TY - JOUR
T1 - 2,3,7,8-Tetrachlorodibenzo-p-dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice
AU - Moore, Robert W.
AU - Fritz, Wayne A.
AU - Schneider, Andrew J.
AU - Lin, Tien Min
AU - Branam, Amanda M.
AU - Safe, Stephen
AU - Peterson, Richard E.
N1 - Funding Information:
This research was supported by the following National Institutes of Health grants: CA095751 (R.E.P) , ES001332 (R.E.P.) , P30-ES023512 (S.S.) , and T32 ES007015 (W.A.F and A.M.B.) . We thank the Biostatistics Shared Resource for assistance with data analysis and the Experimental Pathology Lab for histology services (supported by University of Wisconsin-Madison Carbone Cancer Center, Cancer Center Support Grant P30-CA014520).
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/8/15
Y1 - 2016/8/15
N2 - It is well established that the prototypical aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can both cause and protect against carcinogenesis in non-transgenic rodents. But because these animals almost never develop prostate cancer with old age or after carcinogen exposure, whether AHR activation can affect cancer of the prostate remained unknown. We used animals designed to develop this disease, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, to investigate the potential role of AHR signaling in prostate cancer development. We previously reported that AHR itself has prostate tumor suppressive functions in TRAMP mice; i.e., TRAMP mice in which Ahr was knocked out developed neuroendocrine prostate carcinomas (NEPC) with much greater frequency than did those with both Ahr alleles. In the present study we investigated effects of AHR activation by three different xenobiotics. In utero and lactational TCDD exposure significantly increased NEPC tumor incidence in TRAMP males, while chronic TCDD treatment in adulthood had the opposite effect, a significant reduction in NEPC incidence. Chronic treatment of adult TRAMP mice with the low-toxicity selective AHR modulators indole-3-carbinol or 3,3′-diindolylmethane did not significantly protect against these tumors. Thus, we demonstrate, for the first time, that ligand-dependent activation of the AHR can alter prostate cancer incidence. The nature of the responses depended on the timing of AHR activation and ligand structures.
AB - It is well established that the prototypical aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can both cause and protect against carcinogenesis in non-transgenic rodents. But because these animals almost never develop prostate cancer with old age or after carcinogen exposure, whether AHR activation can affect cancer of the prostate remained unknown. We used animals designed to develop this disease, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, to investigate the potential role of AHR signaling in prostate cancer development. We previously reported that AHR itself has prostate tumor suppressive functions in TRAMP mice; i.e., TRAMP mice in which Ahr was knocked out developed neuroendocrine prostate carcinomas (NEPC) with much greater frequency than did those with both Ahr alleles. In the present study we investigated effects of AHR activation by three different xenobiotics. In utero and lactational TCDD exposure significantly increased NEPC tumor incidence in TRAMP males, while chronic TCDD treatment in adulthood had the opposite effect, a significant reduction in NEPC incidence. Chronic treatment of adult TRAMP mice with the low-toxicity selective AHR modulators indole-3-carbinol or 3,3′-diindolylmethane did not significantly protect against these tumors. Thus, we demonstrate, for the first time, that ligand-dependent activation of the AHR can alter prostate cancer incidence. The nature of the responses depended on the timing of AHR activation and ligand structures.
KW - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)
KW - 3,3′-Diindolylmethane
KW - Indole-3-carbinol
KW - Neuroendocrine prostate cancer
KW - TRAMP mice
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U2 - 10.1016/j.taap.2016.04.018
DO - 10.1016/j.taap.2016.04.018
M3 - Article
C2 - 27151233
AN - SCOPUS:84976907944
SN - 0041-008X
VL - 305
SP - 242
EP - 249
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
ER -