide/melamine hybrid system

In this study, a solution-processable precursor of melamine and silicon oxide, was prepared and thermally converted into inorganic thin films of SiNxCyOz. Using tetra-ethoxysilane and hydroxyl-methyl-melamine, a transparent coating with a high loading content of silica of up to 50% was achieved through the hydrolysis/condensation reactions, which provided a transmittance of 85.1% (thickness of 1.5 ± 0.2 μm) and hard coating grade of 4H pencil test. When the silica/melamine coating was further heat-treated up to 900 °C in an inert environment, the organic melamine was converted into an inorganic compound composed of Si, N, C, and O atoms in the form of SiNxCyOz. The relative compositions of films varied with the heat-treatment temperature, e.g., providing SiN0.03C0.59O1.87 for the thin film heat-treated at 700 °C. The resulting inorganic thin films were mechanically strong and optically shiny with a low root mean square of roughness (\u3c 1.0 nm) giving dielectric constants varying from 2.75 to 1.82 with heat treatment temperature that could be used as low-k materials in commercialized optoelectronic devices

microRNA as a Maternal Marker for Prenatal Stress-Associated ASD, Evidence from a Murine Model

Autism Spectrum Disorder (ASD) has been associated with a complex interplay between genetic and environmental factors. Prenatal stress exposure has been identified as a possible risk factor, although most stress-exposed pregnancies do not result in ASD. The serotonin transporter (SERT) gene has been linked to stress reactivity, and the presence of the SERT short (S)-allele has been shown to mediate the association between maternal stress exposure and ASD. In a mouse model, we investigated the effects of prenatal stress exposure and maternal SERT genotype on offspring behavior and explored its association with maternal microRNA (miRNA) expression during pregnancy. Pregnant female mice were divided into four groups based on genotype (wildtype or SERT heterozygous knockout (Sert-het)) and the presence or absence of chronic variable stress (CVS) during pregnancy. Offspring behavior was assessed at 60 days old (PD60) using the three-chamber test, open field test, elevated plus-maze test, and marble-burying test. We found that the social preference index (SPI) of SERT-het/stress offspring was significantly lower than that of wildtype control offspring, indicating a reduced preference for social interaction on social approach, specifically for males. SERT-het/stress offspring also showed significantly more frequent grooming behavior compared to wildtype controls, specifically for males, suggesting elevated repetitive behavior. We profiled miRNA expression in maternal blood samples collected at embryonic day 21 (E21) and identified three miRNAs (mmu-miR-7684-3p, mmu-miR-5622-3p, mmu-miR-6900-3p) that were differentially expressed in the SERT-het/stress group compared to all other groups. These findings suggest that maternal SERT genotype and prenatal stress exposure interact to influence offspring behavior, and that maternal miRNA expression late in pregnancy may serve as a potential marker of a particular subtype of ASD pathogenesis