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.