Interspecies Differences in Activation of Peroxisome Proliferator-Activated Receptor gamma by Pharmaceutical and Environmental Chemicals

Endocrine disrupting chemicals (EDCs) are able to deregulate the hormone system, notably through interactions with nuclear receptors (NRs). The mechanisms of action and biological effects of many EDCs have mainly been tested on human and mouse but other species such as zebrafish and xenopus are increasingly used as a model to study the effects of EDCs. Among NRs, peroxisome proliferator-activated receptor gamma (PPAR gamma) is a main target of EDCs, for which most experimental data have been obtained from human and mouse models. To assess interspecies differences, we tested known human PPAR gamma ligands on reporter cell lines expressing either human, mouse, zebrafish, or xenopus PPAR gamma. Using these cell lines, we were able to highlight major interspecies differences. Known hPPAR gamma pharmaceutical ligands modulated hPPAR gamma and mPPAR gamma activities in a similar manner, while xPPAR gamma was less responsive and zfPPAR gamma was not modulated at all by these compounds. On the contrary, human liver X receptor (hLXR) ligands GW 3965 and WAY-252623 were only active on zfPPAR gamma. Among environmental compounds, several molecules activated the PPAR. of the four species similarly, e.g., phthalates (MEHP), perfluorinated compounds (PFOA, PFOS), and halogenated derivatives of BPA (TBBPA, TCBPA), but some of them like diclofenac and the organophosphorus compounds tri-o-tolyl phosphate and triphenyl phosphate were most active on zfPPAR gamma. This study confirms or shows for the first time the h, m, x, and zfPPAR gamma activities of several chemicals and demonstrates the importance of the use of species-specific models to study endocrine and metabolism disruption by environmental chemicals.