Effects of Di-2-ethylhexyl phthalate (DEHP) on gap-junctional intercellular communication (GJIC), DNA synthesis, and peroxisomal beta oxidation (PBOX) in rat, mouse, and hamster liver.
The present study evaluated the effect of di-2-ethylhexyl phthalate (DEHP) on gap-junctional intercellular communication (GJIC), peroxisomal beta-oxidation (PBOX) activity, and replicative DNA synthesis in several rodent species with differing susceptibilities to peroxisome proliferator-induced hepatic tumorigenesis. A low (non-tumorigenic) and high (tumorigenic) dietary concentration of DEHP was administered to male F344 rats for 1, 2, 4, and 6 weeks. Additionally, a previously non-tumorigenic dose (1000 ppm) and tumorigenic dose of DEHP (12,000 ppm), as determined by chronic bioassay data, were examined following 2 weeks dietary administration. Male B6C3F1 mice were fed the non-tumorigenic concentration, 500 ppm, and the tumorigenic concentration, 6000 ppm, of DEHP for two and four weeks. The hepatic effects of low and high concentrations of DEHP, 1000 and 6000 ppm, were also examined in male Syrian Golden hamsters (refractory to peroxisome proliferator-induced tumorigenicity). In rat and mouse liver, a concentration-dependent increase in the relative liver weight, PBOX activity, and replicative DNA synthesis was observed at the earliest time point examined. Concurrent to these observations was an inhibition of GJIC. In hamster liver, a slight increase in the relative liver weight, PBOX activity, and replicative DNA synthesis was observed. However, these effects were not of the same magnitude or consistency as those observed in rats or mice. Furthermore, DEHP had no effect on GJIC in hamster liver at any of the time points examined (2 and 4 weeks). HPLC analysis of DEHP and its primary metabolites, mono-2-ethylhexyl phthalate (MEHP), and phthalate acid (PA), indicated a time- and concentration-dependent increase in the hepatic concentration of MEHP. At equivalent dietary concentrations and time points, the presence of MEHP, the primary metabolite responsible for the hepatic effects of DEHP, demonstrated a species-specific response. The largest increase in the hepatic concentration of MEHP was observed in mice, which was greater than the concentration observed in rats. The hepatic concentration of MEHP was lowest in hamsters. Hepatic concentrations of DEHP and phthalic acid were minimal and did not correlate with concentration and time. Collectively, these data demonstrate the inhibition of hepatic GJIC and increased replicative DNA synthesis correlated with the observed dose- and species-specific tumorigenicity of DEHP and may be predictive indicators of the nongenotoxic carcinogenic potential of phthalate esters.
Isenberg
J S
JS
Division of Toxicology, Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, 46202, USA.
Kamendulis
L M
LM
Smith
J H
JH
Ackley
D C
DC
Pugh
G
G
Lington
A W
AW
Klaunig
J E
JE
D000818:Animals; D002450:Cell Communication / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects*; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D020675:Peroxisomes / Q000187:drug effects* / Q000378:metabolism; D010795:Phthalic Acids / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D015430:Weight Gain / Q000187:drug effects
D020025:Peroxisome Proliferators; D010795:Phthalic Acids; C032279:phthalic acid; D004247:DNA; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate