Abstract WP241: Transcriptome Analysis Of The Liver Reveals Novel Mechanisms By Which Prenatal Alcohol Exposure Contributes To Worse Stoke Outcome

Abstract

Introduction: Susceptibility to adult-onset disease has been linked to early life adversity. In this study, we assessed the impact of a common early adverse experience, prenatal alcohol exposure (PAE), on neurobehavioral outcomes following cerebrovascular ischemic stroke. We also assessed impact of PAE and stroke on the transcriptome of intermediary organs of the gut-brain axis. Specifically, mesenteric adipose and liver, which are supplied by portal circulation from the gut are hypothesized to mediate inflammatory and neuroprotective adaptations to stroke. Methods: Pregnant Sprague Dawley rats were exposed to either vaporized ethanol or room air from gestation day 8 to 19. At 5 months, progeny were subjected to unilateral endothelin-1 induced occlusion of the middle cerebral artery and outcomes evaluated after 2 days. Stroke induced disabilities were assessed from behavioral assays (adhesive removal, Vibrissae evoked fore-limb placement and circling) and infarct size. The liver transcriptome was assessed by sequencing, from age-matched stroke-exposed and naïve offspring. Results: PAE rats had worse neurological scores 2 days post stroke compared to control (p<0.05). We observed that the liver was substantially more transcriptionally responsive to PAE status than adipose tissue. Moreover, PAE offspring exhibited a 1.6-fold increase in upregulated genes and a 2.4-fold increase in down-regulated liver gene transcripts following stroke, compared to control offspring. Only 448 differentially expressed genes (DEGs) were common between the control and PAE groups. DEGs unique to PAE contribute to triglyceride metabolism, steroid metabolism, and cholesterol biosynthesis pathways. Weighted correlation network analysis identified 24 gene network modules, one of which, a liver proinflammatory network, was strongly correlated with post stroke neurological function (Pearson's r=-0.63, p<0.01). Conclusion: The present study shows that PAE predisposes middle-aged rat offspring for worse outcomes following cerebrovascular ischemic stroke. This effect is associated with persistent reprogramming of the liver transcriptome and an exacerbated proinflammatory response.