Assessing the impact of domoic acid exposure on the zebrafish (Danio rerio) brain across life stages

Abstract

Domoic acid (DA) is a neurotoxin produced by diatoms in genus Pseudo-nitzschia. DA accumulates in seafood and can affect the health of humans and wildlife. DA is a structural analog of glutamate - an excitatory neurotransmitter - that activates ionotropic glutamate receptors leading to excitotoxicity and ultimately neurobehavioral defects. While current seafood regulations prevent acute toxicity from high-level exposure, low-level exposure can still have effects on brain development and function. Developmental stages are particularly sensitive to low-level exposure. This thesis assesses the impact of DA exposure on brain health in both development and adulthood, and investigates whether developmental exposure to DA has persistent effects. In the first data chapter, I employed microarray analysis to demonstrate that exposure to an asymptomatic dose of DA significantly altered gene expression patterns in the adult zebrafish brain. These changes were distinct from those resulting from symptomatic exposure, suggesting that low levels of DA could affect brain function in unique ways. In the second data chapter, I investigated the effect of developmental exposure to DA on immune cells in the brain (microglia). Microglia have critical roles in brain homeostasis, development, and the response to injury or infection. Using transgenic zebrafish (Tg(mpeg1:mCherry)), I characterized developmental windows of microglial sensitivity to DA exposure. Developmental exposure to DA (0.1 ng/embryo) at 2 days post-fertilization (dpf) resulted in microglial reactivity without permanent gross morphological defects. These findings suggest that microglia may be an understudied target of DA toxicity. My final chapter investigates the effects of developmental exposure on later-life behavior and sensitivity to subsequent exposures. I exposed larval zebrafish to 0.1ng DA at 2 dpf and raised these individuals to adulthood, where they received a second exposure to DA or vehicle. Fish exposed to DA in early life showed no significant changes in survival or sensitivity to a second dose of DA. Furthermore, there was no effect of developmental or adult treatment on behavior in novel tank or Y-maze spatial discrimination assays. This thesis contributes to our understanding of neurodevelopmental effects of DA exposure during developmental and adult life stages, emphasizing the potential for microglia as a target of DA.