Date of Award

6-2007

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Dr. Susan R. Stapleton

Second Advisor

Dr. Alexander Enyedi

Third Advisor

Dr. Pamela Hoppe

Fourth Advisor

Dr. William F. Jackson

Abstract

Cadmium, a non-essential toxic heavy metal, has been classified as a human carcinogen and one of the most hazardous substances in our environment. Since it can circulate within the food chain, has a long biological half-life and can bio-accumulate, it has the potential to induce detrimental health effects linked to toxicity, cancer and chronic diseases.

In recent years progress has been made to dissect and understand the molecular mechanisms underlying the effects of cadmium exposure. However, few studies have focused on investigating potential protective and/or defense mechanisms naturally applied by cells upon initial exposure, prior to any damage or toxic outcomes. Therefore, studies were conducted to investigate early molecular events orchestrated by changes in gene expression under low dose and short exposure of cadmium in primary rat hepatocytes in culture.

First, we established that under this condition, changes in cell signaling and gene expression occurred. The stress sensitive signal protein JNK, immediate early gene c-Jun and redox sensitive transcription factor AP-1 are activated in a time dependent manner with cadmium exposure.

Second, using Affymetrix microarray global transcript profiling, we identified cadmium-responsive genes whose expression changes at this early sensing stage. The most dramatic and significant changes were for those genes associated with transcriptional regulation, antioxidant response and control of protein integrity. Changes in other genes involved in cellular physiological responses such as inflammation, growth and apoptosis were also observed.

Third, we further investigated ten selected cadmium-responsive genes (HO-1, MT-1, Zfp36, Egr1, Atf3, Fosl1, Gclm, TrxR, HSP70 and HSP40) using qRT-PCR to evaluate the potential mechanism of Cd induction. The data suggest that either the Cd-disturbance of the redox environment or the subsequently generated reactive oxygen species, which act as second messengers, play a role in mediating the response. Therefore at least two different mechanisms appear to be involved in cadmium-induced gene expression under non-toxic conditions.

Overall, the early sensing and regulatory networks orchestrated by a cell include changes in signaling, gene expression and diverse molecular activities that are synchronized to perform a fine-tuned molecular symphony to promote protection and maintenance of cellular homeostasis against early cadmium insult.

Access Setting

Dissertation-Open Access

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