Developmental Effects of Perfluorononanoic Acid in the Mouse Are Dependent on Peroxisome Proliferator-Activated Receptor-Alpha
Developmental Effects of Perfluorononanoic Acid in the Mouse Are Dependent on Peroxisome Proliferator-Activated Receptor-Alpha
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DOI：
10.1155/2010/282896
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发表时间：
2010-01-01
期刊：
影响因子：
2.9
通讯作者：
Abbott, Barbara D.
中科院分区：
文献类型：
--
作者：
Wolf, Cynthia J.;Zehr, Robert D.;Abbott, Barbara D.
全氟壬酸 (PFNA) 是在环境以及人类和野生动物组织中发现的全氟烷基酸之一。产前接触 PFNA 会对小鼠的生存和发育产生负面影响，并激活小鼠和人类过氧化物酶体增殖物激活受体-α (PPAR α)。在当前的研究中，我们使用 PPAR α 敲除 (KO) 和 129S1/SvlmJ 野生型 (WT) 小鼠来研究 PPAR α 在介导 PFNA 诱导的体内效应中的作用。妊娠 KO 和 WT 小鼠在妊娠天数 (GD) 1-18（精子塞日 = GD 0）口服水（载体对照：10 ml/kg）、0.83、1.1、1.5 或 2 mg/kg PFNA。两种品系的母体体重增加、着床、窝产仔数和幼仔出生体重均不受影响。在 WT 1.1 和 2 mg/kg 组中，PFNA 暴露降低了出生时活幼仔的数量以及后代断奶时的存活率。 2 mg/kg 的 WT 幼仔睁眼延迟（平均延迟 2.1 天），断奶时幼仔体重降低。这些发育终点在 KO 中没有受到影响。在所有剂量水平下，WT品系的母鼠和幼崽的相对肝脏重量均以剂量依赖性方式增加，但在KO品系的最高剂量组中仅略有增加。总之，PFNA 改变了 WT 中母鼠和幼鼠的肝脏重量、幼鼠的存活率、体重和发育，而在 KO 小鼠中，2 mg/kg 时仅诱导母鼠和幼鼠的相对肝脏重量略有增加。这些结果表明 PPAR α 是 PFNA 诱导的小鼠发育毒性的重要介质。
Perfluorononanoic acid (PFNA) is one of the perfluoroalkyl acids found in the environment and in tissues of humans and wildlife. Prenatal exposure to PFNA negatively impacts survival and development of mice and activates the mouse and human peroxisome proliferator-activated receptor-alpha (PPAR alpha). In the current study, we used PPAR alpha knockout (KO) and 129S1/SvlmJ wild-type (WT) mice to investigate the role of PPAR alpha in mediating PFNA-induced in vivo effects. Pregnant KO and WT mice were dosed orally with water (vehicle control: 10 ml/kg), 0.83, 1.1, 1.5, or 2 mg/kg PFNA on gestational days (GDs) 1-18 (day of sperm plug = GD 0). Maternal weight gain, implantation, litter size, and pup weight at birth were unaffected in either strain. PFNA exposure reduced the number of live pups at birth and survival of offspring to weaning in the 1.1 and 2 mg/kg groups in WT. Eye opening was delayed (mean delay 2.1 days) and pup weight at weaning was reduced in WT pups at 2 mg/kg. These developmental endpoints were not affected in the KO. Relative liver weight was increased in a dose-dependent manner in dams and pups of the WT strain at all dose levels but only slightly increased in the highest dose group in the KO strain. In summary, PFNA altered liver weight of dams and pups, pup survival, body weight, and development in the WT, while only inducing a slight increase in relative liver weight of dams and pups at 2 mg/kg in KO mice. These results suggest that PPAR alpha is an essential mediator of PFNA-induced developmental toxicity in the mouse.