Maternal influence on epigenetics and offspring behavior outcomes : exploring underlying mechanisms and sex-specific sensitivities in a gene environment interaction mouse model
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Autism Spectrum Disorder (ASD) is a lifelong neurodevelopmental disorder characterized by impaired social communication, overly regimented adherence to routine, restricted interests, and repetitive behaviors. Even though early studies implicated genetic risk factors, recent evidence emphasize environmental factors, including experiencing adverse life events elevating increasing ASD risk, which is of greater importance in pregnancies of genetically stress susceptible individuals. We previously reported the SLC6A4 gene, encoding the human serotonin transporter (SERT), along with the variant, the serotonin transporter gene linked polymorphic region (5-HTTLPR), playing a critical role in elevated stress responsivity and embryonic methylation dysregulation in our gene-environment interaction (GxE) mouse model. MicroRNA (miR) molecules negatively regulate gene expression and has been duly implicated in physiological and pathophysiological processes, including cell differentiation, neurodevelopment, and neuropsychiatric disorders and has recently demonstrated a critical role in stress- and behavior- related disorders including ASD. Therefore, to examine maternal stress susceptibility's impact on underlying microRNA expression and behavioral outcomes in offspring, pregnant wild type and SERT (+/-) dams were exposed to a chronic variable stress (CVS) protocol, after which, maternal microRNA profiles were examined. Furthermore, cohorts of female and male offspring underwent a battery of behavioral tests beginning at postnatal day 60 (PD60) to examine SERT (+/-) x CVS effects on behaviors associated with ASD including, anxiety, elevated repetitive behaviors and sociability deficits. Maternal molecular profiling detected three upregulated microRNAs unique to SERT (+/-) x CVS cohort, mmu-miR-5622-3p, mmu-miR-6900-3p and mmu-miR-7684-3p with predicted genetic projections associated with stress and autism spectrum disorders with biological enrichment implicated in forebrain and central nervous system development. Moreover, offspring assays revealed selective, sex-specific behavioral differences with female offspring demonstrating maternal genotype and interaction mediated behaviors, while male offspring displayed maternal stress and interaction mediated behaviors, which suggests the combination of both or individual factors of SERT (+/-) x CVS can sufficiently impact offspring behavior outcomes. Taken together, the results of this study demonstrate the complexity and dynamism of the interplay between maternal genotype and adverse prenatal stress exposure on underlying regulators of ASD- and stress- associated gene networks. And furthermore, provides evidence of their effects on behavioral outcomes of offspring
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Ph. D.