Hepatic peroxisome proliferator-activated receptor α may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice

Yumi Hayashi, Yuki Ito, Nozomi Yamagishi, Yukie Yanagiba, Hazuki Tamada, Dong Wang, Doni Hikmat Ramdhan, Hisao Naito, Yukiko Harada, Michihiro Kamijima, Frank J. Gonzales, Tamie Nakajima

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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 (m. PPARα), Pparα-null and humanized PPARα (h. PPARα) 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 m. PPARα mice. In h. PPARα 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 m. PPARα and at the high dose in h. PPARα mice. No such findings were observed in Pparα-null mice. High-dose DEHP decreased plasma triglyceride in pregnant m. PPARα mice, but not in Pparα-null and h. PPARα ones. Above the medium dose in m. PPARα 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 m. PPARα and h. PPARα 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 m. PPARα mice and not in h PPARα mice.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalToxicology
Volume289
Issue number1
DOIs
Publication statusPublished - 28-10-2011

All Science Journal Classification (ASJC) codes

  • Toxicology

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    Hayashi, Y., Ito, Y., Yamagishi, N., Yanagiba, Y., Tamada, H., Wang, D., Ramdhan, D. H., Naito, H., Harada, Y., Kamijima, M., Gonzales, F. J., & Nakajima, T. (2011). Hepatic peroxisome proliferator-activated receptor α may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice. Toxicology, 289(1), 1-10. https://doi.org/10.1016/j.tox.2011.02.007