The overall goal of the proposed work is to determine whether developmental or adult exposures to inorganic arsenic (iAs) increase prostate cancer (PCa) risk by reprogramming human prostate stem cells. Prior studies have revealed that environmental iAs exposure from natural sources (e.g. drinking water) increases PCa incidence. Recent findings also indicate that iAs directly alters stem cells and augments transformation and studies with PCa cell lines support that this may occur in the prostate gland. To further delineate iAs action(s) in normal human prostate stem cells, determine windows of sensitivity for human exposures and link iAs stem cell exposures to PCa development, novel human prostate stem cell models have been established using primary epithelial cells from disease-free human prostates and human embryonic stem cells (hESC). Importantly, in vivo models using either hESC or adult prostate stem cells mixed with rat inductive mesenchyme have been produced to generate chimeric prostate tissues with normal human prostate epithelium. These original approaches are in place to directly address several unresolved issues regarding iAs exposures and stem cell reprogramming events and to potentially link iAs to growth of human PCa. To accomplish this three specific aims are proposed.
Specific Aim 1 : Delineate the effects of iAs in modulating normal human prostate and embryonic stem cell self-renewal and differentiation to epithelial cell lineages. To accomplish this, FACS and prostasphere assay of adult human prostate stem cells and directed differentiation of hESC in vitro will be utilized to interrogate te actions of a range of iAs doses in perturbing normal prostate development and growth.
Specific Aim 2 : Elucidate the molecular underpinnings of As reprogramming of prostate stem cells by identifying DNA methylation modifications and resultant changes in gene expression. In parallel with Specific Aim 1, analysis of prostasphere DNA methylome, DNA hydroxymethylome and transcriptome will be undertaken to identify genome-wide marks in stem cells with resultant As gene expression signatures.
Specific Aim 3 : Determine whether As exposure initiates carcinogenesis, acts as a co-carcinogen or promotes PCa progression in human prostate epithelium using novel in vivo chimeric prostate models. Adult prostate stem cells from normal men, PCa patients or hESC will be used to generate chimeric tissues grown as renal grafts in nude mice. Carcinogenesis in normal epithelium will be monitored after iAs exposures alone or with steroids as co-carcinogens. PCa progression will be examined in PCa stem cell-derived grafts exposed to iAs. Finally, aberrant expression of iAs-reprogrammed genes will be evaluated in tissue microarrays constructed from PCa patients for translational relevance. The present approaches using fresh human specimens with in vivo models combined with state-of-the-art epigenomic technologies are a marked advance over current approaches that will undoubtedly provide significant new and useful information pertaining to human prostate health. Together, these studies will generate novel information on how iAs increases PCa risk and provide a rationale framework for iAs exposure assessment.

Public Health Relevance

Epidemiology studies have shown a strong positive association between levels of iAs in drinking water and prostate cancer incidence and mortality. The overall goal of the proposed studies is to determine whether early-life or adult As exposures increase prostate cancer risk by targeting human prostate stem cells which in turn contribute to prostate cancer onset and progression.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1-TN-D (ST))
Program Officer
Reinlib, Leslie J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois at Chicago
Schools of Medicine
United States
Zip Code
Ho, Shuk-Mei; Cheong, Ana; Adgent, Margaret A et al. (2017) Environmental factors, epigenetics, and developmental origin of reproductive disorders. Reprod Toxicol 68:85-104
Dambal, Shweta; Baumann, Bethany; McCray, Tara et al. (2017) The miR-183 family cluster alters zinc homeostasis in benign prostate cells, organoids and prostate cancer xenografts. Sci Rep 7:7704
Shah, Palak; Trinh, Elaine; Qiang, Lei et al. (2017) Arsenic Induces p62 Expression to Form a Positive Feedback Loop with Nrf2 in Human Epidermal Keratinocytes: Implications for Preventing Arsenic-Induced Skin Cancer. Molecules 22:
Hu, Wen-Yang; Hu, Dan-Ping; Xie, Lishi et al. (2017) Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution. Stem Cell Res 23:1-12
Xu, Zongli; Taylor, Jack A; Leung, Yuet-Kin et al. (2016) oxBS-MLE: an efficient method to estimate 5-methylcytosine and 5-hydroxymethylcytosine in paired bisulfite and oxidative bisulfite treated DNA. Bioinformatics 32:3667-3669
Gore, A C; Chappell, V A; Fenton, S E et al. (2015) EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocr Rev 36:E1-E150
Calderon-Gierszal, Esther L; Prins, Gail S (2015) Directed Differentiation of Human Embryonic Stem Cells into Prostate Organoids In Vitro and its Perturbation by Low-Dose Bisphenol A Exposure. PLoS One 10:e0133238
Grandjean, Philippe; Barouki, Robert; Bellinger, David C et al. (2015) Life-Long Implications of Developmental Exposure to Environmental Stressors: New Perspectives. Endocrinology 156:3408-15
Prins, Gail S; Calderon-Gierszal, Esther L; Hu, Wen-Yang (2015) Stem Cells as Hormone Targets That Lead to Increased Cancer Susceptibility. Endocrinology 156:3451-7
Tam, Neville Ngai-Chung; Zhang, Xiang; Xiao, Hong et al. (2015) Increased susceptibility of estrogen-induced bladder outlet obstruction in a novel mouse model. Lab Invest 95:546-60

Showing the most recent 10 out of 11 publications