Effects of Aryl Hydrocarbon Receptor Null Mutation and in Utero and Lactational 2,3,7,8-Tetrachlorodibenzo-p-dioxin Exposure on Prostate and Seminal Vesicle Development in C57BL/6 Mice

Lin, Tien-Min; Ko, Kinarm; Moore, Robert W.; Simanainen, Ulla; Oberley, Terry D.; Peterson, Richard E.

doi:10.1093/toxsci/68.2.479

Cited by 104 publications

(68 citation statements)

References 20 publications

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“…CV-1 cells express high levels of ARNT, which explains why additional ARNT had no significant effect on the reduction of AR transcriptional activity. Hence, AHR expression is required for the inhibitory effect of TCDD on AR-driven gene transcription, as observed in studies with AHR knockout mice (Lin et al, 2002). The presence of the activated AHR blocked AR-driven reporter activity from all three reporters regardless of the presence of AhRE motifs in the regulatory elements of the promoter, indicating that AHR directly inhibits AR activity through squelching mechanisms independent of the binding to inhibitory motifs in the regulatory region of the PSA gene.…”

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confidence: 63%

2,3,7,8-Tetrachlorodibenzo-p-dioxin Blocks Androgen-Dependent Cell Proliferation of LNCaP Cells through Modulation of pRB Phosphorylation

Barnes-Ellerbe

Knudsen²,

Puga

2004

Mol Pharmacol

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Cell-cycle regulatory events associated with inhibition of androgen-dependent cell proliferation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied in the human-derived LNCaP cell line. TCDD blocked the G 1 to S transition of LNCaP cells synchronized in G 0 /G 1 when these cells were induced to reinitiate cell-cycle progression by dihydrotestosterone (DHT). Western blot analyses of these cells revealed altered expression levels of G 1 regulatory proteins, including increases in hypophosphorylated retinoblastoma protein and concomitant decreases in cyclin D1. p21 WAF1/CIP1 , which is involved in the assembly of cyclin D1/cyclin-dependent kinase-4 complexes, was increased by DHT or TCDD when each compound was administered singly but was reduced to background levels in cells simultaneously treated with DHT and TCDD. Reporter gene assays revealed the presence of several Ah receptor response-element motifs in the promoter and first intron of the p21 WAF1/CIP1 gene that respond to TCDD-mediated Ah receptor activation independently of p53. Transcription studies showed that activation of aryl hydrocarbon receptor blocks androgen-dependent gene induction in LNCaP cells as well as in African green monkey CV-1 cells. These data point to at least two mechanisms whereby TCDD blocks androgen receptor function: 1) by blocking androgen-induced cell proliferation through modulation of the expression and activities of regulatory proteins controlling cell-cycle progression; and 2) by squelching androgen receptor-mediated gene transcription through receptor cross-talk, possibly involving competition for coregulators or by direct protein interaction.Depending on cell type and lineage, exposure to TCDD often leads to multiple diverse responses, including changes in cell proliferation and differentiation. Most, if not all, of the effects of TCDD are mediated through binding to a ligandactivated transcription factor known as the Ah receptor. In brief, TCDD binds to the AHR and facilitates the release of bound 90-kDa heat-shock proteins, resulting in receptor activation. Subsequent to this release, liganded AHR translocates to the nucleus, in which it heterodimerizes with ARNT.

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confidence: 63%

2,3,7,8-Tetrachlorodibenzo-p-dioxin Blocks Androgen-Dependent Cell Proliferation of LNCaP Cells through Modulation of pRB Phosphorylation

Barnes-Ellerbe

Knudsen²,

Puga

2004

Mol Pharmacol

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“…Investigation of PR knockout (PRKO) mice reveals normal embryonic development of the female genital tract, even though progesterone signaling through the PR is essential in the mature uterus during the estrous cycle and during the establishment and maintenance of pregnancy and lactogenesis of the mammary gland (Lydon et al, 1996;Lydon et al, 1995). Likewise, the AhR knockout (AhRKO) mouse provides a useful tool for producing tissue recombinants lacking AhR in one or more tissue compartment and for investigating the mechanism by which AhR agonists inhibit uterine epithelial proliferation (Lin et al, 2002). Thus, the profound phenotypes of these receptor mutant mice have provided the means for testing the relative roles of epithelial versus stromal steroid receptors in hormone action in male and female reproductive organs.…”

Section: Introductionmentioning

confidence: 99%

Role of stromal-epithelial interactions in hormonal responses

Cunha¹,

Cooke

Kurita

2004

Arch. Histol. Cytol.

273

191

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“…Common features of the AhR −/− mice are decreased liver size, hepatic portal fibrosis, and decreased constitutive expression of drug metabolizing enzymes such a P4501A1 and 1B1 (10). In the AhR mice produced in the Bradfield laboratory, seminal vesicle weight was higher than that of WT mice at postnatal day 35 (11), whereas in the AhR −/− mice produced in the Fujii-Kuriyama laboratory, seminal vesicles were reported to regress in an age-dependent manner (12). To date no abnormalities in the metabolism of purines or excretion of urate have been reported in AhR −/− mice and variable effects on the immune system have been reported in the three AhR −/− strains.…”

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Uric acid stones in the urinary bladder of aryl hydrocarbon receptor (AhR) knockout mice

Butler

Inzunza

Suzuki

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The aryl hydrocarbon receptor (AhR) knockout mice raised in the laboratory of Fujii-Kuriyama have been under investigation for several years because of the presence in their urinary bladder of large, yellowish stones. The stones are composed of uric acid and become apparent in the bladders as tiny stones when mice are 10 wk of age. By the time the mice are 6 mo of age, there are usually two or three stones with diameters of 3-4 mm. The urate concentration in the serum was normal but in the urine the concentration was 40-50 mg/dL, which is 10 times higher than that in the WT littermates. There were no apparent histological pathologies in the kidney or joints and the levels of enzymes involved in elimination of purines were normal. The source of the uric acid was therefore judged to be from degradation of nucleic acids due to a high turnover of cells in the bladder itself. The bladder was fibrotic and the luminal side of the bladder epithelium was filled with eosinophilic granules. There was loss of E-cadherin between some epithelial cells, with an enlarged submucosal area filled with immune cells and sometimes invading epithelial cells. We hypothesize that in the absence of AhR there is loss of detoxifying enzymes, which leads to accumulation of unconjugated cytotoxins and carcinogens in the bladder. The presence of bladder toxins may have led to the increased apoptosis and inflammation as well as invasion of epithelial cells in the bladders of older mice.

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Effects of Aryl Hydrocarbon Receptor Null Mutation and in Utero and Lactational 2,3,7,8-Tetrachlorodibenzo-p-dioxin Exposure on Prostate and Seminal Vesicle Development in C57BL/6 Mice

Cited by 104 publications

References 20 publications

2,3,7,8-Tetrachlorodibenzo-p-dioxin Blocks Androgen-Dependent Cell Proliferation of LNCaP Cells through Modulation of pRB Phosphorylation

2,3,7,8-Tetrachlorodibenzo-p-dioxin Blocks Androgen-Dependent Cell Proliferation of LNCaP Cells through Modulation of pRB Phosphorylation

Role of stromal-epithelial interactions in hormonal responses

Uric acid stones in the urinary bladder of aryl hydrocarbon receptor (AhR) knockout mice

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