Characterization of Sex-specific Hormone and Gene Expression Alterations in Experimental Model of Traumatic Brain Injury
Purpose/Objective: Traumatic Brain Injury (TBI) results from a blow or jolt to the head and leads to complex pathologies that can extend years after the initial injury. Unfortunately, current treatments for TBI focus on managing symptoms such as edema and intracranial hemorrhage rather than targeting the pathologies that lead to neurodegeneration. Additionally, little is known about how TBI pathology differs between sexes and how alterations in circulating sex steroid hormones contribute to chronic TBI pathologies. To address these challenges, our group employs both male and female models to assess sex-dependent pathologies of traumatic brain injury. In this project, our goal is to evaluate sex differences in circulating sex steroid hormones alterations, BBB disruption and neuroinflammation after TBI.
Methods: We used a well-established mouse controlled cortical impact (CCI) model to induce a moderate TBI over the primary somatosensory cortex in C57BL/6J mice. Male (n=10) and female (n=12) cohorts were injured at 9-10 weeks of age followed by tissue and blood collection at 24 and 72 hrs post-injury. Plasma samples were analyzed with an LC-MS/MS hormone panel for testosterone, androstenedione, estradiol, estrone, progesterone, DHEA and corticosterone. For the RNA-sequencing, a 4 mm cortical punch was taken directly over the injury penumbra and contralateral hemisphere at sacrifice.
Results: Notably, we observe sex-specific alterations in circulating sex steroid hormones after TBI at both 24 and 72 hours. Females exhibit decreases in progesterone, androstenedione, and testosterone at 24 and 72 hrs compared to naïve females, while males exhibit increases in DHEA and decreases in estradiol at 72 hrs compared to naïve males. Additionally, RNA-sequencing reveals sex- and timepoint-specific gene sets when compared to sex-matched controls. Furthermore, functional enrichment analysis of these gene sets shows the injured groups had significant upregulation in genes associated with innate immune trafficking and activation compared to naïve groups.
Conclusion/Future Work: Our results indicate there are sex-specific responses to traumatic brain injury, including sex specific alterations in steroid hormone profile and gene expression. We aim to further elucidate hormone-related pathologies by conducting a correlation analysis using gene expression and hormone level.