Twenty-six-week oral toxicity of diheptyl phthalate with special emphasis on its induction of liver proliferative lesions in male F344 rats

Abstract

(Mannaerts et al., 1993). PPARs are members of the steroid hormone receptor superfamily, and three related isotypes, specifically PPARα, PPARβ and PPARγ, have been identified (Desvergne and Wahli, 1999). Based on target gene expression patterns, PPARα appears to have critical roles in the regulation of fatty acid metabolism, including fatty acid β-oxidation, apolipoproteins, and fatty acid transport proteins (Lee et al., 1995;Auwerx et al., 1996;Aoyama et al., 1998;Peters et al., 1997;Ren et al., 1997;Martin et al., 1997). Additionally, chronic exposure to numerous PPARα agonists has been reported to increase the incidence of hepatocellular tumors in rodents ABSTRACT -The 26-week oral toxicity of diheptyl phthalate (DHP), a peroxisome proliferator-activated receptor α (PPARα) agonist, with special emphasis on the potential induction of hepatocellular proliferative lesions was investigated in this study. DHP was administered to male F344 rats via gavage at 0 (control), 1,000 or 2,000 mg/kg/day for 26 weeks. Body weight gain was significantly lower, whereas food and water consumption was significantly higher in DHP-treated rats compared with controls. DHPtreated rats exhibited decreases in blood triglyceride, total cholesterol, phospholipid and glucose levels, which were likely related to biological effects of the PPARα agonist. Absolute and relative organ weights of the livers with pale brown discoloration and dark brown spots significantly increased in DHP-treated rats. Histopathological examinations revealed remarkable diffuse hypertrophy of hepatocytes with groundglass appearance, intracytoplasmic inclusion bodies and/or vacuolation in the DHP-treated groups. These findings were associated with increases in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and γ-glutamyltranspeptidase. The number and area of glutathione S-transferase placental form positive foci, a marker of hepatocellular preneoplastic lesions in rats, significantly increased in DHP-treated groups. Additionally, proliferating cell nuclear antigen positive liver cell counts in DHPtreated groups were significantly higher than those of the controls. Testicular alterations were not detected histopathologically, whereas absolute and relative prostate weights significantly decreased at both doses. These results indicate that DHP induces liver pre-neoplastic foci, and suggest the possibility that DHP is a possible genotoxic carcinogen in the liver of rats.

Association between <i>in vitro</i> nuclear receptor-activating profiles of chemical compounds and their <i>in vivo</i> hepatotoxicity in rats

“…PPARα has been an attractive target for drug discovery because of its functions in hepatic energy metabolism, but it has also been reported to be responsive to various environmental compounds such as diheptyl phthalate (S039 in this study) and perfluorooctanoic acid (Nakane et al, 2012;Wolf et al, 2008). In this study, 2,4,6-tribromophenol (S232) and 2,4-diamino-6-phenyl-1,3,5-triazine (S233) were newly identified as PPARα agonists.…”

“…However, S204 showed clear cytotoxicity against HepG2 cells at concen-trations above 30 μM. Furthermore, two environmental compounds S039 and S267, which have been known as PPARα agonists, were confirmed to activate PPARα weakly but clearly (Nakane et al, 2012;Wolf et al, 2008). Notably, S232 was found to strongly activate PPARα about 120-fold at 10 μM, although it had cytotoxic effects on HepG2 cells at the concentrations above 30 μM.…”

Influence of phthalates on glucose homeostasis and atherosclerosis in hyperlipidemic mice

“…Previous studies have shown that phthalates cause a significant reduction in plasma triglyceride levels in high fat-fed wild-type C57BL/6 mice [ 16 ] and F344 rats [ 15 ]. However, we did not find any changes in plasma triglyceride level of Apoe −/− mice treated with phthalates.…”

“…However, direct evidence supporting a causal role is scarce and even conflicting. For example, some studies showed that perinatal or adult exposure to phthalates lead to elevated blood glucose, reduced serum insulin, impaired glucose tolerance and insulin secretion in rodents [ 11 - 14 ] while others found the opposite results [ 15 ] or no effect at all [ 16 ]. Moreover, because the animals used in the studies did not develop type 2 diabetes, a causal link to the disease is still hypothetical.…”

Fast determination of phthalate ester residues in soft drinks and light alcoholic beverages by ultrasound/vortex assisted dispersive liquid–liquid microextraction followed by gas chromatography-ion trap mass spectrometry

“…2 Humans are also exposed to low levels of PAEs by eating food packaged in plastics containing PAEs. Although PAEs are suspected to be endocrine disruptors, 3 their effects on human health are not yet fully known, although they are being studied by several international government agencies, e.g., the US Food and Drug Administration and the National Institute of Environmental Health Sciences. The current levels of seven PAEs [dimethyl phthalate (DMP), diethyl phthalate (DEP), diisobutyl phthalate (DiBP), dibutyl phthalate (DBP), butyl benzyl phthalate (BBP), isobutyl cyclohexyl phthalate (iBcEP) and diethylhexyl phthalate (DEHP)] have been identied as posing "minimal" concern for causing reproductive effects.…”