trans-activation of PPARα and PPARγ by structurally diverse environmental chemicals

A large number of industrial chemicals and environmental pollutants, including trichloroethylene (TCE), di(2-ethylhexyl)phthalate (DEHP), perfluorooctanoic acid (PFOA), and various phenoxyacetic acid herbicides, are nongenotoxic rodent hepatocarcinogens whose human health risk is uncertain. Rodent model studies have identified the receptor involved in the hepatotoxic and hepatocarcinogenic actions of these chemicals as peroxisome proliferator-activated receptor alpha (PPAR alpha), a nuclear receptor that is highly expressed in liver. Humans exhibit a weak response to these peroxisome proliferator chemicals, which in part results from the relatively low level of PPAR alpha expression in human liver. Cell transfection studies were carried out to investigate the interactions of peroxisome proliferator chemicals with PPAR alpha, cloned from human and mouse, and with PPAR gamma, a PPAR isoform that is highly expressed in multiple human tissues and is an important regulator of physiological processes such as adipogenesis and hematopoiesis, With three environmental chemicals, TCE, per-chloroethylene, and DEHP, PPARa was found to be activated by metabolites, but not by the parent chemical. A decreased sensitivity of human PPAR alpha compared to mouse PPAR alpha to trans-activation was observed with some (Wy-14,643, PFOA), but not other, peroxisome proliferators (TCE metabolites, trichloroacetate and dichloroacetate; and DEHP metabolites, mono[2-ethylhexyl]phthalate and 2-ethylhexanoic acid). Investigation of human and mouse PPAR gamma revealed the transcriptional activity of this receptor to be stimulated by mono(2-ethylhexyl)phthalate, a DEHP metabolite that induces developmental and reproductive organ toxicities in rodents. This finding suggests that PPAR gamma, which is highly expressed in human adipose tissue, where many lipophilic foreign chemicals tend to accumulate, as well as in colon, heart, liver, testis, spleen, and hematopoietic cells, may be a heretofore unrecognized target in human cells for a subset of industrial and environmental chemicals of the peroxisome proliferator class. (C) 1999 Academic Press.