- Null Mice α Peroxisome Proliferator - Activated Receptor Receptor and Nonreceptor - Mediated Organ - Specific Toxicity of Di ( 2 - ethylhexyl ) phthalate

The peroxisome proliferator-activated reccptora (PPARa) is the mediator of the biological effects of pcroxisome proliferators through control of gene transcription. To determine if the toxic effects of di(2-ethylhexy1)phthalate (DEHP) are mediated by PPARa, we examined its effect in PPARa-null micc. Male Sv1129 mice. PPARa-null (-/-) or wild-typc (+I+) were fed nd libirirrn either a control diet or one containing 12.000 ppm DEHP for up to 24 wk. Significant body weight loss and high mortality was observcd in (+/+) mice fed DEHP. By 16 wk, all DEHP-fed (+I+) 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 lcsions but did show cvidence 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 (-1 -) mice. These results provide evidence that PPARa 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 PPARa-independcnt pathways in mediating renal and testicular toxicity. Knockout mice; peroxisomal proliferator; liver; peroxisomal proliferator activated receptor; di(2-ethylhexy1)phthalate (DEHP); kidney; cystic kidneys