Organotin Compounds Promote Adipocyte Differentiation as Agonists of the Peroxisome Proliferator-Activated Receptor /Retinoid X Receptor Pathway

Nuclear receptors play important roles in the maintenance of the endocrine system, regulation of organ differentiation, and fetal development. Endocrine disruptors exert their adverse effects by disrupting the endocrine system via various mechanisms. To assess the effects of endocrine disruptors on nuclear receptors, we developed a high-throughput method for identifying activators of nuclear receptors. Using this system, we found that triphenyltin and tributyltin were activators of peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor. Because PPAR is a master regulator of adipocyte differentiation, we assessed the effect of organotin compounds on preadipocyte 3T3-L1 cells. We found that organotin compounds stimulated differentiation of 3T3-L1 cells as well as expression of adipocyte marker genes. An endocrine disruptor is an exogenous substance or mixture that alters functions of the endocrine system and consequently causes adverse health effects in an intact organism, its progeny, or (sub)populations (WHO, 1996). Many naturally occurring and synthetic compounds, including DDT and its metabolites, polychlorinated biphenyls, and some alkylphenols, have hormonal activities (Sohoni and Sumpter, 1998; Nishihara et al., 2000; Gray et al., 2001; Sanderson et al., 2002). Although the levels of natural hormones are precisely regulated metabolically, synthetic chemicals elude this regulation to stimulate organs by mechanisms different from those of natural hormones. The importance of nuclear receptors in endocrine function has been well established by many studies. The human genome contains at least 48 members of the nuclear receptor family (Chawla et al., 2001), and various chemicals bind to nuclear receptors and influence the expression of target genes (Blair et al., 2000; Sultan et al., 2001). To evaluate the effects of numerous synthetic chemicals on many nuclear receptors, we developed the CoA-BAP system, a highthroughput method for identifying nuclear receptor ligands (Kanayama et al., 2003). In the present study, we applied the CoA-BAP system to the evaluation of 16 human nuclear receptors and 40 suspected endocrine disruptors. We found that organotin compounds such as triphenyltin (TPT) and tributyltin (TBT) strongly activated retinoid X receptor