Date of Award

1-1-2025

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Department

Biomedical and Pharmaceutical Sciences

First Advisor

Angela L. Slitt

Abstract

Natural products from phytoplankton, specifically from benthic cyanobacteria, are widely explored for their therapeutic potential, while phytoplankton blooms have been recognized for their ecological impact on coastal environments. Phytoplankton have evolved through complex evolutionary processes to survive in dynamic environmental conditions, which have favored the production of structurally diverse metabolites that serve as valuable scaffolds for medicinal chemists. Among phytoplankton, cyanobacteria represent a source for a unique range of metabolites and their synthetic analogs have made major contributions to pharmacotherapy in cancer, inflammatory diseases, and neurodegenerative diseases. A major bottleneck in natural product chemistry is the evaluation and optimization of natural products, which heavily relies on collections and isolation to obtain more biomass for dereplication. Additionally, obtaining biomaterial during an ephemeral bloom or through repeated environmental collections can become problematic for further evaluation. Thus, methods including chemical synthesis are important in evaluating activity to facilitate the development of novel therapeutics.

Over the past decade, incidences of harmful algal blooms (HABs) have risen due to climate change and anthropogenic influences. Many harmful algal bloom (HAB) species produce a suite of cytotoxic metabolites that negatively impact both ecosystems and human health. The marine planktonic diatom genus, Pseudo-nitzschia (P-n) produces domoic acid, a neurotoxin that can be fatal to both humans and animals; exposure to a few milligrams per kilogram can elicit gastrointestinal effects and neurological symptoms. In 2017, elevated levels of domoic acid in shellfish prompted the first and only shellfish harvest closures in Narragansett Bay, Rhode Island. To investigate the causative reasons for this event, weekly sampling from 2017 to 2019 was conducted, and closure samples were compared. Results revealed that P-n spp. assemblages were responsible for seasonal domoic acid maxima in the fall and summer periods. However, the annual and seasonal environmental trends and chemical grouping patterns in regard to toxin dynamics are not completely understood. Implementing both an untargeted and targeted LC-MS/MS approach revealed seasonal chemical patterns and domoic acid concentrations in Narragansett Bay. These results will provide a better understanding of toxin dynamics, especially during low persistent levels of domoic acid, by providing temporal resolution of recurring chemical patterns and environmental variables in Narragansett Bay.

Additionally, anthropogenic contaminants were also investigated due to their ability to disrupt and alter phytoplankton communities as well as their human health risks from potential bioaccumulation of contaminants in seafood. In our study, LC-MS/MS untargeted metabolomics analysis was employed and revealed various contaminants such as pharmaceuticals, cosmeceuticals, plasticizers, pollutants, and herbicides in both biomass from filtered seawater samples and mussel tissue samples. These findings illustrate the complex array of toxicants that are present in the marine environment that can impact food security for human health.

The increase of human population and intensification of human activity along with deficient water management have led to eutrophication in freshwater bodies, which may lead to cyanobacterial harmful algal blooms (cyanoHABs). Massive proliferation of (cyanoHABs) in freshwater lakes is responsible for the production of a suite of cytotoxic metabolites. Freshwater cyanobacteria produce a complex suite of hepatotoxins, most notably microcystins. Microcystin-LR has been documented to not only cause acute poisoning but also increase the risk of hepatotoxicity by inhibiting the serine/threonine protein phosphatases 1A and 2A. Due to emerging threat of novel cytotoxic cyanobacterial metabolites, a proteomics platform was used to serve as a hypothesis driver for cyanotoxin mechanism of action.

Download

Available for download on Thursday, May 27, 2027

Share

COinS