Hepatic peroxisome proliferator-activated receptor a may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice
Hepatic peroxisome proliferator-activated receptor a may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice
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DOI：
10.1016/j.tox.2011.02.007
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发表时间：
2011-10-28
期刊：
影响因子：
4.5
通讯作者：
Nakajima, Tamie
中科院分区：
文献类型：
--
作者：
Hayashi, Yumi;Ito, Yuki;Nakajima, Tamie
母体暴露于邻苯二甲酸二（2-乙基己基）酯（DEHP）与对后代的不良影响相关，其代谢物是过氧化物酶体增殖物激活受体（PPAR）α的激动剂，在表达和功能方面存在物种差异。本研究旨在阐明DEHP诱导的与母体小鼠和人类PPAR α相关的后代不良反应的机制。雄性和雌性Sv/129野生型（mPPAR α）、Ppar α-null和人源化PPAR α（hPPAR α）小鼠用含0%、0.01%、0.05%（中等）或0.1%（高）DEHP的饲料处理。4周后，雄性和雌性交配。在妊娠第18天和产后第2天（PND）处死母鼠。高剂量DEHP降低了mPPAR α小鼠的总胎仔数和活胎数，并增加了再吸收。在hPPAR α小鼠中，高于中剂量时吸收增加，高剂量时出生数量减少。在中剂量组mPPAR α和高剂量组hPPAR α小鼠中，PND 2时的存活幼仔数量减少。在Ppar α缺失小鼠中未观察到此类发现。高剂量DEHP可降低妊娠mPPAR α小鼠的血浆甘油三酯，但在Ppar α缺失和hPPAR α小鼠中则无此作用。在mPPAR α小鼠中，高于中等剂量显著降低了肝微粒体甘油三酯转移蛋白（MTP）表达。中剂量和/或高剂量DEHP增加了mPPAR α和hPPAR α小鼠母体PPAR α靶基因的水平。综上所述，胎儿和幼崽中DEHP的毒性需要PPAR α表达，通过调节MTP改变血浆甘油三酯水平可能对mPPAR α小鼠而不是hPPAR α小鼠很重要。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
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) alpha, 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 PPAR alpha. Male and female Sv/129 wild-type (mPPAR alpha), Ppar alpha-null and humanized PPAR alpha (hPPAR alpha) 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 mPPAR alpha mice. In hPPAR alpha 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 mPPAR alpha and at the high dose in hPPAR alpha mice. No such findings were observed in Ppar alpha-null mice. High-dose DEHP decreased plasma triglyceride in pregnant mPPAR alpha mice, but not in Ppar alpha-null and hPPAR alpha ones. Above the medium dose in mPPAR alpha mice significantly reduced hepatic microsomal triglyceride transfer protein (MTP) expression. Medium-and/or high-dose DEHP increased the levels of maternal PPAR alpha target genes in mPPAR alpha and hPPAR alpha mice. Taken together, PPAR alpha 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 mPPAR alpha mice and not in hPPAR alpha mice. (C) 2011 Elsevier Ireland Ltd. All rights reserved.