title: Hepatic peroxisome proliferator-activated receptor α may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice.
abstract: Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with adverse effects on offspring, and the metabolites are agonists of peroxisome proliferator-activated receptor (PPAR) α, which exhibits species differences in expression and function. This study aimed to clarify the mechanism of DEHP-induced adverse effects on offspring in relation to maternal mouse and human PPARα. Male and female Sv/129 wild-type (mPPARα), Pparα-null and humanized PPARα (hPPARα) mice were treated with diets containing 0%, 0.01%, 0.05% (medium) or 0.1% (high) DEHP. After 4 weeks, males and females were mated. Dams were killed on gestational day 18 and postnatal day (PND) 2. High-dose DEHP decreased the number of total and live fetuses, and increased resorptions in mPPARα mice. In hPPARα mice, resorptions were increased above the medium dose, and the number of births was decreased at the high dose. The number of live pups on PND2 was decreased over the medium dose in mPPARα and at the high dose in hPPARα mice. No such findings were observed in Pparα-null mice. High-dose DEHP decreased plasma triglyceride in pregnant mPPARα mice, but not in Pparα-null and hPPARα ones. Above the medium dose in mPPARα mice significantly reduced hepatic microsomal triglyceride transfer protein (MTP) expression. Medium- and/or high-dose DEHP increased the levels of maternal PPARα target genes in mPPARα and hPPARα mice. Taken together, PPARα expression is required for the toxicity of DEHP in fetuses and pups and altered plasma triglyceride levels, through regulation of MTP may be important in mPPARα mice and not in hPPARα mice.
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ito
authors.forename: Nozomi
authors.initials: N
authors.lastname: Yamagishi
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yanagiba
authors.forename: Hazuki
authors.initials: H
authors.lastname: Tamada
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Doni Hikmat
authors.initials: DH
authors.lastname: Ramdhan
authors.forename: Hisao
authors.initials: H
authors.lastname: Naito
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Harada
authors.forename: Michihiro
authors.initials: M
authors.lastname: Kamijima
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzales
authors.forename: Tamie
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D005260:Female; D005838:Genotype; D006801:Humans; D008098:Litter Size / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D010968:Plasticizers / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D014280:Triglycerides / Q000097:blood
chemical_list: C099283:Laptm4a protein, mouse; D026901:Membrane Transport Proteins; D047493:PPAR alpha; D010968:Plasticizers; D012333:RNA, Messenger; D014280:Triglycerides; D004051:Diethylhexyl Phthalate