Receptor and nonreceptor-mediated organ-specific toxicity of di(2-ethylhexyl)phthalate (DEHP) in peroxisome proliferator-activated receptor alpha-null mice

Abstract

The peroxisome proliferator-activated receptor alpha (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.