Heintz Melissa M, Buerger Amanda N, Haws Laurie C, Cullen John M, East Alexander W, Thompson Chad M
ToxStrategies LLC, Asheville, NC 28801, United States.
ToxStrategies LLC, Austin, TX 78731, United States.
Toxicol Sci. 2025 Jul 1;206(1):183-201. doi: 10.1093/toxsci/kfaf049.
Recent in vitro transcriptomic analyses for short-chain per- and polyfluoroalkyl substances HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate) added to the weight of evidence supporting the peroxisome proliferator-activated receptor alpha (PPARα) activator-induced hepatocarcinogenesis mode of action (MOA) for HFPO-DA-mediated liver effects in rodents. Importantly, PPARα-mediated key events (KEs) including hepatocellular hypertrophy and proliferation that have been shown to occur prior to tumor development in this MOA are rodent-specific and likely not human-relevant. To further inform the MOA of HFPO-DA and evaluate other hypothesized MOAs, phenotypic and transcriptomic responses in wild-type (WT) and Ppara-null mice were investigated following short-term exposure to HFPO-DA or prototypical agonists of PPARα (GW7647), PPARγ (rosiglitazone), or cytotoxicity (acetaminophen). Phenotypic and transcriptomic assessment of mouse livers demonstrated a general lack of response to HFPO-DA or GW7647 exposure in Ppara-null but not WT mice. Conversely, rosiglitazone or acetaminophen elicited similar phenotypic and transcriptomic responses between genotypes demonstrating a lack of PPARα-dependence. In WT mice, HFPO-DA-mediated responses were similar to GW7647 but different from rosiglitazone or acetaminophen. Dose-dependent increases in liver weight, karyomegaly, and mitosis, as well as increased transcriptomic signaling related to PPARα activation and cell proliferation were observed in HFPO-DA and GW7647-exposed WT mice. The consistent phenotypic and transcriptomic signaling patterns between HFPO-DA and GW7647 in WT mice, and the lack of changes in Ppara-null mice, provide further support that HFPO-DA-mediated early KEs in mouse liver are PPARα-dependent, occur via the rodent-specific PPARα MOA, and therefore are not appropriate for use in human health risk assessment.
近期对短链全氟和多氟烷基物质六氟环氧丙烷二聚酸（HFPO-DA，铵盐，2,3,3,3-四氟-2-(七氟丙氧基)丙酸酯）进行的体外转录组学分析，为支持过氧化物酶体增殖物激活受体α（PPARα）激活剂诱导的肝癌发生作用模式（MOA）以解释HFPO-DA对啮齿动物肝脏的影响增加了证据权重。重要的是，PPARα介导的关键事件（KEs），包括肝细胞肥大和增殖，在该作用模式中已显示在肿瘤发生之前就会发生，这些是啮齿动物特有的，可能与人类无关。为了进一步了解HFPO-DA的作用模式并评估其他假设的作用模式，在短期暴露于HFPO-DA或PPARα的典型激动剂（GW7647）、PPARγ（罗格列酮）或细胞毒性物质（对乙酰氨基酚）后，研究了野生型（WT）和Ppara基因敲除小鼠的表型和转录组反应。对小鼠肝脏的表型和转录组评估表明，Ppara基因敲除小鼠对HFPO-DA或GW7647暴露普遍无反应，而WT小鼠有反应。相反，罗格列酮或对乙酰氨基酚在不同基因型之间引发了相似的表型和转录组反应，表明缺乏PPARα依赖性。在WT小鼠中，HFPO-DA介导的反应与GW7647相似，但与罗格列酮或对乙酰氨基酚不同。在暴露于HFPO-DA和GW7647的WT小鼠中，观察到肝脏重量、核肿大和有丝分裂呈剂量依赖性增加，以及与PPARα激活和细胞增殖相关的转录组信号增加。WT小鼠中HFPO-DA和GW7647之间一致的表型和转录组信号模式，以及Ppara基因敲除小鼠中无变化，进一步支持了HFPO-DA介导的小鼠肝脏早期关键事件是PPARα依赖性的，通过啮齿动物特有的PPARα作用模式发生，因此不适用于人类健康风险评估。
