Enhancement of Androgen-Dependent Transcription and Cell Proliferation by Tributyltin and Triphenyltin in Human Prostate Cancer Cells

Published on Dec 1, 2000in Toxicology and Applied Pharmacology 3.62
· DOI :10.1006/taap.2000.9067
Yukako Yamabe4
Estimated H-index: 4
(Kitasato University),
Azusa Hoshino1
Estimated H-index: 1
(Kitasato University)
+ 2 AuthorsSeiichiro Himeno16
Estimated H-index: 16
(Kitasato University)
Tributyltin (TBT) and triphenyltin (TPT) are known to cause imposex, the superimposing of male genitals on female ones, in some species of gastropods. However, the molecular mechanism of the trialkyltin-induced endocrine dysfunction remains to be elucidated. To clarify the effects of organotin compounds on the activation of androgen receptor (AR)-mediated responses in mammals, a LA16 clone that stably expresses androgen-responsive luciferase reporter gene and proliferates in response to androgen was established from human prostate cancer cell line LNCaP. Stimulation of LA16 cells with 100 nM TBT or 1 nM TPT enhanced both AR-dependent transcription of luciferase gene and cell growth to the same extent as those by 1 nM dihydrotestosterone (DHT). TBT or TPT also enhanced the DNA synthesis and expression of endogenous AR target genes such as prostate specific antigen, but not the expression of AR itself. However, an androgen antagonist, flutamide, did not inhibit the TBT- or TPT-induced AR activation. On the other hand, simultaneous treatment of LA16 cells with DHT and TBT or TPT caused highly enhanced effects on AR activation. These results indicate that trialkyltin compounds have an ability to activate AR-mediated transcription in mammalian cells and suggest that a novel target site other than the ligand-binding site of AR is involved in this activation.
  • References (45)
  • Citations (70)
Published on Jul 1, 1989in Cancer Research 9.13
Carlos Sonnenschein57
Estimated H-index: 57
Nicolás Olea39
Estimated H-index: 39
+ 1 AuthorsAna M. Soto68
Estimated H-index: 68
LNCaP cells represent a useful tool to explore the mechanism of sex hormone action on cell proliferation in an “in culture-in animal” model. Results indicated that: ( a ) these cells were inhibited from proliferating for extended periods (up to 30 days) when placed in charcoal-dextran-stripped sera; they remained, however, viable because they proliferated when sex hormones were added to this medium; ( b ) the inhibitory effect of sera was reversed by the addition of 5α-dihydrotestosterone at 3 ×...
191 Citations
Published on Feb 25, 1991in Journal of Biological Chemistry 4.01
J H van Laar1
Estimated H-index: 1
Cor Berrevoets20
Estimated H-index: 20
+ 2 AuthorsBrinkmann Ao59
Estimated H-index: 59
Abstract Phosphorylation of the androgen receptor was investigated in the absence of hormone as well as during and after transformation of the receptor to the tight nuclear binding form. Human prostate tumor cells (LNCaP) were labeled for 4 h with [32P]orthophosphate in the presence or absence of steroid. Subsequently, androgen receptors were immunoprecipitated either from total cell lysates or from nuclear extracts using a specific monoclonal antibody. The immunoprecipitated receptor preparatio...
65 Citations
Published on Nov 1, 1951in Journal of Biological Chemistry 4.01
Oliver H. Lowry67
Estimated H-index: 67
(Washington University in St. Louis),
Nira J. Rosebrough1
Estimated H-index: 1
(Washington University in St. Louis)
+ 1 AuthorsRose J. Randall1
Estimated H-index: 1
(Washington University in St. Louis)
Since 1922 when Wu proposed the use of the Folin phenol reagent for the measurement of proteins, a number of modified analytical procedures utilizing this reagent have been reported for the determination of proteins in serum, in antigen-antibody precipitates, and in insulin. Although the reagent would seem to be recommended by its great sensitivity and the simplicity of procedure possible with its use, it has not found great favor for general biochemical purposes. In the belief that this reagent...
241k Citations
Published on Jan 1, 1991in Marine Environmental Research 3.16
N. Spooner1
Estimated H-index: 1
(University of Liverpool),
P.E. Gibbs15
Estimated H-index: 15
(Plymouth Marine Laboratory)
+ 1 AuthorsL.J. Goad1
Estimated H-index: 1
(University of Liverpool)
Abstract Exposure of female Nucella lapillus to tributyltin (TBT) in seawater at a concentration of 40 ng Sn/litre led to accumulation of TBT in the tissues, and an increase in penis length compared to control animals. Investigation of the steroid concentrations by radioimmunoassay revealed a significant increase in testosterone after 28 days exposure to TBT. No significant effect was noted upon the amounts of progesterone or estradiol-17β. When testosterone was injected into female N. lapillus ...
186 Citations Source Cite
Published on Feb 1, 1981in Journal of Applied Toxicology 2.91
Blakeman S. Smith4
Estimated H-index: 4
(University of Rochester)
This study continues an investigation of ananatomical abnormality, named ‘imposex’, which consists of a superimposition of male characteristics on to a functionally normal female reproductive anatomy of the dioecious snail Nassarius obsoletus Say. Imposex is prevalent in natural populations living near yacht basins and rarely found distant from them. In the current study caged snails were transferred between a yacht basin and a distant ‘clean’ locality where the natural population of snails was ...
144 Citations Source Cite
Published on Oct 1, 1995in Nature 41.58
Ronald M. Evans173
Estimated H-index: 173
(Salk Institute for Biological Studies),
J. Don Chen2
Estimated H-index: 2
(Salk Institute for Biological Studies)
In accordance with the present invention, there are provided novel receptor interacting factors, referred to herein as “SMRT”, i.e., a silencing mediator (co-repressor) for retinoic acid receptor (RAR) and thyroid hormone receptor (TR). SMRT is a novel protein whose association with RAR and TR both in solution and on DNA response elements is destabilized by ligand. The interaction of SMRT with mutant receptors correlates with the transcriptional silencing activities of receptors. In vivo, SMRT f...
1,769 Citations Source Cite
Published on Nov 1, 1999in Environmental Research 4.73
Yolanda Morcillo11
Estimated H-index: 11
(Spanish National Research Council),
Cinta Porte51
Estimated H-index: 51
(Spanish National Research Council)
Testosterone/estradiol tissue levels and cytochrome P450-dependent aromatase activity have been evaluated in the gastropod Bolinus brandaris. Samples were collected from two locations on the Mediterranean coast (St. Carles and Barcelona) according to their different degrees of imposex development and organotin residues. St. Carles was chosen as a relatively clean site, as only 37% of the females were imposex affected compared to 100% of the females from Barcelona. A strong reduction of estradiol...
73 Citations Source Cite
Published on Jan 1, 1999in Toxicology and Applied Pharmacology 3.62
Jun-ichi Nishikawa21
Estimated H-index: 21
(Osaka University),
Koichi Saito4
Estimated H-index: 4
(Osaka University)
+ 3 AuthorsMasatoshi Matsuo3
Estimated H-index: 3
(Osaka University)
Abstract The endocrine system exerts important functions in a multitude of physiological processes including embryogenesis, differentiation, and homeostasis. Xenobiotics may modify natural endocrine function and so affect human health and wildlife. It is necessary, therefore, to understand the degree to which xenobiotics can disrupt endocrine systems. The key targets of endocrine disruptors are nuclear hormone receptors, which bind to steroid hormones and regulate their gene transcription. We ha...
296 Citations Source Cite
Published on May 1, 1989in Toxicology 3.27
Ivan J. Boyer1
Estimated H-index: 1
(Food and Drug Administration)
Abstract Alkyltin compounds are used as stabilizers and antifouling agents. Food chain accumulation and bioconcentration have been demonstrated in crabs, oysters and salmon exposed to tributyltin oxide. In mammalian species, tributylin compounds may be metabolized to dibutyltin derivatives and related metabolites. Di- and tributyltins appear to be less potent neurotoxicants than trimethyltins and triethyltins. Dibutyltins and tributyltins produced bile duct damage in rats, mice and hamsters. Tri...
351 Citations Source Cite
Published on Aug 16, 1996in Journal of Biological Chemistry 4.01
Lynne V. Nazareth32
Estimated H-index: 32
(Baylor College of Medicine),
Nancy L. Weigel58
Estimated H-index: 58
(Baylor College of Medicine)
Abstract Aberrant activation of the androgen receptor through signaling pathways independent of androgen may be responsible for the progression of prostate tumors to the rapidly proliferating androgen-independent state. In this study, the effects of protein kinase A modulators on human androgen receptor activity were tested. Using an adenoviral DNA delivery system, we demonstrate that the androgen receptor can be activated by a protein kinase A activator, forskolin, in the absence of androgen wh...
385 Citations Source Cite
Cited By70
Published on Apr 1, 2015in Medical Hypotheses 1.12
Maria C. Mazioti1
Estimated H-index: 1
(Athens State University),
Konstantinos P. Markakis2
Estimated H-index: 2
(Athens State University),
Athanasios E. Raptis8
Estimated H-index: 8
(Athens State University)
Source Cite
Published on Jan 1, 2012in Journal of Toxicology
Harald F. Krug30
Estimated H-index: 30
(Swiss Federal Laboratories for Materials Science and Technology)
Tributyltin (TBT) is one of the most toxic compounds produced by man and distributed in the environment. A multitude of toxic activities have been described, for example, immunotoxic, neurotoxic, and endocrine disruptive effects. Moreover, it has been shown for many cell types that they undergo apoptosis after treatment with TBT and the cell death of immune cells could be the molecular background of its immunotoxic effect. As low as 200 nM up to 1 μM of TBT induces all signs of apoptosis in Jurk...
9 Citations Source Cite
Masayuki Saitoh4
Estimated H-index: 4
(Kyushu University),
Toshihiko Yanase42
Estimated H-index: 42
(Kyushu University)
+ 8 AuthorsHajime Nawata26
Estimated H-index: 26
(Kyushu University)
The superimposition of male sex organs (penis and vas deferens) in a female gastropod, called imposex, is widely attributed to the exposure to tributyltin (TBT) compounds, used world-wide in antifouling paints for ships. It has been hypothesized that the TBT-induced imposex is mediated by an increasing androgen level relative to the estrogen level, namely a decreased conversion of androgens to estrogens (i.e., aromatization). In the present study, we tested this hypothesis by examining the effec...
118 Citations Source Cite
Published on Oct 21, 2005in Environmental Health Perspectives 8.44
Toshihiro Horiguchi22
Estimated H-index: 22
Mitsuhiro Kojima4
Estimated H-index: 4
+ 4 AuthorsMakoto Shimizu45
Estimated H-index: 45
We histopathologically examined gonads and chemically determined organotin compounds in tissues of the ivory shell, Babylonia japonica. Imposex (a superimposition of male-type genital organs on females) occurred in approximately 80–90% of B. japonica specimens that we examined, with the penis and vas deferens both well developed. No oviduct blockage by vas deferens formation was observed. Ovarian spermatogenesis and suppressed ovarian maturation were observed in the females that exhibited impose...
57 Citations Source Cite
Published on Jan 1, 2003in Journal of Toxicology and Environmental Health 2.71
Vincent F. Garry19
Estimated H-index: 19
(University of Minnesota),
Seth Holland3
Estimated H-index: 3
(University of Minnesota)
+ 1 AuthorsBarbara Burroughs5
Estimated H-index: 5
(University of Minnesota)
In the present effort, 144 pesticide applicators and 49 urban control subjects who reported no chronic disease were studied. Applicators provided records of the season's pesticides used by product, volumes, dates, and methods of application. Blood specimens for examination of hormone levels were obtained in summer and fall. In the herbicide-only applicator group, significant increases in testosterone levels in fall compared to summer and also elevated levels of follicle-stimulating hormone (FSH)...
41 Citations Source Cite
Published on Oct 1, 2004in Toxicology 3.27
Konstanze Grote15
Estimated H-index: 15
Beate Stahlschmidt1
Estimated H-index: 1
+ 3 AuthorsIbrahim Chahoud17
Estimated H-index: 17
Tributyltin (TBT) and triphenyltin (TPT) induce effects in male and female reproductive organs of rodents. They also cause tumors in these organs and it is theorized that they result from endocrine disruption. We studied the effects of 40 mg methyltestosterone (MTT), 0.5 or 15 mg TBT and 2, 6 or 12 mg TPT/kg bw on the male sexual development using a modification of the Rodent 20-Day Thyroid/Pubertal Male Assay. Male Wistar rats were treated per gavage for 30 days beginning at 23 days of age. A d...
83 Citations Source Cite
Mari S. Golub10
Estimated H-index: 10
(California Environmental Protection Agency),
John D. Doherty6
Estimated H-index: 6
(United States Environmental Protection Agency)
Organotin compounds have been implicated as reproductive toxicants and endocrine disruptors primarily through studies in aquatic organisms, with little information available in mammals. Among the organotins, aryltins have been less studied than alkyltins. Extensive data is available on mammalian developmental and reproductive toxicity of one aryltin compound, triphenyltin (TPT), from toxicity studies conducted in connection with the registration of triphenyltin hydroxide (TPTH) as a pesticide an...
62 Citations Source Cite
Published on May 1, 2006in Environmental Toxicology and Pharmacology 2.78
Olivier Champeau4
Estimated H-index: 4
(University of Bordeaux),
Jean-François Narbonne27
Estimated H-index: 27
(University of Bordeaux)
Abstract Freshwater clams Corbicula fluminea were experimentally exposed to a range of tributyltin (TBT) (50, 250 and 500 ng Sn/L) and 17β-estradiol (20, 200, 2000 ng/L) for 30 days. After 15 and 30 days, phagocytosis activity of haemocytes and lysosomal structural changes in the digestive cells were assayed. 17β-Estradiol exerted a higher inhibition on phagocytosis than tributyltin. This would suggest the existence of estrogen receptors, influencing the immune function. The stereological parame...
19 Citations Source Cite
Published on Sep 1, 2002in Marine Environmental Research 3.16
Toshihiro Horiguchi22
Estimated H-index: 22
(National Institute for Environmental Studies),
Mitsuhiro Kojima4
Estimated H-index: 4
(National Institute for Environmental Studies)
+ 4 AuthorsY Adachi1
Estimated H-index: 1
(Ibaraki University)
Abstract Two-month flow-through exposure experiments of tributyltin (TBT) and triphenyltin (TPhT) were conducted with abalone, Haliotis gigantea . Nominal concentrations of 100 ng TBT/l and 100 ng TPhT/l caused significant spermatogenesis in ovaries of exposed females. There were also significantly more contracted primary oocytes observed in females exposed to either TBT or TPhT than controls. The incidence of two types of unknown cells was also significant in females exposed to TPhT. No signifi...
52 Citations Source Cite
Published on Jul 1, 2004in Gynecological Endocrinology 1.45
S Prifti1
Estimated H-index: 1
(National and Kapodistrian University of Athens),
I. Lelle2
Estimated H-index: 2
(Heidelberg University)
+ 1 AuthorsThomas Rabe17
Estimated H-index: 17
(Heidelberg University)
The function and clinical significance of the androgen receptor (AR) in human breast cancer are still not clear. The synthetic progestins, norgestimate and norelgestromin, were designed to minimize the adverse effects such as acne, hirsuitism and metabolic changes observed with older oral contraceptives while maintaining contraceptive effectiveness and cycle control. AR-mediated effects of these synthetic progestins were studied in an in vitro transactivation assay, employing DNA co-transfection...
3 Citations Source Cite