Abstract 3185: Sub-lethal autolysis in livers of mice given phthalate esters precedes development of hepatic lesions
Authors: Carter Julia H. , Vogelpohl Steven , Tucker Mary Kay , Tagher Robert 
Published: May 2015

Abstract
Primary prevention of human cancers through identification of potential environmental carcinogens is an important goal. Phthalates such as di(2-ethylhexyl)phthalate (DEHP) and di-n-octylphthalate (DOP), the most widely used industrial plasticizers, are low-level environmental contaminants. As plasticizers they impart flexibility to plastics and comprise a large portion of the final product. However, they are non-covalently bound and easily migrate out of the final products, leading to human exposure. Previous studies have shown that exposure to these compounds in the diet is associated with the development of hepatocellular carcinomas and adenomas in rodents. DEHP and DOP are most likely non-genotoxic, therefore the mechanism(s) by which these compounds induce changes in hepatocyte structure and function is unknown, although recently a peroxisome proliferator-activated receptor alpha mode of action has been suggested for DEHP. Bosmann (BBA, 264:339, 1972) proposed that sub-lethal autolysis at the cell surface resulting from secretion of lysosomal enzymes can alter cell-cell and cell-matrix interactions leading to loss of growth control and neoplastic transformation. Indeed, cultured 3T3 cells express increased levels of lysosomal enzymes following viral transformation and increased expression of lysosomal enzymes is found in many human malignancies including cancers of the breast, colon, larynx and prostate. To determine if there is an association between the expression of lysosomal enzymes and the carcinogenicity of phthalates, the effects of chronic exposure of male B6C3F1 mice to diets containing DEHP or DOP on liver lysosomal enzymes was evaluated. Mice were fed diets containing 0.12%, 0.60%, and 1.20% DEHP and 0.1%, 0.5% and 1.0% DOP. Groups of animals were sacrificed after 15, 30, 35, 52, 78 and 104 weeks of exposure. Expression of hepatic β-galactosidase, aryl sulfatase, n-acetyl-β-glucosaminidase, and cathepsin D was increased significantly following 15 weeks of treatment with either 0.6% or 1.2% DEHP. By 30 weeks of treatment animals in these groups had focal hepatic lesions and some liver tumors. Increased expression of β-glucuronidase was found only in animals receiving 0.6% and 1.2% DEHP for 52 weeks. Hepatomegaly was found in all the animals receiving the phthalates. The close association between early increases in expression of some lysosomal enzymes and later development of hepatic lesions following chronic exposure to non-genotoxic phthalate esters suggests that sub-lethal autolyis may be a contributing factor in carcinogenesis induced by these low-level environmental contaminants.
Citation Format: Julia H. Carter, Steven Vogelpohl, Mary Kay Tucker, Robert Tagher. Sub-lethal autolysis in livers of mice given phthalate esters precedes development of hepatic lesions. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3185. doi:10.1158/1538-7445.AM2014-3185