Pre- and post-natal programming of the neuroendocrine-immune system: Implications for stress resilience, disease resistance, and longevity

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Livestock and aquaculture species are often subjected to different types of stressors, like microbial infections. The neuroendocrine-immune (NEI) system plays a central role in mounting and regulating the host response to stressors, and helps restore physiological balance after a stress event has passed. The developing NEI system is very sensitive to prenatal and postnatal stress (PPS), and when PPS is experienced during certain windows of development, genetic programming of the NEI system can be permanently affected. It has been proposed that this NEI malleability is an adaptive mechanism that helps newborn animals prepare for their novel environment; however, if NEI programming is mismatched to the postnatal environment, it can negatively impact offspring stress resilience, disease resistance, and longevity; all of which are important health, welfare and economic concerns for the Canadian livestock and aquaculture sectors (CLASs). Human studies, have shown the effects of stress-induced developmental programming can manifest across generations, and sex-specific responses are common; but the impact of this on the CLASs is currently unknown. Researchers have historically focused on maternal and neonatal stress; however, paternal stress appears to be equally important. The mechanisms of action (MOAs) by which NEI system programming occurs are just beginning to be understood, and appear to involve epigenetics changes affecting gene regulation. ***A major limitation of large animal studies in this research area is that they are extremely costly and time consuming to conduct, especially when generational, parental and sex effects, and MOAs are investigated. We believe the zebrafish (Zf), which is a well-established model of human physiology and disease, has the potential to greatly advance CLASs research in this area. In this proposal, we plan to develop Zf PPS models using bacterial lipopolysaccharide (LPS) endotoxin immune stimulation (BEIS); LPS makes up the cell membrane of Gram-negative bacteria such as Escherichia coli, and is commonly used in research to simulate a bacterial infection. These PPS models will then be used to assess larval and neonatal NEI programming, including MOAs, following BEIS stress. Since fish lack the main LPS receptor possessed by mammals, Toll-like receptor 4, it will be important to identify receptors that enable LPS recognition; these can serve as alternative targets for nutrition- and vaccine-induced innate immune stimulation, and may be polymorphic across species, which is important for genetic selection. This research will help us to better understand the long-term impact of PPS on developing animals, and will allow us to investigate regulatory processes may be modulated to enhance overall stress resilience, disease resistance, and longevity of animals reared in the CLASs without relying on antimicrobials to prevent neonatal disease.