Molecular modelling of phthalates – PPARs interactions

Abstract

Di(2-ethylhexyl) phthalate (DEHP) is the most widely plasticizer for polyvinyl chloride (PVC) that is used in plastic tubes, in medical and paramedical devices as well as in food storage packaging. The toxicological profile of DEHP has been evaluated in a number of experimental animal models and has been extensively documented. Its toxicity is in part linked to the activation of the peroxisome proliferator-activated receptor a (PPAR a ). As a response, an intensive research for a new, biologically inert plasticizer has been initiated. Among the alternative studied, tri(2-ethylhexyl) trimellitate (TEHTM) or trioctyl trimellitate (TOTM) has attracted increasing interest. However, very little information is available on their biological effects. We proceeded to dock TOTM, DEHP and its metabolites in order to identify compounds that are likely to interact with PPAR a and PPAR g binding sites. The results obtained hint that TOTM is not able to bind to PPARs and should therefore be safer than DEHP.

Docking study: PPARs interaction with the selected alternative plasticizers to di(2-ethylhexyl) phthalate

“…DEHP showed a slightly larger cluster of conformations in PPARa, corresponding to a third of the solutions, with its benzene at the very entrance of the pocket (Figure 2). A similar conformation was also found in the previous study, albeit with a lesser frequency 22 . Interestingly, DEHP also forms a number of hydrogen bonds, mostly with the skeletal NH of Ala 333 and the side chain of Thr 279.…”

“…It did not induce developmental effects in rats following gavage treatment during gestation. This is probably due to its inability to fit into the binding sites of the PPARs receptors 22 . However, a single-generation study found no effects on reproductive function, but did report decreased spermatocyte and spermatid counts in males treated by gavage at high dose 18 .…”

Structural Insight into PPARγ Ligands Binding

“…A first study of their mechanism of action was devolved to PPAR [71], then a large virtual screening of 73 phthalate monoesters from the ACD database was performed on PPAR [72], leading to the discrimination between potential or already known agonists and putative inactive derivatives. A long standing interest in the effect of phthalate esters led us to investigate the binding mode of three derivatives, the diester di(2-ethylhexyl) phthalate (DEHP), its metabolite mono-ethylhexyl phthalate (MEHP) and a putative replacement as plasticizer, trioctyl trimellitate (TOTM) [73]. Apparently, TOTM is hardly able to fit into the pocket of PPAR due to its large size, while the smaller MEHP could occupy the pocket fairly easily and forms the hydrogen bonds network of classical agonists.…”

Effects of Exposure to Plasticizers Di-(2-Ethylhexyl) Phthalate and Trioctyltrimellitate on the Histological Structure of Adult Male Albino Rats’ Liver

“…Moreover, PPARs plays an important role as a modulator of signal molecules that mediate alternations in gene expression of different enzymes involved in lipid homeostasis. Altered hepatic β oxidation pathways lead to medium and long chain fatty acids overload with subsequent increase of acyl coA activity that exceeds the free radicals elimination by catalase resulting in progressive DNA and parenchymal damage [24]. Marked periportal cellular infiltration was observable in DEHP treated subgroup IIA.…”