Activation of Mouse and Human Peroxisome Proliferator-Activated Receptors (PPARs) by Phthalate Monoesters

Abstract

Administration of phthalates is known to cause toxicity and liver cancer in rodents through the activation of peroxisome proliferator-activated receptors (PPARs), and the monoesters appear to be the active metabolites that function as ligands of PPARs. There is evidence that PPARs exhibit significant species differences in response to ligand activation. In this study, the activation of mouse and human PPARalpha, PPARbeta, and PPARgamma by a broad class of phthalate monoesters was investigated using a trans-activation assay, functional analysis of PPARalpha target gene expression, and a PPARgamma-mediated differentiation assay. These studies demonstrated a range in the ability of various phthalate monoesters to activate PPARalpha, with the mouse PPARalpha generally being activated at lower concentrations and exhibiting a greater response than human PPARalpha. Similarly, a range in the trans-activation of mouse PPARbeta by phthalate monoesters was also observed, but this effect was not found with human PPARbeta. A number of phthalate monoesters activated both mouse and human PPARgamma, with similar sensitivity being exhibited by both receptors. These studies show that the potency and efficacy of phthalate monoesters for the activation of PPARalpha and PPARgamma increase with increasing side-chain length. These studies also show that mouse PPARalpha and PPARbeta are generally activated at lower concentrations of phthalate monoesters than human PPARalpha and PPARbeta, and that both mouse and human PPARgamma exhibit similar sensitivity to phthalate monoesters. Lastly, there is a good relationship between the relative ability of phthalate monoesters to trans-activate PPARalpha and PPARgamma, and the relative induction of PPARalpha target gene mRNA and PPARgamma-mediated adipocyte differentiation, respectively.

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

“…However, the mechanisms involved in these new aspects of phthalate metabolic impact remain poorly understood. At the molecular level, the activation of the three isoforms of the peroxisome proliferator-activated receptor (PPAR, , , ) by phthalate metabolites and the resulting metabolic consequences have been extensively documented [28]. In adipose cells, mono-ethylhexyl-phthalate (MEHP), a potent metabolite of DEHP, activates PPAR (Nr1c3) and promotes adipogenesis [29].…”

Interference of pollutants with PPARs: endocrine disruption meets metabolism

“…[38][39][40] MEHP can indeed activate all mouse and human PPARg isoforms, even though with different efficacies between isoforms and cell lines.…”

“…Indeed, PPARa is a recognized target for pollutants as it mediates peroxisome proliferation and associated carcinogenic effects in rodent liver in response to a class of chemicals referred to as peroxisome proliferator chemicals. In addition, several reports have showed PPAR activation by environmental pollutants such as phthalates produced by the plastic industry, [38][39][40] perfluorooctane-based chemicals found in industrial surfactants, 41,42 organotins used as agricultural fungicides and anti-fouling agents in ship paints, 13,43 as well as several other pesticides. 44,45 However, fairly little is known on the metabolic consequences of PPAR activation by pollutants, both in terms of molecular mechanism of action and physiological outputs.…”

“…47,48 This involvement of PPARs in the action of phthalate is consistent with the in vitro activation of PPARa, but also PPARb and PPARg using transactivation assays and intact cellular systems with endogenous receptors and target genes. 38,39 These studies determined the range of potency and efficacy of phthalate monoesters on PPARa, PPARb and PPARg activation. They also showed that mouse PPARa and PPARb are generally activated at relatively lower concentrations of phthalate monoesters than human PPARa and PPARb, whereas human and mouse PPARg exhibit similar sensitivity.…”

Phtalates: new cardiovascular health disruptors?

“…Importantly, MEHP induces a selective activation of different PPARγ co-regulators including Med1 and PGC-1α, but not p300 and SRC (Feige et al 2007). In addition to PPARγ, phthalate monoesters have been reported to activate PPARα and PPARβ both in mice and humans with similar sensitivity (Bility et al 2004). Hurst et al investigated the activation of PPARα and PPARγ by phthalate monoesters using cell-based transactivation assays and by monitoring PPAR target gene expression (PPARα) or PPAR-dependent adipocyte differentiation (PPARγ) (Hurst and Waxman 2003).…”