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-oxid ation (PBOX) activity, and replicative DNA synthesis in several rodent spec ies with differing susceptibilities to peroxisome proliferator-induced hepa tic tumorigenesis. A low (non-tumorigenic) and high (tumorigenic) dietary c oncentration of DEHP was administered to male F344 rats for 1, 2, 4, and 6 weeks. Additionally, a previously non-tumorigenic dose (1000 ppm) and tumor igenic dose of DEHP (12,000 ppm), as determined by chronic bioassay data, w ere examined following 2 weeks dietary administration. Male B6C3F1 mice wer e fed the non-tumorigenic concentration, 500 ppm, and the tumorigenic conce ntration, 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-induc ed tumorigenicity). In rat and mouse liver, a concentration-dependent incre ase in the relative liver weight, PBOX activity, and replicative DNA synthe sis was observed at the earliest time point examined. Concurrent to these o bservations 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 cons istency 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 phth alate (MEHP), and phthalate acid (PA), indicated a time- and concentration- dependent increase in the hepatic concentration of MEHP. At equivalent diet ary concentrations and time points, the presence of MEHP, the primary metab olite responsible for the hepatic effects of DEHP, demonstrated a species-s pecific 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 co ncentrations of DEHP and phthalic acid were minimal and did not correlate w ith concentration and time. Collectively, these data demonstrate the inhibi tion of hepatic GJIC and increased replicative DNA synthesis correlated wit h the observed dose- and species-specific tumorigenicity of DEHP and may be predictive indicators of the nongenotoxic carcinogenic potential of phthal ate esters.