Chronic peroxisome proliferation and hepatomegaly associated with the hepatocellular tumorigenesis of di(2-ethylhexyl)phthalate and the effects of recovery

Abstract

This study compared the levels of cell proliferation and peroxisome proliferation in rodent liver with tumor incidence, to provide more information on the relationship between these events following chronic exposure. Fischer 344 rats were treated with 0, 100, 500, 2500, or 12,500 ppm DEHP, and B6C3F1 mice were treated with 0, 100, 500, 1500, or 6000 ppm DEHP in the diet for up to 104 weeks. Additional groups of rats and mice received the highest concentration for 78 weeks and then the control diet for an additional 26 weeks (recovery groups). Animals were terminated at weeks 79 and 105 for histopathologic examination. Elevated palmitoyl CoA oxidation activity and higher liver-to-body weight ratios were observed for the 2500- and 12,500-ppm groups of rats, and for the 500-, 1500-, and 6000-ppm groups of mice at Week 105. No increase in palmitoyl CoA oxidation activity was evident in the recovery group, and relative liver weights were near control levels following recovery. No hepatic cell proliferation was detected at Weeks 79 or 105 in either species although preliminary data indicated that cell proliferation did occur within the first 13 weeks of exposure. A significantly higher incidence of hepatocellular tumors was only observed for the 2500- and 12,500-ppm group and its recovery group of rats, and for the 500-, 1500-, and 6000-ppm groups and the recovery group of mice. The tumor incidences were reduced for the recovery groups compared with the groups fed DEHP continuously for 104 weeks. The data indicate that high levels of peroxisome proliferation and hepatomegaly are associated with DEHP hepatocarcinogenesis in rodent liver, and that the tumorigenic process may be arrested by cessation of DEHP treatment, suggesting that extended treatment with DEHP acts to promote tumor growth.

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

“…A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 long-term exposures in rodents [13,48]. 284 genes with measurable expression levels were initially retained for further analysis.…”

Effects of endocrine disruptors on imprinted gene expression in the mouse embryo

“…DEHP is a carcinogen, which induces tumors in the liver and testes of rodents. 19,20 DEHP, through its active metabolite mono-ethylhexyl phthalate (MEHP), exerts toxicity on the female reproductive system. 21 In female rodents, it causes decreased serum estradiol levels, suppression of aromatase, and it activates peroxisome proliferatoractivated receptors (PPARs).…”

Di(2‐ethylhexyl) phthalate (DEHP) [MAK Value Documentation, 2016]

“…The vacuolation of Sertoli cells was observed in adult rats given doses of 38 mg/ kg body weight and day and above (Poon et al 1997), and reduced relative testis weights were reported in mice at doses of 100 mg/kg body weight and above (David et al 1999(David et al , 2000. Fertility was impaired in adult rats of the F0 and F1 generations that received 343 and 391 mg/kg body weight and day and above, respectively, with the diet (NTP 2003(NTP , 2005.…”