Molecular targets of organotin compounds in endocrine disruption: do organotin compounds function as aromatase inhibitors in mammals?
Tributyltin (TBT) and triphenyltin (TPT) cause masculinization in female mollusks. These compounds may act as potential competitive inhibitors of aromatase, which converts androgens to estrogens, although effective concentrations are high. TBT and TPT may, therefore, increase the levels of unconverted androgens in invertebrates and vertebrates. However, at concentrations effective for aromatase inhibition, they are generally toxic to mammalian cells. These compounds markedly enhance aromatase activity and human chorionic gonadotropin (hCG) production, along with their mRNA expression, at very low concentrations in human choriocarcinoma cells. In ovarian granulosa cells, these compounds suppress aromatase gene expression at the same low concentrations. Therefore, it is suspected that, in mammals, these organotin compounds affect target molecules that regulate the gene expressions of aromatase and hCG, rather than functioning as aromatase inhibitors. Recently, it has been demonstrated that TBT and TPT directly bind to the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor (PPAR) gamma with high affinity and function as transcriptional activators. These compounds promoted adipocyte differentiation, which is triggered by the PPAR gamma/RXR signaling pathway. They may, therefore, exert their toxic effects through the activation of these pathways in mammals. Here, we review the potential endocrine disruption of organotin compounds via these nuclear receptors in mammals.
Nakanishi
Tsuyoshi
T
Department of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka, Suita, Osaka 565-0871, Japan. nakanishi@phs.osaka-u.ac.jp
Nishikawa
Jun-ichi
J
Tanaka
Keiichi
K
D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000633:toxicity; D006063:Chorionic Gonadotropin / Q000235:genetics / Q000378:metabolism; D052244:Endocrine Disruptors / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009947:Organotin Compounds / Q000633:toxicity*; D047495:PPAR gamma / Q000819:agonists*; D047488:Retinoid X Receptors / Q000819:agonists*
D047072:Aromatase Inhibitors; D006063:Chorionic Gonadotropin; D052244:Endocrine Disruptors; D009947:Organotin Compounds; D047495:PPAR gamma; D047488:Retinoid X Receptors; D001141:Aromatase