Comparative in Vivo Hepatic Effects of Di-Isononyl Phthalate (DINP) and Related C7–C11 Dialkyl Phthalates on Gap Junctional Intercellular Communication (GJIC), Peroxisomal Beta-Oxidation (PBOX), and DNA Synthesis in Rat and Mouse Liver

• Published in: Toxicological sciences 2000-04, Vol.54 (2), p.312-321
• Main Authors: Smith, Jacqueline H., Isenberg, Jason S., Pugh, George, Kamendulis, Lisa M., Ackley, David, Lington, Arthur W., Klaunig, James E.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Cell Communication - drug effects; Chemical agents; di-heptyl; di-isodecyl phthalate (DIDP); di-isoheptyl phthalate (DIHP); di-isononyl phthalate (DINP); di-n-octyl phthalate (DNOP); DNA - biosynthesis; DNA - drug effects; DNA Replication - drug effects; DNA synthesis; gap junctional intercellular communication (GJIC); Gap Junctions - drug effects; Gap Junctions - metabolism; in situ dye transfer (ISDT); Liver - drug effects; Liver - metabolism; Male; Medical sciences; Mice; Mice, Inbred Strains; nonyl; Organ Size - drug effects; Oxidation-Reduction; peroxisome proliferation; Peroxisomes - drug effects; Peroxisomes - metabolism; phthalate esters; Phthalic Acids - pharmacokinetics; Phthalic Acids - toxicity; Rats; Rats, Inbred F344; rodent liver; Tumors; undecyl phthalate (D711P)
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/54.2.312

The short-term hepatic effects of DINP (CAS 68515-48-0, designated DINP-1) in rats and mice were evaluated at tumorigenic and nontumorigenic doses from previous chronic studies. Groups of male F344 rats were fed diets with DINP-1 at concentrations of 0, 1000, or 12,000 ppm and male B6C3F1 mice at 0, 500, or 6000 ppm DINP-1. After 2 or 4 weeks of treatment, changes in liver weight, gap junctional intercellular communication (GJIC), peroxisomal beta-oxidation (PBOX), and replicative DNA synthesis were examined. In addition, hepatic and serum concentrations of the parent compound and major metabolites were determined. Relative to controls in both species, increased liver weight and PBOX at the high dose of DINP-1 were consistent with peroxisomal proliferation. Hepatic GJIC was inhibited and DNA synthesis was increased at the high dose of DINP-1, which is also consistent with the tumorigenic response in rats and mice reported in other chronic studies at these doses. These hepatic effects were not observed at the low doses of DINP-1. At comparable low doses of DINP-1 in other chronic studies, no liver tumors were observed in rats and mice. The monoester metabolite (MINP-1) was detected in the liver at greater concentrations in mice than rats. This result is also consistent with the dose-response observations in rat and mouse chronic studies. Additionally, other structurally similar dialkyl phthalate esters ranging from C7 to C11 were evaluated using a similar protocol for comparison to DINP-1; these included an alternative isomeric form of DINP (DINP-A), di-isodecyl phthalate (DIDP), di-isoheptyl phthalate (DIHP), di-heptyl, nonyl undecyl phthalate (D711P), and di-n-octyl phthalate (DNOP). Collectively, these data indicate that in rats and mice, DINP-1 and other C7–C11 phthalates exhibit a threshold for inducing hepatic cellular events. Further, where previous chronic data were available for these compounds, these phthalates elicited hepatic effects at doses that correlated with the tumorigenic response. Overall, these studies suggest a good correlation between the inhibition of GJIC when compared with the data on production of liver tumors in chronic studies.