Doctor of Philosophy
Stillman, Martin J.
The rise of the Anthropocene has seen more global pollution than before in history. With the explosion of consumer electronics in the last half century, the rise of metal pollution from their extraction and disposal results in the unnatural introduction of heavy and rare metals into the ecosystem. Organisms have a metal defense protein, metallothionein, which has multiple roles in essential metal regulation and protection against minimal toxic metal exposure. However, these modern heavy metals prominent in electronics are not found biologically and their interactions in the body are generally unknown. Some of these metals are employed as therapeutic agents in the treatment of cancers, and as such this Thesis describes an investigation of therapeutic agents as models for heavy metal pollution to provide insight into the mechanisms of metal metabolism. Using electrospray ionization mass spectrometry and spectroscopic techniques, the binding of human metallothionein with the exotic metals platinum and rhodium is explored. Platinum and Rhodium bind readily to human metallothionein, raising concerns for toxicity.
Summary for Lay Audience
Metals are everywhere. Some metals are required by humans and organisms as nutrients, while some can be extremely toxic. These toxic metals can be deadly depending on amount of exposure, often causing heavy damage to cells and tissues. Life has adapted to light levels of toxic metal exposure with proteins that are involved in metal binding - a group of proteins known as Metallothioneins. When exposed to toxic metals, cells will increase the production of this protein, metallothionein, to counteract the increased exposure. These metallothionein proteins capture the toxic metal and isolate it from performing its toxic activity. This response also can occur in some cancer cells, in response to metal-based therapy (cisplatin, a platinum-based drug), where the metal in the drug triggers the cancer cell to have an aggressively defensive response. At the chemical level, metallothionein acts to break apart the drug molecule and isolate the toxic metal for safe excretion from the body. Recent research in constructing robust molecular frameworks for these drugs to improve cancer treatment efficacy may be able to bypass Metallothionein’s defensive nature in these aggressive cancers. Using an extremely precise analytical methods known as mass spectrometry that show the changes in the exact mass as the protein breaks down the metal from the drug. While metal-based drugs are a specific type of toxic metal exposure, there is a fear of the increased impact of human activity on ecosystems, climate, and the environment will result in toxic metal exposure to all life in ways that has not been done before. These involve toxic metals that have never had a biological role and are found in major electronics and consumer goods that are now a standard of living. The implications of these cancer drug analyses with metallothioneins are extended to address this issue of toxic metal pollution and its effects.
Wong, Daisy L., "Non-Traditional Metallation of Metallothioneins with Xenobiotic Therapeutic Metals" (2019). Electronic Thesis and Dissertation Repository. 6338.
Available for download on Thursday, October 31, 2019