BACKGROUND Per- and polyfluoroalkyl substances (PFAS) are a diverse class of industrial chemicals with widespread environmental occurrence. Exposure to long-chain PFAS is associated with developmental toxicity, prompting their replacement with short-chain and fluoroether compounds. There is growing public concern over the safety of replacement PFAS. OBJECTIVE We aimed to group PFAS based on shared toxicity phenotypes. METHODS Zebrafish were developmentally exposed to 4,8-dioxa-3H-perfluorononanoate (ADONA), perfluoro-2-propoxypropanoic acid (GenX Free Acid), perfluoro-3,6-dioxa-4-methyl-7-octene-1-sulfonic acid (PFESA1), perfluorohexanesulfonic acid (PFHxS), perfluorohexanoic acid (PFHxA), perfluoro-n-octanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), or 0.4% dimethyl sulfoxide (DMSO) daily from 0-5 d post fertilization (dpf). At 6 dpf, developmental toxicity and developmental neurotoxicity assays were performed, and targeted analytical chemistry was used to measure media and tissue doses. To test whether aliphatic sulfonic acid PFAS cause the same toxicity phenotypes, perfluorobutanesulfonic acid (PFBS; 4-carbon), perfluoropentanesulfonic acid (PFPeS; 5-carbon), PFHxS (6-carbon), perfluoroheptanesulfonic acid (PFHpS; 7-carbon), and PFOS (8-carbon) were evaluated. RESULTS PFHxS or PFOS exposure caused failed swim bladder inflation, abnormal ventroflexion of the tail, and hyperactivity at nonteratogenic concentrations. Exposure to PFHxA resulted in a unique hyperactivity signature. ADONA, PFESA1, or PFOA exposure resulted in detectable levels of parent compound in larval tissue but yielded negative toxicity results. GenX was unstable in DMSO, but stable and negative for toxicity when diluted in deionized water. Exposure to PFPeS, PFHxS, PFHpS, or PFOS resulted in a shared toxicity phenotype characterized by body axis and swim bladder defects and hyperactivity. CONCLUSIONS All emerging fluoroether PFAS tested were negative for evaluated outcomes. Two unique toxicity signatures were identified arising from structurally dissimilar PFAS. Among sulfonic acid aliphatic PFAS, chemical potencies were correlated with increasing carbon chain length for developmental neurotoxicity, but not developmental toxicity. This study identified relationships between chemical structures and in vivo phenotypes that may arise from shared mechanisms of PFAS toxicity. These data suggest that developmental neurotoxicity is an important end point to consider for this class of widely occurring environmental chemicals. https://doi.org/10.1289/EHP5843.

中文翻译：

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对暴露于 GenX 和其他 PFAS 的斑马鱼的发育毒性、发育神经毒性和组织剂量的评估。

背景全氟烷基物质和多氟烷基物质 (PFAS) 是一类广泛存在于环境中的工业化学品。暴露于长链 PFAS 与发育毒性有关，促使它们被短链和氟醚化合物取代。公众越来越关注替代 PFAS 的安全性。目标 我们旨在根据共有的毒性表型对 PFAS 进行分组。方法斑马鱼在发育过程中暴露于 4,8-dioxa-3H-perfluorononanoate (ADONA)、perfluoro-2-propoxypropanoic acid (GenX Free Acid)、perfluoro-3,6-dioxa-4-methyl-7-octene-1-sulfonic受精后 0-5 天每天使用酸 (PFESA1)、全氟己烷磺酸 (PFHxS)、全氟己酸 (PFHxA)、全氟正辛酸 (PFOA)、全氟辛烷磺酸 (PFOS) 或 0.4% 二甲亚砜 (DMSO)（ dpf)。在 6 dpf 时，进行了发育毒性和发育神经毒性试验，并使用靶向分析化学来测量培养基和组织剂量。为了测试脂肪族磺酸 PFAS 是否会导致相同的毒性表型，全氟丁烷磺酸（PFBS；4-碳）、全氟戊烷磺酸（PFPeS；5-碳）、PFHxS（6-碳）、全氟庚烷磺酸（PFHpS；7-碳）、和全氟辛烷磺酸（8-碳）进行了评估。结果 PFHxS 或 PFOS 暴露导致鱼鳔膨胀失败、尾巴异常腹屈以及在非致畸浓度下活动过度。接触全氟己烷磺酸导致了独特的多动症特征。ADONA、PFESA1 或 PFOA 暴露导致幼虫组织中可检测水平的母体化合物，但产生负面毒性结果。GenX 在 DMSO 中不稳定，但在去离子水中稀释时稳定且无毒性。接触 PFPeS、PFHxS、PFHpS 或 PFOS 会导致共同的毒性表型，其特征是体轴和鳔缺陷和多动症。结论 所有新出现的氟醚 PFAS 测试的评估结果均为阴性。确定了由结构不同的 PFAS 引起的两种独特的毒性特征。在磺酸脂肪族全氟和多氟烷基物质中，化学效力与碳链长度的增加相关，导致发育神经毒性，但与发育毒性无关。这项研究确定了化学结构和体内表型之间的关系，这些关系可能源于 PFAS 毒性的共同机制。这些数据表明，发育神经毒性是这类广泛存在的环境化学物质的重要终点。https://doi.org/10.1289/EHP5843。