Adverse Maternal, Fetal, and Postnatal Effects of Hexafluoropropylene Oxide Dimer Acid (GenX) from Oral Gestational Exposure in Sprague-Dawley Rats
Adverse Maternal, Fetal, and Postnatal Effects of Hexafluoropropylene Oxide Dimer Acid (GenX) from Oral Gestational Exposure in Sprague-Dawley Rats
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DOI：
10.1289/ehp4372
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发表时间：
2019-03-01
影响因子：
10.4
通讯作者：
Gray, L. Earl, Jr.
中科院分区：
文献类型：
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作者：
Conley, Justin M.;Lambright, Christy S.;Gray, L. Earl, Jr.
背景：六氟环氧丙烷二聚酸[HEPO-DA，GenX]是全氟和多氟烷基物质(PFAS)化学类别中的一员，在美国和欧洲的地表水、空气和经处理的饮用水中发现HFPO-DA水平升高。目的：研究口服HFPO-DA对大鼠性分化过程中潜在的母体和出生后毒性。鉴于一些PFAs激活了过氧化体增殖物激活受体(PPAR)，我们试图评估HFPO-DA是否影响雄激素依赖的发育或干扰雌激素、雄激素或糖皮质激素受体的活性。方法：采用一套体外反式激活试验评估类固醇受体活性，并使用SpragueDawley大鼠评估HFPO-DA暴露对母体、胎儿和出生后的影响。在雄性生殖发育期间(怀孕14-18天)，每天经口灌胃给药。我们评估了胎儿睾丸、母体和胎儿肝脏、母体血清临床化学和F1动物的生殖发育。结果：HFPO-DA暴露导致体外受体活性可以忽略不计，不影响睾酮的产生或男性生殖发育关键基因在胎儿睾丸中的表达；但是，孕期体内暴露导致母体肝脏重量增加(>；=62.5 mg/kg)，母体血清甲状腺激素和血脂水平降低(>；=30 mg/kg)，母体和胎儿肝脏PPAR信号通路相关基因表达上调(>；=1 mg/kg)。此外，出生后的初步研究表明，F1动物的雌性体重和雄性生殖组织重量较低。结论：HFPO-DA暴露产生的多种影响与先前对全氟辛烷磺酸(PFOS)和全氟辛酸(PFOA)的毒性评估相似，但被视为较高口服剂量的结果。最低剂量组的平均DAM血清浓度是HFPO-DA制造厂工人检测到的最高血清浓度的4倍。需要进行研究来检查与全氟辛烷磺酸不良影响有关的机制和下游事件，评估多种全氟辛烷磺酸的基于混合物的研究也是如此。
BACKGROUND: Hexafluoropropylene oxide dimer acid [(HEPO-DA), GenX] is a member of the per- and polyfluoroalkyl substances (PFAS) chemical class, and elevated levels of HFPO-DA have been detected in surface water, air, and treated drinking water in the United States and Europe.OBJECTIVES: We aimed to characterize the potential maternal and postnatal toxicities of oral HFPO-DA in rats during sexual differentiation. Given that some PFAS activate peroxisome proliferator-activated receptors (PPARs), we sought to assess whether HFPO-DA affects androgen-dependent development or interferes with estrogen, androgen, or glucocorticoid receptor activity.METHODS: Steroid receptor activity was assessed with a suite of in vitro transactivation assays, and Sprague-Dawley rats were used to assess maternal, fetal, and postnatal effects of HFPO-DA exposure. Dams were dosed daily via oral gavage during male reproductive development (gestation days 14-18). We evaluated fetal testes, maternal and fetal livers, maternal serum clinical chemistry, and reproductive development of F1 animals.RESULTS: HFPO-DA exposure resulted in negligible in vitro receptor activity and did not impact testosterone production or expression of genes key to male reproductive development in the fetal testis; however, in vivo exposure during gestation resulted in higher maternal liver weights (>= 62.5 mg/kg), lower maternal serum thyroid hormone and lipid profiles (>= 30 mg/kg), and up-regulated gene expression related to PPAR signaling pathways in maternal and fetal livers (>= 1 mg/kg). Further, the pilot postnatal study indicated lower female body weight and lower weights of male reproductive tissues in F1 animals.CONCLUSIONS: HFPO-DA exposure produced multiple effects that were similar to prior toxicity evaluations on PFAS, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), but seen as the result of higher oral doses. The mean dam serum concentration from the lowest dose group was 4-fold greater than the maximum serum concentration detected in a worker in an HFPO-DA manufacturing facility. Research is needed to examine the mechanisms and downstream events linked to the adverse effects of PFAS as are mixture-based studies evaluating multiple PFAS.