Peroxisome Proliferator–Activated Receptor α 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 α (PPARα), but this contention remains controversial. For investigation of the long-term toxicity of DEHP and determination of whether PPARα mediates toxicity, wild-type and PPARα-null mice were fed a diet that contained 0.05 or 0.01% DEHP for 22 mo. PPARα-null mice that were exposed to DEHP exhibited prominent immune complex glomerulonephritis, most likely related to elevated glomerular oxidative stress. Elevated NADPH oxidase, low antioxidant enzymes, and absence of the PPARα-dependent anti-inflammatory effects that normally antagonize the NFκB signaling pathway accompanied the glomerulonephritis in PPARα-null mice. The results reported here indicate that PPARα protects against the nephrotoxic effects of long-term exposure to DEHP.