Concentration-dependent inhibition of development of GGT positive foci in rat liver by the environmental contaminant di(2-ethylhexyl) phthalate.

Abstract

The ability of di(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer and environmental contaminant, to suppress development of putative preneoplastic lesions in rat liver was evaluated. y-Glutamyl transpeptidase-positive (GGT + ) foci were initiated in the livers of Sprague-Dawley male rats with a single dose of diethylnitrosamine (DEN) following partial hepatectomy. Promotion of foci was commenced by feeding a choline-deficient diet (CD). A group of control rats was fed a choline-supplemented diet (CS). The ability of DEHP to suppress the emergence of GGT + foci was evaluated by feeding additional groups of rats the CD diet containing either 0.1%, 0.5%, 1.0% or 2.0% DEHP. The CD diet promoted the number of GGT+ foci above levels in control livers. Inclusion of the plasticizer to the levels of 0.5%, 1.0% and 2.0% in the CD diet effectively inhibited the appearance of the foci. However, DEHP was unable to inhibit the promoting effect of the CD diet at a concentration of 0.1%. DEHP's ability to block development of GGT+ foci correlated with its ability to increase liver weight and to induce carnitine acetyltransferase (EC 2.3.1.7), a marker of peroxisome proliferation.

Quantitative image cytometry of hepatocytes expressing gamma-glutamyl transpeptidase and glutathione S-transferase in diethylnitrosamine-initiated rats treated with phenobarbital and/or phthalate esters.

“…DEHP, which induces formation of peroxisomes, has been shown to be a hepatocarcinogen per se in rats when given in the diet at 0.6% or 1.2% (35). Earlier we had reported on the interaction of DEHP with DENAinitiated hepatocarcinogenic markers evaluated after only 10 weeks of exposure (5,6). In the present studies, expression of two putative markers of neoplasia in rat liver, GGT and GST-P, was used as probes to detect AT; and N. AF staining for GGT and GST-P is not found in livers of rats exposed to some peroxisome proliferators such as Wy-14,643, Br-91, and cibrofibrate (36,37).…”

“…Earlier experiments demonstrated that a 10-week exposure to di(2-ethylhexy1)phthalate (DEHP) significantly reduced the number of AF appearing in livers of rats previously initiated with a single dose of the liver carcinogen diethylnitrosamine (DENA) (5,6). Conversely, exposure of DENA-initiated animals to di-n-octylphthalate (DOP) for 10 weeks caused a fivefold increase in the number of foci compared with animals treated with DENA alone (6).…”

Plasticizer DBP Activates NLRP3 Inflammasome through the P2X7 Receptor in HepG2 and L02 Cells

“…In addition, DEHP profoundly caused structural and functional properties of the liver. It affected the cell organelles, such as peroxisomes and mitochondria, and expression of the enzymes involving in fatty acid transport and β‐oxidation . The U.S. Environmental Protection Agency has defined plasticizes as water and air pollutants .…”