Publikationsdatum:
2022-05-26
Beschreibung:
Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Oceanography and Applied Ocean Science and Engineering at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution June 2019.
Beschreibung:
Harmful algal blooms (HABs) can produce potent neurotoxins that accumulate in seafood and affect human health. One HAB toxin of concern is domoic acid (DomA), a glutamate analog produced by the marine diatom Pseudo-nitzschia spp. Current regulatory limits are designed to prevent acute neurotoxicity in adult humans. However, research shows that low-level exposure
during early life can lead to long-term changes in behavior, neural connectivity, and brain morphology. To determine the underlying mechanisms of developmental toxicity, this dissertation used zebrafish as a tool to: i) Establish the developmental window of susceptibility for DomA toxicity, ii) Characterize the behavioral consequences of exposures, and iii) Identify the cellular targets and processes perturbed by DomA. I found that DomA exposure particularly at 2 days post fertilization (dpf) led to altered startle response behavior, myelination defects, and the downregulation of axonal and myelin structural genes. Using vital dyes and immunolabeling, I assessed DomA-induced alterations in cells required for the startle response. I found no differences in the number of sensory neuromasts or in the sensory cranial ganglia structures that detect the acoustic stimuli. However, the majority of DomA-treated larvae lacked one or both Mauthner cells – hindbrain neurons critical for fast startle responses. DomA-treated larvae also had oligodendrocytes with fewer and shorter myelin sheaths, and appeared to aberrantly myelinate neuronal cell bodies. The loss of the Mauthner neurons and their axons may lead to a cellular environment where oligodendrocytes myelinate neuronal cell bodies in the absence of adequate axonal targets. Indeed, pharmacological treatment that reduced the oligodendrocyte number also led to the reduction in the number of these aberrant, myelinated cell bodies. These results indicate that exposure to DomA at a particular period in neural development targets specific cell types, disrupts myelination in the spinal cord, and leads to prolonged behavioral deficits. These mechanistic insights support hazard assessments of DomA exposures in humans during critical periods in early development.
Beschreibung:
This work would simply not be possible without many generous funding sources. Funding for my research came from the Ocean Ventures Fund, Hill family foundation, Woods Hole Sea grant NA14OAR4170074, and the Woods Hole Center for Oceans and Human Health (COHH), which is jointly funded by the National Institutes of Health (P01ES02192, P01ES028938), and the National Science Foundation (OCE-1314642, OCE-1840381).
My funding came from the National Institutes of Health (NIH) P01ES021923-04S1, the Ocean Ridge Initiative Fellowship, the Von Damm Fellowship, and the MIT/WHOI Joint Program Academic Programs Office.
Schlagwort(e):
Domoic acid
;
HAB toxins
;
developmental toxicity
;
windows of susceptibility
;
startle response
;
myelination
;
harmful algal bloom toxins
;
escape response
;
Mauthner cells
;
Harmful algal blooms
;
Reticulospinal neurons
;
Mauthner neuron
;
Myelin
;
Oligodendrocytes
;
Oligodendrocyte precursor cells
;
Algae
;
Neurotoxic agents
;
Health
Repository-Name:
Woods Hole Open Access Server
Materialart:
Thesis
Permalink
