RECEPTOR AND NONRECEPTOR-MEDIATED ORGAN-SPECIFIC TOXICITY OF DI(2-ETHYLHEXYL)PHTHALATE (DEHP) IN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA-NULL MICE

The peroxisome proliferator-activated receptor alpha (PPAR alpha) is t he mediator of the biological effects of peroxisome proliferators thro ugh control of gene transcription. To determine if the toxic effects o f di(2-ethylhexyl)phthalate (DEHP) are mediated by PPAR alpha, we exam ined its effect in PPAR alpha-null mice. Male Sv/129 mice, PPAR alpha- null (-/-) or wild-type (+/+) were fed ad libitum either a control die t 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 disea se. 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 testi s while (-/-) mice fed DEHP had no toxic liver lesions but did show ev idence of toxicity in kidney and testis after 4-8 wk of feeding, which progressed into moderate lesions by 24 wk. Analysis of hepatic and re nal mRNAs showed a typical pleiotropic response in gene expression in the DEHP-fed (+/+) mice that was absent in the DEHP-fed (-/-) mice. Th ese results provide evidence that PPAR alpha mediates the subacute-chr onic toxicity of DEHP in liver, kidney, and testis. However, because ( -/-) mice did develop toxic lesions in kidney and testis, DEHP can als o act through PPAR alpha-independent pathways in mediating renal and t esticular toxicity.