Peroxisome proliferator-activated receptor alpha protects against glomerulonephritis induced by long-term exposure to the plasticizer di-(2-ethylhexyl)phthalate

Safety concerns about di-(2-ethylhexyl)phthalate (DEHP), a plasticizer and a probable endocrine disruptor, have attracted considerable public attention, but there are few studies about long-term exposure to DEHP. DEHP toxicity is thought to involve peroxisome proliferator-activated receptor a (PPAR alpha), but this contention remains controversial. For investigation of the long-term toxicity of DEHP and determination of whether PPAR alpha mediates toxicity, wild-type and PPAR alpha-null mice were fed a diet that contained 0.05 or 0.01% DEHP for 22 mo. PPAR alpha-null mice that were exposed to DEHP exhibited prominent immune complex glomerulortephritis, most likely related to elevated glomerular oxidative stress. Elevated NADPH oxidase, low antioxidant enzymes, and absence of the PPAR alpha-dependent anti-inflammatory effects that normally antagonize the NF kappa B signaling pathway accompanied the glomerulonephritis in PPAR alpha-null mice. The results reported here indicate that PPAR alpha protects against the nephrotoxic effects of long-term exposure to DEHP.