The goal is to determine consequences perinatal TCDD exposure on prostate development in the C57BL/6 mouse and elucidate the mechanisms involved.
Specific aims are to identify aberrant effects of TCDD on development of ventral, dorsolateral, and anterior prostate and to determine using aryl hydrocarbon receptor (AhR) knockout (AhRKO) mice if these effects require AhR.
The specific aims of the proposal are: 1) to determine critical periods for producing TCDD effects and elucidate androgen-dependent mechanisms involved in causing them. 2) to assess if TCDD acts directly on urogenital sinus (UGS) to disrupt prostate development and if AhR is required in UGS mesenchyme or epithelium to cause certain effects. 3) to evaluate if coexposure to a natural AhR antagonist in human food, resveratrol, ameliorates TCDD disruption of prostate development. 4) to identify TCDD-responsive genes in UGS and determine which ones are involved in TCDD inhibition of prostate budding. 5)to determine the long-term consequence of perinatal TCDD exposure on prostate size, histology, and growth regulation in senescent mice. Hypotheses to be tested are that perinatal TCDD exposure inhibits prostatic bud formation, ductal branching morphogenesis, ductal canalization, luminal cell differentiation and prostatic secretory function, and may alter normal age-related changes in androgen dependence. The long-range goal is to identify genes that are the most sensitive to TCDD exposure and whose altered expression may be critical for producing particular aberrant prostate effects later in life. Genes implicated in prostate development including those for proto-oncogenes, transcription factors, homeobox genes, growth factors, and cell adhesion molecules, will be assessed for differential expression along with other genes. The innovation in this approach is that, for the first time, it may shed light on TCDD-induced alterations in gene expression during fetal stage of development that cause latent, adverse effects on the prostate. The human health significance is that aberrant effects on prostate development are among the most sensitive and highly reproducible responses to TCDD in animals. AhR and ARNT are expressed in human fetal, benign hyperplastic, and malignant prostate, suggesting that human prostate responds to TCDD. There is an extraordinarily high incidence of benign prostate hyperplasia (BPH) and prostate cancer in humans, yet the function of AhR signaling in human prostate remains unknown. The proposed research may clarify the mechanisms by which TCDD disrupts early prostate development and possibly prostate growth in senescence and provide insight into naturally occurring chemicals in the human diet that may ameliorate the adverse development effects of TCDD on the prostate.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37ES001332-31
Application #
7121159
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Heindel, Jerrold
Project Start
1978-06-01
Project End
2010-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
31
Fiscal Year
2006
Total Cost
$426,662
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Moore, Robert W; Fritz, Wayne A; Schneider, Andrew J et al. (2016) 2,3,7,8-Tetrachlorodibenzo-p-dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice. Toxicol Appl Pharmacol 305:242-249
Ricke, William A; Lee, Calvin W; Clapper, Tyler R et al. (2016) In Utero and Lactational TCDD Exposure Increases Susceptibility to Lower Urinary Tract Dysfunction in Adulthood. Toxicol Sci 150:429-40
Keil, Kimberly P; Vezina, Chad M (2015) DNA methylation as a dynamic regulator of development and disease processes: spotlight on the prostate. Epigenomics 7:413-25
Schneider, Andrew J; Branam, Amanda M; Peterson, Richard E (2014) Intersection of AHR and Wnt signaling in development, health, and disease. Int J Mol Sci 15:17852-85
Keil, Kimberly P; Abler, Lisa L; Laporta, Jimena et al. (2014) Androgen receptor DNA methylation regulates the timing and androgen sensitivity of mouse prostate ductal development. Dev Biol 396:237-45
Keil, Kimberly P; Abler, Lisa L; Mehta, Vatsal et al. (2014) DNA methylation of E-cadherin is a priming mechanism for prostate development. Dev Biol 387:142-53
Schneider, Andrew J; Moore, Robert W; Branam, Amanda M et al. (2014) In utero exposure to TCDD alters Wnt signaling during mouse prostate development: linking ventral prostate agenesis to downregulated ?-catenin signaling. Toxicol Sci 141:176-87
Branam, Amanda M; Davis, Nicole M; Moore, Robert W et al. (2013) TCDD inhibition of canonical Wnt signaling disrupts prostatic bud formation in mouse urogenital sinus. Toxicol Sci 133:42-53
Mehta, Vatsal; Vezina, Chad M (2011) Potential protective mechanisms of aryl hydrocarbon receptor (AHR) signaling in benign prostatic hyperplasia. Differentiation 82:211-9
Yoshioka, Wataru; Peterson, Richard E; Tohyama, Chiharu (2011) Molecular targets that link dioxin exposure to toxicity phenotypes. J Steroid Biochem Mol Biol 127:96-101

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