Neonatal mortality from in utero exposure to perfluorooctanesulfonate (PFOS) in Sprague-Dawley rats: Dose-response, and biochemical and pharamacokinetic parameters
Neonatal mortality from in utero exposure to perfluorooctanesulfonate (PFOS) in Sprague-Dawley rats: Dose-response, and biochemical and pharamacokinetic parameters
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DOI：
10.1016/j.tox.2005.07.019
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发表时间：
2005-11-05
期刊：
影响因子：
4.5
通讯作者：
Butenhoff, JL
中科院分区：
文献类型：
--
作者：
Luebker, DJ;York, RG;Butenhoff, JL
全氟辛烷磺酸（PFOS）是一种广泛分布的环境持久性酸，在人类、野生动物和环境介质样本中含量较低。在一项对大鼠进行的两代生殖研究中，以及在妊娠大鼠和小鼠妊娠期间给药后，观察到新生儿在接触全氟辛烷磺酸后死亡。本研究的目的是更好地确定接触全氟辛烷磺酸的母鼠所生幼鼠的新生儿死亡率的剂量反应曲线，并调查可能与在新生幼鼠中观察到的影响的病因有关的生化和药代动力学参数。在本研究中，包括0.8、1.0、1.2和2.0 mg/kg/天的额外剂量，以及两代研究中使用的0.4和1.6 mg/kg/天的原始剂量，以获得剂量-反应曲线临界范围内的数据。在母鼠和窝仔中研究的生化参数包括：（1）血清脂质、葡萄糖、甲羟戊酸和甲状腺激素;（2）乳汁胆固醇;和（3）肝脏脂质。所调查的药代动力学参数包括全氟辛烷磺酸口服剂量与母体全氟辛烷磺酸负荷之间的相互关系，以及母体全氟辛烷磺酸负荷转移给子宫内胎儿和哺乳期幼崽的情况，因为这些因素可能会影响新生儿毒性。在与未给药的育种雄性交配前6周，通过确认交配、妊娠和哺乳期第4天对母鼠给药。用于剂量反应和病因调查的剂量水平为0.0、0.4、0.8、1.0、1.2、1.6和2.0毫克/千克/天全氟辛烷磺酸。在0.8 mg/kg和更高剂量组中观察到妊娠时间统计学显著性缩短。在0.8 mg/kg及更高剂量组中观察到哺乳期第5天活力下降，在1.6和2.0 mg/kg剂量组中变得具有统计学意义。新生儿存活率的降低似乎不是脂质、葡萄糖利用或甲状腺激素减少的结果。妊娠期长短和生存能力下降的终点呈正相关，表明在子宫内接触全氟辛烷磺酸的幼崽的后期胎儿发育可能受到影响，并可能导致观察到的死亡率。妊娠期缩短、出生体重、哺乳期第5天幼仔体重、哺乳期第5天幼仔增重和存活率的基准剂量（BMD）估计值导致BMD 5（BMDL 5）95%置信下限的值范围为0.27 - 0.89 mg/kg/天。生物基质中全氟辛烷磺酸的分析结果表明，在交配前和妊娠前两个三个月，血清中全氟辛烷磺酸的平均浓度与母体给药剂量呈线性比例关系。然而，在妊娠第21天，血清中全氟辛烷磺酸的平均浓度与妊娠早期的测量值相比明显降低。尿液和粪便消除较低，与先前在成年大鼠中观察到的结果一致。已证实全氟辛烷磺酸在子宫内从母体大量转移到胎儿，结果表明，母体和相应胎儿体内的负荷（如血清和肝脏全氟辛烷磺酸水平所示）与新生儿存活率相关。(c)2005爱思唯尔爱尔兰有限公司保留所有权利。
Perfluorooctanesulfonate (PFOS) is a widely distributed, environmentally persistent acid found at low levels in human, wildlife, and environmental media samples. Neonatal mortality has been observed following PFOS exposure in a two-generation reproduction study in rats and after dosing pregnant rats and mice during gestation. Objectives of the current study were to better define the dose-response curve for neonatal mortality in rat pups born to PFOS-exposed dams and to investigate biochemical and pharmacokinetic parameters potentially related to the etiology of effects observed in neonatal rat pups. In the current study, additional doses of 0.8, 1.0, 1.2, and 2.0 mg/kg/day were included with original doses used in the two-generation study of 0.4 and 1.6 mg/kg/day in order to obtain data in the critical range of the dose-response curve. Biochemical parameters investigated in dams and litters included: (1) serum lipids, glucose, mevalonic acid, and thyroid hormones; (2) milk cholesterol; and (3) liver lipids. Pharmacokinetic parameters investigated included the interrelationship of administered oral dose of PFOS to maternal body burden of PFOS and the transfer of maternal body burden to the fetus in utero and pup during lactation, as these factors may affect neonatal toxicity. Dosing of dams occurred for 6 weeks prior to mating with untreated breeder males, through confirmed mating, gestation, and day four of lactation. Dose levels for the dose-response and etiological investigation were 0.0, 0.4, 0.8, 1.0, 1.2, 1.6, and 2.0 mg/kg/day PFOS. Statistically significant decreases in gestation length were observed in the 0.8 mg/kg and higher dose groups. Decreases in viability through lactation day 5 were observed in the 0.8 mg/kg and higher dose groups, becoming statistically significant in the 1.6 and 2.0 mg/kg dose groups. Reduced neonatal survival did not appear to be the result of reductions in lipids, glucose utilization, or thyroid hormones. The endpoints of gestation length and decreased viability were positively correlated, suggesting that late-stage fetal development may be affected in pups exposed to PFOS in utero and may contribute to the observed mortality. Benchmark dose (BMD) estimates for decreased gestation length, birth weight, pup weight on lactation day 5, pup weight gain through lactation day 5, and viability resulted in values ranging from 0.27 to 0.89 mg/kg/day for the lower 95% confidence limit of the BMD5 (BMDL5). Results of analyses for PFOS in biological matrices indicate a linear proportionality of mean serum PFOS concentration to maternal administered dose prior to mating and through the first two trimesters of gestation. However, at 21 days of gestation, mean serum PFOS concentrations were notably reduced from values measured earlier in gestation. Urinary and fecal elimination was low as expected from prior observations in adult rats. Significant transfer of PFOS from dam to fetus in utero was confirmed, and results suggest that dam and corresponding fetal body burdens, as indicated by serum and liver PFOS levels, correlate with neonatal survival. (c) 2005 Elsevier Ireland Ltd. All rights reserved.