Abstract:
Global oceans play an important role in many aspects of human life. We build our homes on the shores, take our food from the waters, and create our economies from the wealth of resources in marine waters. There is a growing recognition, however, that certain species of marine algae produce potent toxins that can accumulate in seafood and pose health risks to human and wildlife populations. Domoic acid (DA), the focus of this dissertation, is produced by algae in the genus Pseudo-nitzschia. DA is a potent glutamate receptor agonist and neurotoxin, and high-dose exposure to this toxin has been associated with severe illness and permanent memory loss. Although there are strict regulatory limits preventing human exposures greater than 0.075-0.1 mg/kg, recent studies have suggested that repeated and chronic exposures below these levels may affect memory and learning in adults (Grattan et al., 2016, 2018). The studies described in this dissertation took place as part of a larger investigation on the reproductive and developmental consequences of low-dose, chronic DA exposure during pregnancy in a nonhuman primate model (Macaca fascicularis). Early results from this study demonstrated that daily, oral exposure to 0.075 to 0.15 mg DA/kg/day for up to two years, induced symptoms in adults that were manifested as intention tremors (Burbacher et al., 2019). Given that previous studies have found oral doses up to ten times greater than those used in the present study were not overtly toxic, this observation was unexpected (Truelove et al., 1998). The three experiments detailed in Chapters 2, 3 and 4 were designed to further identify the brain’s structural, physiological, and cellular effects in this unique cohort of animals and provide a greater understanding of the health risks associated with chronic, low-dose DA exposure. In the first study, in vivo work using magnetic resonance imaging (MRI) demonstrated that the previously observed intention tremors were associated with white matter deficits in a key neural circuit involved in memory processing, including the fornix and internal capsule (Petroff et al., 2019). In the second study, electroencephalography (EEG) data were collected from sedated adult females, and results suggested subtle changes in power of DA-exposed animals that may be associated with neurophysiological changes (Petroff, et al., submitted). The final body of work in this dissertation integrates these findings by using in vivo MRI scans and ex vivo histopathology to understand the cellular level effects of low-level chronic exposure to DA. Study data revealed that animals exposed to DA and displaying clinical symptomology have a higher incidence of focal microglia reactions, which may be related to the observed decreases in white matter integrity and due to the activation of neuroinflammation pathways (Petroff et al., in preparation). Collectively, the studies described in this dissertation provide the first data on chronic, low-dose oral exposure in a preclinical nonhuman primate model and explore the consequences of DA on adult neurophysiology and macro and microstructural changes in the brain. Vulnerable human populations, such as high-frequency shellfish consumers and coastal-dwelling communities, may not be fully protected by existing guidelines and further longitudinal investigation is warranted to adequately protect public health.
URI
http://hdl.handle.net/1773/45987
