Abstract: “Disinfection By-Products (DBPs) are compounds which are produced during the water disinfection process. Currently, there are many DBPs that are unregulated by the U.S Environmental Protection Agency due to a lack of current research studies. Humans and other animals can be exposed to DBPs through inhalation, ingestion, and dermal absorption. Iodoacetic Acid (IAA), one of the current DBPs that goes unregulated has high cytotoxicity and genotoxicity in animals. There are many studies that have linked IAA exposure to developmental dysfunctions but not for female processes. In this study, whether IAA exposure has toxic effects on mouse oocyte maturation will be explored. In vitro, we show that IAA exposure caused abnormal spindle assembly and chromosome misalignment. We also found out that IAA exposure increased the Reactive Oxygen Species (ROS) levels in oocytes; this indicates that IAA treatment could induce oxidative stress in oocytes. Naturally, ROS is formed as a byproduct of everyday metabolism of oxygen which has important roles in initiating biologically processes and homeostasis. Concurrently, an increase in H2AX intensity showed that DNA damage was also elevated in the nuclei of IAA exposed mouse oocytes.”

Text Transcript_Shrestha

Abstract: In the traditional paradigm of pharmacology, diseases arising from excess protein function are treated through potent and selective inhibitors. In contrast, diseases originating from lack of protein function are refractory to this approach and present a tremendous unmet medical need. In the Burke lab, we propose that small molecules can imperfectly mimic missing proteins, acting as a prosthesis on the molecular scale. We have identified hinokitiol, a tropolone natural product capable of replacing protein iron transporters. In order to understand hinokitiol’s activity and enable the development of a mobilization-optimized therapeutic, we seek to understand the atomistic underpinnings that govern its transport activity through establishment of structure activity relationships (SAR). We synthesized an array of tropolones with alkyl substituents with different length, branching patterns, and isotopes to systematically analyze the impact of both lipophilicity and substituent constitution. We have also shown that other iron chelators can be engineered for iron mobilization, following the same rules we uncovered for tropolones. Using our synthetic route, we have synthesized site-selective 13C-tropolones, which will serve as mechanistic probes in solid-state NMR paramagnetic relaxation enhancement (PRE) experiments. The understanding gained from our SAR studies will allow for rational design of a hinokitiol-inspired derivative with optimal iron mobilization.

Text_Transcript_Chen