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 PPARα, PPARβ, and PPARγ by a broad class of phthalate monoesters was investigated using a trans-activation assay, functional analysis of PPARα target gene expression, and a PPARγ -mediated differentiation assay. These studies demonstrated a range in the ability of various phthalate monoesters to activate PPARα, with the mouse PPARα generally being activated at lower concentrations and exhibiting a greater response than human PPARα. Similarly, a range in the trans-activation of mouse PPARβ by phthalate monoesters was also observed, but this effect was not found with human PPARβ. A number of phthalate monoesters activated both mouse and human PPARγ, with similar sensitivity being exhibited by both receptors. These studies show that the potency and efficacy of phthalate monoesters for the activation of PPARα and PPARγ increase with increasing side-chain length. These studies also show that mouse PPARα and PPARβ are generally activated at lower concentrations of phthalate monoesters than human PPARα and PPARβ, and that both mouse and human PPARγ exhibit similar sensitivity to phthalate monoesters. Lastly, there is a good relationship between the relative ability of phthalate monoesters to trans-activate PPARα and PPARγ, and the relative induction of PPARα target gene mRNA and PPARγ-mediated adipocyte differentiation, respectively.
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