title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice.
abstract: 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.
authors.affiliation: School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular and Environmental Toxicology Center, 1400 University Ave., University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: robert.moore@wisc.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Moore
authors.affiliation: School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular and Environmental Toxicology Center, 1400 University Ave., University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: Wayne.Fritz@covance.com.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Fritz
authors.affiliation: School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: ajschnei@wisc.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schneider
authors.affiliation: School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: tlin1@facstaff.wisc.edu.
authors.forename: Tien-Min
authors.initials: TM
authors.lastname: Lin
authors.affiliation: School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular and Environmental Toxicology Center, 1400 University Ave., University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: bran2117@hotmail.com.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Branam
authors.affiliation: Department of Veterinary Physiology and Pharmacology, 4466 TAMU, Texas A&M University, College Station, TX 77843, USA. Electronic address: SSAFE@cvm.tamu.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.affiliation: School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular and Environmental Toxicology Center, 1400 University Ave., University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: richard.peterson@wisc.edu.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Peterson
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000633:toxicity; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy; D005260:Female; D007774:Lactation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology / Q000633:toxicity; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011471:Prostatic Neoplasms / Q000188:drug therapy; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon
keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); 3,3′-Diindolylmethane; Indole-3-carbinol; Neuroendocrine prostate cancer; TRAMP mice