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

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Peroxisome Proliferator-Activated Receptors
Poisons
Liver
phthalic acid
Triglycerides
Fetus
Mothers
Plasmas
Maternal Exposure
Nutrition

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Hayashi, Yumi ; Ito, Yuki ; Yamagishi, Nozomi ; Yanagiba, Yukie ; Tamada, Hazuki ; Wang, Dong ; Ramdhan, Doni Hikmat ; Naito, Hisao ; Harada, Yukiko ; Kamijima, Michihiro ; Gonzales, Frank J. ; Nakajima, Tamie. / Hepatic peroxisome proliferator-activated receptor α may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice. In: Toxicology. 2011 ; Vol. 289, No. 1. pp. 1-10.
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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.",
author = "Yumi Hayashi and Yuki Ito and Nozomi Yamagishi and Yukie Yanagiba and Hazuki Tamada and Dong Wang and Ramdhan, {Doni Hikmat} and Hisao Naito and Yukiko Harada and Michihiro Kamijima and Gonzales, {Frank J.} and Tamie Nakajima",
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Hayashi, Y, Ito, Y, Yamagishi, N, Yanagiba, Y, Tamada, H, Wang, D, Ramdhan, DH, Naito, H, Harada, Y, Kamijima, M, Gonzales, FJ & 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, vol. 289, no. 1, pp. 1-10. https://doi.org/10.1016/j.tox.2011.02.007

Hepatic peroxisome proliferator-activated receptor α may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice. / Hayashi, Yumi; Ito, Yuki; Yamagishi, Nozomi; Yanagiba, Yukie; Tamada, Hazuki; Wang, Dong; Ramdhan, Doni Hikmat; Naito, Hisao; Harada, Yukiko; Kamijima, Michihiro; Gonzales, Frank J.; Nakajima, Tamie.

In: Toxicology, Vol. 289, No. 1, 28.10.2011, p. 1-10.

Research output: Contribution to journalArticle

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T1 - Hepatic peroxisome proliferator-activated receptor α may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice

AU - Hayashi, Yumi

AU - Ito, Yuki

AU - Yamagishi, Nozomi

AU - Yanagiba, Yukie

AU - Tamada, Hazuki

AU - Wang, Dong

AU - Ramdhan, Doni Hikmat

AU - Naito, Hisao

AU - Harada, Yukiko

AU - Kamijima, Michihiro

AU - Gonzales, Frank J.

AU - Nakajima, Tamie

PY - 2011/10/28

Y1 - 2011/10/28

N2 - 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.

AB - 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.

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