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 alpha (PPARalpha), but this contention remains controversial. For investigation of the long-term toxicity of DEHP and determination of whether PPARalpha mediates toxicity, wild-type and PPARalpha-null mice were fed a diet that contained 0.05 or 0.01% DEHP for 22 mo. PPARalpha-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 PPARalpha-dependent anti-inflammatory effects that normally antagonize the NFkappaB signaling pathway accompanied the glomerulonephritis in PPARalpha-null mice. The results reported here indicate that PPARalpha protects against the nephrotoxic effects of long-term exposure to DEHP.
Kamijo
Yuji
Y
Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan. yujibeat@hsp.md.shinshu-u.ac.jp
Hora
Kazuhiko
K
Nakajima
Tamie
T
Kono
Keiichi
K
Takahashi
Kyoko
K
Ito
Yuki
Y
Higuchi
Makoto
M
Kiyosawa
Kendo
K
Shigematsu
Hidekazu
H
Gonzalez
Frank J
FJ
Aoyama
Toshifumi
T
D000818:Animals; D001483:Base Sequence; D004032:Diet; D004051:Diethylhexyl Phthalate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000633:toxicity*; D005921:Glomerulonephritis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D007105:Immune Complex Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010968:Plasticizers / Q000008:administration & dosage / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D047493:PPAR alpha; D010968:Plasticizers; D012333:RNA, Messenger; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate