title: Ability of peroxisome proliferators to induce cell transformation, chromosome aberrations and peroxisome proliferation in cultured Syrian hamster embryo cells.
abstract: Di(2-ethylhexyl)phthalate (DEHP), a commonly used plasticizer, induces proliferation of peroxisomes in liver cells and causes hepatocellular carcinomas when chronically administered in the diet to rodents. To examine possible mechanisms for DEHP-associated cancer, we have measured induction of morphological transformation, chromosome aberrations and peroxisome proliferations of cultured Syrian hamster embryo (SHE) cells by DEHP and other peroxisome proliferators. Morphological transformation of SHE cells was weakly induced by treatment for 48 h with DEHP and its metabolite mono(2-ethylhexyl)phthalate (MEHP). The transformation frequency by DEHP was enhanced by exogenous metabolic activation using rat liver postmitochondrial supernatants. Treatment for 24 h with DEHP resulted in chromosome aberrations of the cells only in the presence of exogenous metabolic activation. 2-(p-chlorophenoxy)-2-methylpropionic acid ethyl ester (clofibrate), a widely used hypolipidemic drug, failed to induce morphological transformation or chromosome aberrations of SHE cells. Treatment with [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (WY-14,643), which is a more potent carcinogen than DEHP or clofibrate, elicited a lower frequency of morphological transformation than DEHP in the presence of exogenous metabolic activation but was more active than DEHP at inducing chromosome aberrations. Similar levels of peroxisome proliferation, as determined by an intensity of diaminobenzidine staining, were observed in cultures treated for 2 h with DEHP, MEHP, clofibrate or WY-14,643. These results suggest a possible involvement of genetic damage by DEHP metabolites in the induction of cell transformation of SHE cells by DEHP; however, no clear relationship among induction of peroxisome proliferation, carcinogenicity in vivo and cell transformation was observed. Although the ability to induce cell transformation and chromosomal mutations is not adequate to explain the carcinogenicity of this class of compounds, these biological effects may be contributory to the carcinogenic activities of peroxisome proliferators.
authors: Department of Pharmacology, Nippon Dental University, School of Dentistry, Tokyo, Japan.
authors: T
authors: T
authors: Tsutsui
authors: E
authors: E
authors: Watanabe
authors: J C
authors: JC
authors: Barrett
mesh_terms: D000818:Animals; D001560:Benzidines / Q000032:analysis; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D002869:Chromosome Aberrations; D002994:Clofibrate / Q000633:toxicity*; D006224:Cricetinae; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives* / Q000633:toxicity*; D008647:Mesocricetus / Q000196:embryology; D008830:Microbodies / Q000187:drug effects*; D011743:Pyrimidines / Q000633:toxicity*
chemical_list: D001560:Benzidines; D011743:Pyrimidines; C006253:pirinixic acid; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate; D002994:Clofibrate