Abstract:
:Peroxisome proliferator-activated receptor gamma (PPARγ) agonists and PPARγ/α dual agonists are used in the treatment of type 2 diabetes mellitus and hyperlipidemias. In carcinogenicity studies, some of these agonists induced hemangiomas/hemangiosarcomas in mice, but not in rats. We hypothesized that increased endothelial cell (EC) proliferation may be involved in the mechanism of PPAR agonist-induced vascular tumors in mice. We previously showed that the sarcomagenic PPARγ agonist troglitazone (TG) increased EC proliferation in brown and white adipose tissue and liver in mice at sarcomagenic doses (400 and 800 mg/kg) after four weeks of treatment. In vitro, TG had a mitogenic effect on mouse microvascular mouse ECs by increasing cell proliferation and survival. The current studies showed that treatment of mouse ECs in vitro induced alterations in proliferation pathway gene expression, especially the expression of insulin-like growth factor-1, but had no effect on mouse oxidative stress pathways. In vivo, treatment with vitamin E did not inhibit TG-induced EC proliferation in liver and adipose tissue. In addition, no hypoxic effect was detected in adipose tissue of TG-treated mice; however, TG had a minor effect on hepatocellular hypoxia. These results provide additional evidence supporting a direct mitogenic effect in the mode of action of TG-induced hemangiosarcomas in mice.
journal_name
Toxicol Patholjournal_title
Toxicologic pathologyauthors
Kakiuchi-Kiyota S,Arnold LL,Yokohira M,Koza-Taylor P,Suzuki S,Varney M,Pennington KL,Cohen SMdoi
10.1177/0192623311422080subject
Has Abstractpub_date
2011-12-01 00:00:00pages
1032-45issue
7eissn
0192-6233issn
1533-1601pii
0192623311422080journal_volume
39pub_type
杂志文章abstract::The kerosene-type jet fuel, JP-8, consists of a complex mixture of aliphatic and aromatic hydrocarbons. Because of the utility of JP-8, studies have been conducted to identify the potential long-term consequence of occupational inhalation exposure. Fischer 344 rats and C57BL/6 mice of both sexes were exposed to JP-8 v...
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