Date of Award

January 2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology

First Advisor

Donald Sens

Abstract

IARC classified arsenic (iAs) as “carcinogenic to humans”, but despite the health consequences, there is no molecular signature available yet to predict when exposure may lead to the disease development. In this study, a three-step analysis was employed: (1) the gene expression profiles obtained from diverse arsenic-exposed populations were utilized to identify differentially expressed genes associated with arsenic exposure in human subjects, (2) the gene expression profiles induced by arsenic exposure in different myeloma cancer cell lines were used to define common genes and pathways altered by arsenic exposure,(3) the genetic profiles of human bladder cancer studies were used to test the significance of the common association of genes, identified in step 1 and step 2, to develop and validate a predictive model of primary bladder cancer risk associated with arsenic exposure. The study identified a unique set of 147 genes associated with arsenic exposure and linked to molecular mechanisms of cancer. The risk prediction model shows the highest prediction ability for recurrent bladder tumors based on a very small subset (NKIRAS2, AKTIP, and HLA-DQA1) of the 147 genes resulting in AUC of 0.94 (95% CI: 0.744-0.995) and 0.75 (95% CI: 0.343-0.933) on training and validation data, respectively. In addition, high arsenic exposure has been associated with adverse kidney disease outcomes. Therefore, we performed a systematic analysis of the association between arsenic and various kidney disease outcomes. Because of the high prevalence of arsenic exposure worldwide, there is a need for additional well-designed epidemiologic and mechanistic studies of arsenic and kidney disease outcomes. The human kidney is known to possess renal progenitor cells (RPCs) that can assist in the repair of acute tubular injury. The RPCs are sparsely located as single cells throughout the kidney. We recently generated an immortalized human renal progenitor cell line (HRTPT) that co-expresses PROM1/CD24 and expresses features expected on a RPCs. This included the ability to form nephrospheres, differentiate on the surface of Matrigel, and to undergo adipogenic, neurogenic, and osteogenic differentiation. These cells were used in the present study to determine how the cells would respond when exposed to a nephrotoxin. Arsenite (iAs) was chosen as the nephrotoxin since the kidney is susceptible to this toxin and there is evidence for its involvement in renal disease. Gene expression profiles when the cells were exposed to iAs for 3, 8, 10 passages (subcultured at 1:3 ratio) identified a shift in from the control unexposed cells. The cells exposed to iAs for 8 passages were then referred with growth media containing no iAs and within 2 passages the cells returned to an epithelial morphology with strong agreement in differential gene expression between control and cells recovered from iAs exposure. Results show within 3 serial passages of the cells exposed to iAs there was a shift in morphology from an epithelial to a mesenchymal phenotype. EMT was suggested based on an increase in known mesenchymal markers. We found RPCs can undergo EMT when exposed to a nephrotoxin and undergo MET when the agent is removed from the growth media.

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