ToxStrategies LLC, Asheville, North Carolina 28801, USA.
ToxStrategies LLC, Austin, Texas 78731, USA.
Toxicol Sci. 2024 Jun 26;200(1):183-198. doi: 10.1093/toxsci/kfae045.
Recent in vitro transcriptomic analyses for the short-chain polyfluoroalkyl substance, HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate), support conclusions from in vivo data that HFPO-DA-mediated liver effects in mice are part of the early key events of the peroxisome proliferator-activated receptor alpha (PPARα) activator-induced rodent hepatocarcinogenesis mode of action (MOA). Transcriptomic responses in HFPO-DA-treated rodent hepatocytes have high concordance with those treated with a PPARα agonist and lack concordance with those treated with PPARγ agonists or cytotoxic agents. To elucidate whether HFPO-DA-mediated transcriptomic responses in mouse liver are PPARα-dependent, additional transcriptomic analyses were conducted on samples from primary PPARα knockout (KO) and wild-type (WT) mouse hepatocytes exposed for 12, 24, or 72 h with various concentrations of HFPO-DA, or well-established agonists of PPARα (GW7647) and PPARγ (rosiglitazone), or cytotoxic agents (acetaminophen or d-galactosamine). Pathway and predicted upstream regulator-level responses were highly concordant between HFPO-DA and GW7647 in WT hepatocytes. A similar pattern was observed in PPARα KO hepatocytes, albeit with a distinct temporal and concentration-dependent delay potentially mediated by compensatory responses. This delay was not observed in PPARα KO hepatocytes exposed to rosiglitazone, acetaminophen, d-galactosamine. The similarity in transcriptomic signaling between HFPO-DA and GW7647 in both the presence and absence of PPARα in vitro indicates these compounds share a common MOA.
最近针对短链全氟烷基物质 HFPO-DA（铵盐，2,3,3,3-四氟-2-（七氟丙氧基）-丙酸钠）的体外转录组分析支持了体内数据的结论，即 HFPO-DA 介导的小鼠肝脏效应是过氧化物酶体增殖物激活受体α (PPARα) 激活剂诱导的啮齿动物肝癌发生作用模式（MOA）中早期关键事件的一部分。HFPO-DA 处理的啮齿动物肝细胞中的转录组反应与 PPARα 激动剂处理的反应高度一致，而与 PPARγ 激动剂或细胞毒性剂处理的反应不一致。为了阐明 HFPO-DA 介导的小鼠肝脏转录组反应是否依赖于 PPARα，在暴露于不同浓度 HFPO-DA、PPARα 敲除（KO）和野生型（WT）小鼠原代肝细胞中的转录组分析进行了进一步的转录组分析）、PPARα （GW7647）和 PPARγ （罗格列酮）的已知激动剂或细胞毒性剂（对乙酰氨基酚或 D-半乳糖胺）12、24 或 72 小时。在 WT 肝细胞中，HFPO-DA 和 GW7647 之间的途径和预测的上游调节剂水平反应高度一致。在 PPARα KO 肝细胞中观察到类似的模式，尽管存在明显的时间和浓度依赖性延迟，可能由代偿性反应介导。在 PPARα KO 肝细胞中未观察到暴露于罗格列酮、对乙酰氨基酚、D-半乳糖胺的这种延迟。HFPO-DA 和 GW7647 在体外有或没有 PPARα 存在时的转录组信号相似表明这些化合物具有共同的作用模式。
