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

Abstract

The peroxisome proliferator-activated receptora (PPARα) 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 PPARα, we examined its effect in PPARα-null mice. Male Sv/129 mice, PPARα-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 PPARα 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 PPARα-independent pathways in mediating renal and testicular toxicity.