Traumatic brain injury (TBI) induces complex molecular and neuroendocrine alterations that extend beyond the site of injury. The hypothalamic–pituitary–adrenal (HPA) axis, a hierarchically organized neuroendocrine system composed of the hypothalamus, pituitary gland, and adrenal glands, plays a central role in coordinating stress and metabolic homeostasis. Despite its critical importance, the temporal transcriptional mechanisms underlying HPA axis dysregulation following TBI remain poorly understood, particularly in relation to coordinated neuronal injury and regeneration processes. This study aimed to investigate the time-dependent transcriptional dynamics of genes associated with neuronal injury and regeneration within the HPA axis following experimental TBI. Moderate-to-severe TBI was induced in Sprague–Dawley rats using a controlled cortical impact (CCI) model. Animals were allocated into sham, acute (24 h), and chronic (30 days) groups. Transcript profiles of 24 HPA axis- and neuroregeneration-related genes were analyzed in hypothalamic, pituitary, and adrenal tissues using quantitative real-time PCR, with normalization to a housekeeping gene and statistical evaluation of differential expression across time points. TBI induced distinct, tissue-specific, and time-dependent transcriptional alterations across the HPA axis. In the acute phase, stress-response genes showed divergent regulation between central and peripheral tissues, whereas the chronic phase was characterized by transcriptional reorganization involving neurotrophic, metabolic, and neuroendocrine pathways. Key regulators such as Hif1a, Rad18, Avp, Gata3, and OxtR exhibited significant and region-specific expression changes. These findings demonstrate that TBI triggers coordinated yet heterogeneous transcriptional responses within the HPA axis, linking central injury to systemic endocrine adaptation. This study provides novel insight into the molecular basis of neuroendocrine dysfunction and recovery after TBI and identifies candidate targets for future therapeutic strategies.

Purpose: Traumatic Brain Injury (TBI) poses a significant global health burden, with Mild TBI (mTBI) being the most prevalent form. TBI triggers activation of the hypothalamic–pituitary–adrenal (HPA) axis, which in turn affects the hypothalamic-pituitary–gonadal (HPG) axis regulating oogenesis and spermatogenesis. In this study, we investigated the impact of mTBI on sperm genome integrity using a repetitive mTBI (r-mTBI) mouse model. Methods: We assessed sperm telomere length (TL), free TERRA (fTERRA), and DNA/RNA hybrid TERRA (hTERRA) levels, alongside transcriptional changes in genes involved in TERRA regulation and DNA damage response. Results: Our findings reveal that a single mTBI event leads to a significant reduction in sperm TL during the acute phase, followed by an increase in TL during the chronic phase of r-mTBI, reminiscent of aging-associated changes. Moreover, we observed alterations in the transcription levels of Rad51, Exo1, Rb1, RNaseH1, and RNaseH2 genes, particularly in association with fTERRA and hTERRA levels, following mTBI. Conclusion: Understanding the potential non-Mendelian effects of TBI holds promise for elucidating TBI pathogenesis, mechanisms of TBI-induced diseases, and conditions of unknown etiology. Given the risks associated with repeated TBI exposure, especially in sports like football and boxing, consideration of potential paternal transmission of effects to offspring is crucial.