Peroxisome Induction Studies On Seven Phthalate Esters

Abstract

Seven phthalate esters, representing a variety of chain lengths and degrees of branching in the alcohol moiety, were tested for their ability to produce peroxisome proliferation in the Fischer 344 rat. Di(2-ethylhexyl)adipate (DEHA) was tested using the same protocol and di(2-ethylhexyl)phthalate (DEHP) was run with each study as an internal control. Each ester was administered in the feed for a period of 21 days at levels of 2.5%, 1.2% and either 0.6% or 0.3%. DEHP and DEHA were also fed at levels of 0.1% and 0.01%. The animals were sacrificed and samples of liver were prepared for both light and electron microscopy. Serum samples were assayed for both triglyceride and cholesterol. The remaining portion of the liver was homogenized and assayed for cyanide-insensitive palmitoyl-CoA oxidation, lauric acid 11-hydroxylase and lauric acid 12-hydroxylase. The results show that there is approximately a ten-fold difference between the weakest and strongest esters in terms of their potency to induce changes in relative liver weight and in several of the biochemical parameters. In general, the longer chain esters were more potent than the shorter chain ones, and branched chain esters seemed more potent than straight. Several statistical analyses of the dataset have been performed and all render similar conclusions. The results of one of these evaluations are presented elsewhere in this volume (Lin, 1987).

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

“…In the rat, liver weight and liver hypertrophy were clearly increased by DEHP, CINN and DCB, as reported by others (30)(31)(32). MON, ETU, and LIM also gave weak increases in liver weight that were sometimes accompanied by liver hypertrophy.…”

“…All of the compounds tested gave increases in cytochrome P450, determined either as total (spectral) P450 or as specific isoforms (Western blots). Where the P450 induction profiles of compounds have previously been described (32,35,36), the results were as expected; for example, the peroxisome proliferator DEHP gave clear increases in total P450 and CYP 4A1 and some weak increases in CYP 2B1/2. In some cases, CEA, for example, total P450 was not increased, but there was weak induction of CYP 2B1/2 and CYP 3A1.…”

“…DEHP produced a much greater increase than CINN in the rat, correlating with the carcinogenicity of DEHP and noncarcinogenicity of CINN in this species. The increases in PCoA after DEHP and CINN treatment are as described previously (31,32).…”

Modes of Action and Species-Specific Effects of Di-(2-ethylhexyl)Phthalate in the Liver

“…By far, this hallmark feature associated with administration of PPARα ligands in rats and mice is the best and well-accepted phenotype that serves as a biomarker that determines the classification of chemical compounds into the class of peroxisome proliferators. A number of investigators over past 30 years demonstrated that DEHP exhibits similar effects on peroxisomal oxidases and other enzymes, as well as density and number of peroxisomes in hepatocytes, in both rats and mice [23,24,80,32]. Multiple strains of rats and mice and both sexes in these species are responsive, and both time-and dose-response have been reported.…”

Role for tumor necrosis factor α receptor 1 and interleukin-1 receptor in the suppression of mouse hepatocyte apoptosis by the peroxisome proliferator nafenopin

“…1 Peroxisome proliferators (PPs) constitute a diverse group of rodent nongenotoxic hepatocarcinogens, including the hypolipidemic drug nafenopin, 2,3 and chemicals of industrial and environmental importance such as the phthalate plasticizers. 4 In rats and mice, PPs cause hepatic peroxisome proliferation and perturb hepatocyte growth regulation leading to liver enlargement and, ultimately, to tumors. 5,6 In vivo, PPs cause peroxisome proliferation, oxidative stress, and the induction of the enzymes of ␤-oxidation.…”