Endocrine-immune networks : modulatory role of early-life influences

The central nervous system, endocrine system and immune system are developmentally and functionally intertwined, with shared receptors and regulatory feedback. Importantly, these systems are highly susceptible to environmental modulation, particularly the early life environment, with impacts on physiological function and communication among systems. Prenatal alcohol exposure (PAE) has been shown to alter neuroendocrine and immune systems, with marked downstream effects. With the overarching aim of elucidating networks of endocrine and immune parameters responsible for long-lasting immune system deficits that occur following PAE, networks were first evaluated under control conditions. Using Sprague Dawley rats from Charles River and Harlan vendor colonies with known endocrine/immune differences, we found a higher incidence and severity of adjuvant-induced arthritis (AA) in Harlan than Charles River rats, which was tied to differential activation of endocrine/immune networks. The multisystem approach utilized in this colony model was applied as a basic framework for investigating the impact of PAE in the AA model. In parallel to heightened sensitivity of Harlan rats, adult PAE rats showed an increased incidence and severity of AA, which were related to alterations in key endocrine/immune networks. Furthermore, examination of a second ‘hit’ of chronic mild stress exposure during adolescence showed heightened levels of inflammation-related damage with the two hits of PAE and stress, further suggestive of the immunomomodulatory impact of early life conditions. Finally, to determine whether the altered course of AA detected following PAE had its origins in the early postnatal period, a developmental time course of immune parameters was investigated. A specific immune signature of PAE was identified on postnatal day 8, characterized by alterations in the cytokine balance within the periphery and brain, with likely consequences for nervous, endocrine and immune system development. Due to the importance of the early postnatal period in shaping development of physiological systems, we propose that endocrine and immune alterations induced by PAE set the stage for increased sensitivity to AA and likely other auto-immune disorders in adulthood. Moving forward, this points to the potential utility of administering immune-based interventions in early life, with the aim of mitigating deficits associated with Fetal Alcohol Spectrum Disorders (FASD).Medicine, Faculty ofGraduat