The role of inhibition of gap junctional intercellular communication in rodent liver tumor induction by phthalates: review of data on selected phthalates and the potential relevance to man.

Inhibition of gap junctional intercellular communication (GJIC) has been postulated as a nongenotoxic carcinogenic mechanism, probably related to tumor promotion. Recent studies assessed the role of GJIC in the induction of rodent liver tumors by high levels of phthalate esters. Studies with di(2-ethylhexyl) (DEHP) and diisononyl (DINP) phthalates demonstrated that inhibition of GJIC in rats and mice was well correlated with induction of both liver tumors and markers for peroxisomal proliferation. However, GJIC was unaffected in hamsters and primates, species in which phthalate treatment does not induce peroxisomal proliferation. In vitro studies which extended the database to include human liver cells mirrored the in vivo situation; GJIC was inhibited in rat and mouse cells but not in cells from unresponsive species including humans. Peroxisomal proliferation has been characterized as a species-specific process essential for phthalate-induced rodent liver tumor induction. That GJIC was not inhibited in primate liver or human liver cells provides evidence for a second species-specific carcinogenic process. Thus the GJIC data along with those from studies of peroxisomal proliferation support the view that the carcinogenic effects of DEHP and DINP in rodents are not relevant to humans.

[1]  J. Ward,et al.  Tumor-initiating and promoting activities of di(2-ethylhexyl) phthalate in vivo and in vitro. , 1986, Environmental health perspectives.

[2]  J. Klaunig,et al.  Inhibition of mouse hepatocyte intercellular communication by phthalate monoesters. , 1988, Cancer letters.

[3]  B. Lake,et al.  A cancer risk assessment of di(2-ethylhexyl)phthalate: application of the new U.S. EPA Risk Assessment Guidelines. , 1999, Regulatory toxicology and pharmacology : RTP.

[4]  J. Reddy,et al.  Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens , 1980, Nature.

[5]  H. Yamasaki,et al.  Gap junctional intercellular communication and carcinogenesis. , 1990, Carcinogenesis.

[6]  J. Trosko.  Comments on "What is a tumor promoter?". , 1999, Environmental Health Perspectives.

[7]  R. M. David,et al.  Chronic peroxisome proliferation and hepatomegaly associated with the hepatocellular tumorigenesis of di(2-ethylhexyl)phthalate and the effects of recovery. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[8]  R. Roberts,et al.  A peroxisome proliferator-activated receptor-alpha (PPARα) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARα: implications for species differences in responses to peroxisome proliferators , 1998, Archives of Toxicology.

[9]  E. Zeiger,et al.  Mutagenicity testing of di(2-ethylhexyl)phthalate and related chemicals in Salmonella. , 1985, Environmental mutagenesis.

[10]  J M Ward,et al.  Receptor and Nonreceptor-Mediated Organ-Specific Toxicity of Di(2-ethylhexyl)phthalate (DEHP) in Peroxisome Proliferator-Activated Receptorα-Null Mice , 1998, Toxicologic pathology.

[11]  M. Katoh,et al.  Subchronic toxicity of Di(2-ethylhexyl)phthalate in common marmosets: lack of hepatic peroxisome proliferation, testicular atrophy, or pancreatic acinar cell hyperplasia. , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[12]  J. Ward,et al.  Dissimilar patterns of promotion by di(2-ethylhexyl)phthalate and phenobarbital of hepatocellular neoplasia initiated by diethylnitrosamine in B6C3F1 mice. , 1983, Carcinogenesis.

[13]  R. Cattley,et al.  Age-related susceptibility to the carcinogenic effect of the peroxisome proliferator WY-14,643 in rat liver. , 1991, Carcinogenesis.

[14]  J. F. Douglas,et al.  The carcinogenicity of dietary di(2-ethylhexyl) phthalate (DEHP) in Fischer 344 rats and B6C3F1 mice. , 1982, Journal of toxicology and environmental health.

[15]  M. Cifone,et al.  Results of the l5178y mouse lymphoma assay and the balb/3t3 cell in vitro transformation assay for eight phthalate esters , 2000, Journal of applied toxicology : JAT.

[16]  J. Klaunig,et al.  Comparative in vivo hepatic effects of Di-isononyl phthalate (DINP) and related C7-C11 dialkyl phthalates on gap junctional intercellular communication (GJIC), peroxisomal beta-oxidation (PBOX), and DNA synthesis in rat and mouse liver. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[17]  I. Budunova,et al.  Review. Alteration of gap junctional intercellular communication during carcinogenesis , 1994 .

[18]  J. Trosko,et al.  In vitro analysis of modulators of intercellular communication: Implications for biologically, based risk assessment models for chemical exposure. , 1990, Toxicology in vitro : an international journal published in association with BIBRA.

[19]  R. Cattley,et al.  Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) in rats. , 1988, Cancer research.

[20]  A. Dayan.  Changes in Human & Experimental Toxicology , 1994 .

[21]  R. Roberts,et al.  The peroxisome proliferator (PP) response element upstream of the human acyl CoA oxidase gene is inactive among a sample human population: significance for species differences in response to PPs. , 1999, Carcinogenesis.

[22]  J. Klaunig,et al.  Effects of di-isononyl phthalate, di-2-ethylhexyl phthalate, and clofibrate in cynomolgus monkeys. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[23]  P Fenner-Crisp,et al.  Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? , 1998, Regulatory toxicology and pharmacology : RTP.

[24]  R. Tennant.  What is a tumor promoter? , 1999, Environmental health perspectives.

[25]  W. Stubblefield,et al.  Chronic toxicity and carcinogenic evaluation of diisononyl phthalate in rats. , 1997, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[26]  R. Schulte‐Hermann,et al.  Role of oxidative stress in age dependent hepatocarcinogenesis by the peroxisome proliferator nafenopin in the rat. , 1991, Cancer research.

[27]  J. Peters,et al.  Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. , 1997, Carcinogenesis.

[28]  M. Rao,et al.  Quantitative analysis of hepatocellular lesions induced by di(2-ethylhexyl)phthalate in F-344 rats. , 1990, Journal of toxicology and environmental health.

[29]  J. Klaunig,et al.  Effects of Di-2-ethylhexyl phthalate (DEHP) on gap-junctional intercellular communication (GJIC), DNA synthesis, and peroxisomal beta oxidation (PBOX) in rat, mouse, and hamster liver. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[30]  C. Hignite,et al.  HYPOLIPIDEMIC HEPATIC PEROXISOME PROLIFERATORS FORM A NOVEL CLASS OF CHEMICAL CARCINOGENS , 1980 .

[31]  R. Harling,et al.  Effects of di-isononyl phthalate (DINP) on peroxisomal markers in the marmoset-DINP is not a peroxisome proliferator. , 1999, The Journal of toxicological sciences.

[32]  K. Griffin,et al.  Peroxisome proliferator activated receptor-alpha expression in human liver. , 1998, Molecular pharmacology.

[33]  B. Pool,et al.  Various shor-term assays and two long-term studies with the plasticizer di(2-ethylhexyl)phthalate in the Syrian golden hamster , 1988 .

[34]  S Kettle,et al.  Mechanistically-based Human Hazard Assessment of Peroxisome Proliferator-induced Hepatocarcinogenesis , 1994, Human & experimental toxicology.

[35]  J. Goodman,et al.  Spontaneous mutation at codon 61 of the Ha-ras gene in the nascent liver of B6C3F1, C3H/He and C57BL/6 mice. , 1994, Mutation research.

[36]  H. Yamasaki.  Gap junctional communication and carcinogenesis , 1990 .

[37]  M. E. Meek,et al.  Bis(2‐ethylhexyl)phthalate: Evaluation of risks to health from environmental exposure in Canada , 1994 .

[38]  B Staels,et al.  A truncated human peroxisome proliferator-activated receptor alpha splice variant with dominant negative activity. , 1999, Molecular endocrinology.