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Toxicologic Pathology
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*BIS(2-ETHYLHEXYL)PHTHALATE
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Journal Article

Receptor and Nonreceptor-Mediated Organ-Specific Toxicity of Di(2-ethylhexyl)phthalate (DEHP) in Peroxisome Proliferator-Activated Receptor{alpha}-Null Mice

Jerrold M. Ward

Veterinary and Tumor Pathology Section, Animal Sciences Branch, Office of Laboratory Animal Resources, Frederick, Maryland 21702–1201

Jeffrey M. Peters

Laboratory of Metabolism, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892

Christine M. Perella

Laboratory Animal Sciences Program, NCI-FCRDC, SAIC–Frederick, Frederick, Maryland 21702–1201

Frank J. Gonzalez

Laboratory of Metabolism, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892

The peroxisome proliferator-activated receptora (PPAR{alpha}) is the mediator of the biological effects of peroxisome proliferators through control of gene transcription. To determine if the toxic effects of di(2-ethylhexyl)phthalate (DEHP) are mediated by PPAR{alpha}, we examined its effect in PPAR{alpha}-null mice. Male Sv/129 mice, PPAR{alpha}-null (–/–) or wild-type (+/+) were fed ad libitum either a control diet or one containing 12,000 ppm DEHP for up to 24 wk. Significant body weight loss and high mortality was observed in (+/+) mice fed DEHP. By 16 wk, all DEHP-fed (+/+) mice had died of cystic renal tubular disease. In contrast, the (–/–) mice fed DEHP had no changes in body weight until later in the study nor increased mortality. Histologically, (+/+) mice fed DEHP had typical toxic lesions in liver, kidney, and testis while (–/–) mice fed DEHP had no toxic liver lesions but did show evidence of toxicity in kidney and testis after 4–8 wk of feeding, which progressed into moderate lesions by 24 wk. Analysis of hepatic and renal mRNAs showed a typical pleiotropic response in gene expression in the DEHP-fed (+/+) mice that was absent in the DEHP-fed (–/ –) mice. These results provide evidence that PPAR{alpha} mediates the subacute-chronic toxicity of DEHP in liver, kidney, and testis. However, because (-/–) mice did develop toxic lesions in kidney and testis, DEHP can also act through PPAR{alpha}-independent pathways in mediating renal and testicular toxicity.

Key Words: Knockout mice • peroxisomal proliferator • liver • peroxisomal proliferator activated receptor • di(2-ethylhexyl)phthalate (DEHP) • kidney • cystic kidneys

Toxicologic Pathology, Vol. 26, No. 2, 240-246 (1998)
DOI: 10.1177/019262339802600208
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