Tributyltin is a potent inhibitor of piscine peroxisome proliferator-activated receptor α and β

Abstract

Increasing evidence suggests that common environmental contaminants can act as endocrine disrupters in fish. However, current data are biased towards environmental estrogens, highlighting the need to elucidate potential pollutant impact on other endocrine axes. Here, we report a highthroughput assay to identify chemicals interacting with piscine peroxisome proliferator-activated receptors (PPARs). Our transactivation assay employs a fish cell line and uses recombinant proteins combining the yeast Gal4 DNA-binding domain with the ligand-binding domain of PPARs from plaice. Compared to assays with full-length PPARs, this approach circumvents interaction of chemicals binding to retinoid X receptors, which form heterodimers with PPAR and many other nuclear receptors. Plaice PPARa and PPARb are activated by fibrate drugs and by phthalate monoesters at concentrations similar to those activating the homologous mammalian receptors. In line with their assumed role as central transcriptional regulators of energy homostasis, a number of fatty acids activate plaice PPARa and PPARb. In contrast, tributyl tin oxide (TBTO) is a potent antagonist of PPARa and PPARb, showing activity at environmentally relevant concentrations of TBTO (1-50 nM). Given the ubiquitous and persistent nature of TBTO, the possibility that chronic environmental effects are occurring via disruption of PPAR signalling in fish should be further investigated. Keywords: tributyltin, TBTO, PPAR, pollutant, fibr