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MECHANISMS INVOLVED IN THE ENHANCED SUSCEPTIBILITY OF SENESCENT RATS TO THE HEPATOCARCINOGENIC EFFECT OF PEROXISOME PROLIFERATORS: ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA (PPARA), CELL PROLIFERATION AND OXIDATIVE STRESS
Youssef, J. A., P. Ammann, B. L. Ghanayem, L S. Birnbaum, AND M. Z. Badr. MECHANISMS INVOLVED IN THE ENHANCED SUSCEPTIBILITY OF SENESCENT RATS TO THE HEPATOCARCINOGENIC EFFECT OF PEROXISOME PROLIFERATORS: ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA (PPARA), CELL PROLIFERATION AND OXIDATIVE STRESS. Presented at Miami 2000: Nature Biotechnology, Miami, FL, Feb 2-7, 2001.
Mechanisms involved in the ENHANCED SUSCEPTIBILITY of SENESCENT Rats TO THE HEPATOCARCINOGENIC EFFECT OF PEROXISOME PROLIFERATORS: Role of peroxisome proliferator-activated receptor alpha (PPARa), cell proliferation and oxidative stress
Jihan A. Youssef1, Pierre Ammann2, Burhan L. Ghanayem2,
Linda S. Birnbaum3 and Mostafa Z. Badr1,*
1University of Missouri-Kansas City, MO 64108, 2Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 and 3National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27709
INTRODUCTION. Nongenotoxic peroxisome proliferating chemicals (PPs) cause hepatocarcinogenesis in rodents, with senescent animals being more susceptible than their younger counterparts (1). Theories have been advanced suggesting a PPARa-dependent role involving Kupffer cells, growth regulating genes, or oxidative stress in PP-induced hepatocarcinogenecity. The purpose of this study was to investigate mechanisms involved in the aging-associated enhanced susceptibility to these chemicals.
METHOD. Using RT-PCR, we investigated age-dependent hepatic gene expression of PPARa, proliferating cell nuclear antigen (PCNA), and the H2O2-producing peroxisomal enzyme acyl-CoA Oxidase (Acose) in male Fischer-344 rats of 4, 10, 50 and 100 weeks of age.
RESULTS. Diethylhexylphtalate (DEHP, 1.2 g/kg, orally), and Wy-14,643 (250 mg/kg, orally) increased liver/body weight ratios more dramatically in young animals (4 weeks old), than in all other groups within 48 hrs. Clofibrate (250 mg/kg, orally) did not cause hepatomegaly in any group. Despite a significant difference in the hepatocarcinogenic potency of Wy-14,643 and DEHP (2), these two PPs increased hepatic expression of PCNA to comparable levels among all age groups. Ironically, clofibrate which is a weak hepatocarcinogen (2) increased PCNA mRNA expression to significantly higher levels in 4 week old rats compared to 100 week old rats. In addition, Wy-14,643 enhanced the expression of Acose mRNA to comparable levels in all age groups, while clofibrate increased the expression of this gene to higher levels in young, adult rats (10 weeks old), than in senescent rats (100 weeks old).
DISCUSSION. Data suggest that hepatic levels of PPARa gene expression, cell proliferation, or oxidative stress do not adequately explain the known enhanced susceptibility of the aged liver to the PP-induced hepatocarcinogenecity. This conclusion is supported by our findings showing that age-related changes in these parameters, in response to treatment with PPs, did not correspond with the known rank of hepatocarcinogenic potencies of the tested chemicals. Other factors such as the impact of aging on PP-induced inhibition of hepatocellular apoptosis remain to be evaluated.
ACKNOWLEDGEMENTS. This work was supported by NIH grants CA/OD 74384 and AG 18479; this abstract does not necessarily reflect EPA policy.
1. Youssef, J., and Badr, M. (1999) Environ. Health Perspect. 107, 791-797.
2. Youssef, J., and Badr, M. (1998) CRC Crit. Rev. Toxicol. 28, 1-33.
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
EXPERIMENTAL TOXICOLOGY DIVISION