Tributyltin or Triphenyltin Inhibits Aromatase Activity in the Human Granulosa-like Tumor Cell Line KGN

Saitoh, Masayuki; Yanase, Toshihiko; Morinaga, Hidetaka; Tanabe, Makito; Mu, Yi Ming; Nishi, Yoshihiro; Nomura, Masatoshi; Okabe, Taijiro; Goto, Kiminobu; Takayanagi, Ryoichi; Nawata, Hajime

doi:10.1006/bbrc.2001.5952

Cited by 135 publications

(84 citation statements)

References 24 publications

(29 reference statements)

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“…Our quantitative analysis of the number of gonocytes/unit area of the seminiferous tubules revealed a significant decrease only at a maternal dose of 10 mg/kg (days [8][9][10][11][12][13][14][15][16][17][18][19]. However, both doses and exposure periods resulted in a reduction in the numbers of Sertoli cells, an effect which could potentially reduce sperm production in adulthood.…”

Section: Discussionmentioning

confidence: 99%

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In utero exposure to tributyltin chloride differentially alters male and female fetal gonad morphology and gene expression profiles in the Sprague–Dawley rat

Kishta

Adeeko

et al. 2007

Reproductive Toxicology

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Tributyltin (TBT) is an environmental contaminant commonly used in anti-fouling agents for boats, as well as a by-product from several industrial processes. It has been shown to accumulate in organisms living in areas with heavy maritime traffic thereby entering the food chain. Here, we determined the consequences of in utero exposure to TBT on the developing fetal gonads in the Sprague-Dawley rat. Timed pregnant rats were gavaged either with vehicle or TBT (0.25, 2.5, 10 or 20 mg/kg) from days 0 to 19 or 8 to 19 of gestation. On gestational day 20, dams were sacrificed; fetal testes and ovaries were processed for light (LM) or electron microscopic (EM) evaluation and RNA was prepared for gene expression profiling. At the highest doses of TBT the number of Sertoli cells and gonocytes was reduced, there were large intracellular spaces between Sertoli cells and gonocytes and there was an increased abundance of lipid droplets in the Sertoli cells; EM studies revealed abnormally dilated endoplasmic reticulum in Sertoli cells and gonocytes. In the intertubular region between adjacent interstitial cells, immunostaining for the gap junctional protein connexin 43 was strong in controls, whereas it was reduced or completely absent in treated rats. In the ovaries, TBT (20 mg/kg, days 0-19; 10 mg/kg, days 8-19) reduced the number of germ cells by 44% and 46%, respectively. On examining gene expression profiles in the testis, 40 genes out of 1176 tested were upregulated more than two-fold over control. While no genes were upregulated in the TBT exposed fetal ovary, eight genes were downregulated. In conclusion, in utero exposure to TBT resulted in gender-specific alterations in gonadal development and gene expression profiles suggesting that there may be different adaptive changes to toxicity in developing male and female rats.

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Section: Discussionmentioning

confidence: 99%

“…TBT inhibits human aromatase activity in a granulosa celllike tumor cell line and transfected cells [9,18,19] and, at noncytotoxic doses, enhances aromatase activity in human placental choriocarcinoma cells [20], raising the possibility of such interactions during exposure. Exposure to organotins can affect mammalian reproduction.…”

Section: Introductionmentioning

confidence: 99%

In utero exposure to tributyltin chloride differentially alters male and female fetal gonad morphology and gene expression profiles in the Sprague–Dawley rat

Kishta

Adeeko

et al. 2007

Reproductive Toxicology

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“…In opposition to the above results, however, Saitoh et al reported that 20 ng/ml (about 60 nM) TBT and TPT suppressed both the activity and gene expression of aromatase in the human ovarian granulose-like cell line, KGN (Saitoh et al, 2001). This discrepancy in the action of organotins on the gene expression of human aromatase is due to the tissue-specific expression of aromatase, which is strictly regulated (Fig.…”

Section: Organotin Compounds Affect Endocrine Functions In Human Placmentioning

confidence: 78%

“…In in vitro experiments, butyltins are demonstrated to exhibit structure-related inhibition of the catalytic activity of human aromatase protein from human placenta (Heidrich et al, 2001) or transfected cells (Cooke, 2002). However, at concentrations effective (micromolar level) for the inhibition of aromatase, TBT and TPT are generally toxic to mammalian cells because (Saitoh et al, 2001;Nakanishi et al, 2002;Watanabe et al, 2003;Nakanishi et al, 2006). In human choriocarcinoma cell lines, JAr, JEG-3 and BeWo, exposure to greater than 300 nM TBT or TPT markedly decreases DNA and protein synthesis (Nakanishi et al, 2002;Nakanishi et al, 2006).…”

Section: Organotins As Endocrine-disrupting Chemicalsmentioning

confidence: 99%

“…In contrast, Ad4Bp/SF-1 is expressed at very low levels in the human placenta and may not play an important role in activation of the placental major promoter I.1 (Bamberger et al, 1996;Simpson et al, 1997). Saitoh et al suggest that the effects of organotin compounds in KGN cells are caused partly by association with Ad4Bp/SF-1 (Saitoh et al, 2001). It is therefore likely that the action of organotin compounds in human placental cells is induced by a pathway clearly different from that in ovarian granulosa cells, giving rise to the promotion of aromatase activity and mRNA expression.…”

Section: Organotin Compounds Affect Endocrine Functions In Human Placmentioning

confidence: 99%

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Endocrine disruption induced by organotin compounds; organotins function as a powerful agonist for nuclear receptors rather than an aromatase inhibitor

Nakanishi

2008

J. Toxicol. Sci.

139

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ABSTRACTing nets, agricultural fungicides and rodent repellents. These widespread uses have resulted in the release of increasing amounts of organotins into the environment. In aquatic invertebrates, particularly marine gastropods, organotin compounds, such as tributyltin (TBT) and triphenyltin (TPT), induce irreversible sexual abnormality in females which is termed "imposex" at very low concentrations. Although it has been theorized that these compounds act as potential competitive inhibitors of aromatase, which converts androgen to estrogen, and then increase levels of unconverted androgens in gastropods, their effective concentrations for aromatase inhibition are high. In addition to wildlife, organotins may have various undesirable effects on human health. Contrary to the theory of organotin-induced aromatase inhibition in gastropods, in human choriocarcinoma cells, these compounds markedly enhance estradiol biosynthe-HSD I) activity, which converts low-activity estrogen estrone to the biologically more active form estradiol, at the same low concentrations. Although there are many reports describing the potential toxicity of organotins in human and mammals, the critical target molecules for the toxicity of organotin compounds are members of the nuclear receptor superfamily. Here, we review the potential genetics action and subsequent toxicity induced by organotins via these nuclear receptors.

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Phenylzinnverbindungen [MAK Value Documentation in German language, 2010]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 48. Lieferung, Ausgabe 2010 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Wirkungsmechanismus Toxikokinetik und Metabolismus Toxikokinetik Metabolismus Erfahrungen beim Menschen Einmalige Exposition Wiederholte Exposition Wirkung auf Haut und Schleimhäute Allergene Wirkung Tierexperimentelle Befunde und In‐vitro‐Untersuchungen Akute Toxizität Subakute, subchronische und chronische Toxizität Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Sonstige Wirkungen Bewertung

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Tributyltin or Triphenyltin Inhibits Aromatase Activity in the Human Granulosa-like Tumor Cell Line KGN

Cited by 135 publications

References 24 publications

In utero exposure to tributyltin chloride differentially alters male and female fetal gonad morphology and gene expression profiles in the Sprague–Dawley rat

In utero exposure to tributyltin chloride differentially alters male and female fetal gonad morphology and gene expression profiles in the Sprague–Dawley rat

Endocrine disruption induced by organotin compounds; organotins function as a powerful agonist for nuclear receptors rather than an aromatase inhibitor

Phenylzinnverbindungen [MAK Value Documentation in German language, 2010]

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