ORCID

http://orcid.org/0000-0002-6707-6785

Date of Award

Summer 8-15-2021

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Cadmium is an environmental pollutant and significant health hazard that is similar to the physiological metal zinc. Residing in the same group of the periodic table, cadmium and zinc share chemical characteristics that are important for their industrial uses in electroplating, batteries, pigments, and metal alloys. The similarities of ionic cadmium and zinc have significant repercussions on biological systems. While it has long been clear that cadmium is toxic to biological systems, the mechanisms of cadmium toxicity remain poorly understood. In contrast, mechanisms of zinc homeostasis have been elucidated in growing detail. In C. elegans high zinc homeostasis is regulated by the HIZR-1 nuclear receptor transcription factor via the High Zinc Activation (HZA) enhancer. To define relationships between the responses to high zinc and cadmium, we analyzed transcription following high zinc and cadmium exposure. Many genes were activated by both high zinc and cadmium, and hizr-1 was necessary for activation of a subset of these genes; in addition, many genes activated by cadmium did not require hizr-1, indicating there are at least two mechanisms of cadmium-regulated transcription. Cadmium directly bound HIZR-1, promoted nuclear accumulation of HIZR-1 in intestinal cells, and activated HIZR-1-mediated transcription via the HZA enhancer. Thus, cadmium binding promotes HIZR-1 activity, indicating that cadmium acts as a zinc mimetic to hijack the high zinc response. To elucidate the relationships between high zinc and cadmium detoxification, we analyzed genes that function in three pathways: the pcs-1/phytochelatin pathway strongly promoted cadmium resistance but not high zinc resistance, the hizr-1/HZA pathway strongly promoted high zinc resistance but not cadmium resistance, and the mek-1/sek-1/kinase signaling pathway promoted resistance to high zinc and cadmium. These studies identify resistance pathways that are specific for high zinc and cadmium as well as a shared pathway. To further our understanding of transcriptional regulation in response to zinc and cadmium, genomic deletions of HZA enhancers of highly induced genes were tested for their response to cadmium and zinc. Interestingly, these HZA enhancers displayed bi-directional activation of adjacent genes in the genome in response to zinc and cadmium. To study the application of these findings to human biology, Hek293 cells were exposed to zinc and pyrithione and screened for activation of metallothioneins and nuclear receptors. Human cells were also transfected with plasmids encoding chimeric Gal4::HIZR-1 proteins that displayed a zinc responsiveness in a luciferase reporter assay. The hizr-1/HZA pathway plays an important role in the C. elegans response to zinc and cadmium toxicity and orthologous systems may be found in human biology

Language

English (en)

Chair and Committee

Kerry Kornfeld

Committee Members

Tim Schedl, Ivan Baxter, John Welch, Holden Thorp,

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