ToxStrategies LLC, Asheville, North Carolina 28801, USA.
ToxStrategies LLC, Austin, Texas 78731, USA.
Toxicol Sci. 2024 Jun 26;200(1):165-182. doi: 10.1093/toxsci/kfae044.
Like many per- or polyfluorinated alkyl substances (PFAS), toxicity studies with HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate), a short-chain PFAS used in the manufacture of some types of fluorinated polymers, indicate that the liver is the primary target of toxicity in rodents following oral exposure. Although the current weight of evidence supports the PPARα mode of action (MOA) for liver effects in HFPO-DA-exposed mice, alternate MOAs have also been hypothesized including PPARγ or cytotoxicity. To further evaluate the MOA for HFPO-DA in rodent liver, transcriptomic analyses were conducted on samples from primary mouse, rat, and pooled human hepatocytes treated for 12, 24, or 72 h with various concentrations of HFPO-DA, or agonists of PPARα (GW7647), PPARγ (rosiglitazone), or cytotoxic agents (ie, acetaminophen or d-galactosamine). Concordance analyses of enriched pathways across chemicals within each species demonstrated the greatest concordance between HFPO-DA and PPARα agonist GW7647-treated hepatocytes compared with the other chemicals evaluated. These findings were supported by benchmark concentration modeling and predicted upstream regulator results. In addition, transcriptomic analyses across species demonstrated a greater transcriptomic response in rodent hepatocytes treated with HFPO-DA or agonists of PPARα or PPARγ, indicating rodent hepatocytes are more sensitive to HFPO-DA or PPARα/γ agonist treatment. These results are consistent with previously published transcriptomic analyses and further support that liver effects in HFPO-DA-exposed rodents are mediated through rodent-specific PPARα signaling mechanisms as part of the MOA for PPARα activator-induced rodent hepatocarcinogenesis. Thus, effects observed in mouse liver are not appropriate endpoints for toxicity value development for HFPO-DA in human health risk assessment.
像许多全氟或多氟烷基物质 (PFAS) 一样，用于制造某些类型含氟聚合物的短链 PFAS——HFPO-DA（铵盐，2,3,3,3-四氟-2-（七氟丙氧基）-丙酸钠）的毒性研究表明，在经口暴露后，肝脏是啮齿动物毒性的主要靶器官。尽管目前的证据支持 HFPO-DA 暴露的小鼠肝脏效应的过氧化物酶体增殖物激活受体α（PPARα）作用模式（MOA），但也假设了其他 MOA，包括 PPARγ 或细胞毒性。为了进一步评估 HFPO-DA 在啮齿动物肝脏中的 MOA，对用不同浓度 HFPO-DA 或 PPARα（GW7647）、PPARγ（罗格列酮）或细胞毒性剂（即对乙酰氨基酚或半乳糖胺）处理 12、24 或 72 小时的原代小鼠、大鼠和混合人肝细胞样本进行了转录组分析。对每个物种内化学物质富集途径的一致性分析表明，HFPO-DA 与 PPARα 激动剂 GW7647 处理的肝细胞之间的一致性最大，而与其他评估的化学物质之间的一致性最小。这些发现得到了基准浓度建模和预测上游调节剂结果的支持。此外，种间转录组分析表明，用 HFPO-DA 或 PPARα 或 PPARγ 激动剂处理的啮齿动物肝细胞的转录组反应更大，表明啮齿动物肝细胞对 HFPO-DA 或 PPARα/γ 激动剂处理更敏感。这些结果与之前发表的转录组分析一致，并进一步支持 HFPO-DA 暴露的啮齿动物肝脏效应是通过啮齿动物特异性 PPARα 信号机制介导的，作为 PPARα 激活剂诱导的啮齿动物肝癌发生的 MOA 的一部分。因此，在小鼠肝脏中观察到的效应不适合作为人类健康风险评估中 HFPO-DA 毒性值制定的终点。
