Molecular Mechanisms of Environmental Organotin Toxicity in Mammals

Organotins such as tributyltin are suspected of having multiple toxic effects in mammals, in addition to their endocrine-disrupting function. Endogenous organotin concentrations in human blood range from a few to a few hundred nM. In this review, we summarize recent findings on the mechanisms of toxicity of environmental organotins such as tributyltin (TBT) and triphenyltin (TPT) in mammals. TBT and TPT are potent inhibitors of mitochondrial ATP synthase, and a recent study suggests that TBT binds directly to ATP synthase. Organotins disturb steroid biosynthesis and degradation. TBT and TPT are dual agonists of retinoid X receptor (RXR) and peroxisome proliferator-activated receptor gamma (PPAR gamma); they also induce the differentiation of adipocytes in vitro and in vivo, probably through PPAR gamma activation, suggesting that they may work as obesogens. Environmental organotins are also neurotoxic; they induce behavioral abnormality and are toxic to the developing central nervous system. In vitro studies have shown that organotins induce intracellular Ca2+ elevation and glutamate excitotoxicity. Recently, it was reported that endogenous levels of TBT decrease expression of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) receptor subunit GluR2, leading to neuronal vulnerability. Most of the experimental studies have employed organotins at concentrations of pm order, and it remains important to clarify the molecular mechanisms of events induced by endogenous levels of environmental organotins.