2,3,7,8-Tetrachlorodibenzo-p-dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice

Journal Article · Mon Aug 15 04:00:00 EDT 2016 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2016.04.018· OSTI ID:22689243

Lin, Tien-Min ^[1]; Safe, Stephen ^[2]

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1. School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705 (United States)
2. Department of Veterinary Physiology and Pharmacology, 4466 TAMU, Texas A&M University, College Station, TX 77843 (United States)

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. - Highlights: • TRAMP mice model aggressive neuroendocrine prostate carcinomas in men • In utero/lactational TCDD exposure raised prostate cancer incidence in TRAMP mice. • TCDD treatment in adulthood lowered prostate cancer incidence in TRAMP mice. • No significant protection was seen in TRAMP mice given I3C or DIM in adulthood. • This is the first report that TCDD alters prostate cancer incidence in lab animals.

• OSTI ID: 22689243
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Vol. 305; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIGENS
CARCINOGENESIS
CARCINOGENS
CARCINOMAS
DIOXIN
INDOLES
LIGANDS
METHANOL
MICE
PROSTATE
RECEPTORS
SIMIAN VIRUS
TOXICITY
XENOBIOTICS