Supplementary data for: Comparison of phenotypic and transcriptomic profiles between HFPO-DA and prototypical PPARα, PPARγ, and cytotoxic agents in wild-type and Ppara-null mouse livers

Recent in vitro transcriptomic analyses for short-chain per- and polyfluoroalkyl substances (PFAS), 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 la..., Chemicals and Dosing Solutions
Ammonium perfluoro(2-methyl-3-oxahexanoate) (HFPO-DA; CASRN 62037-80-3; 95% purity) was purchased from Manchester Organics Ltd. (Runcorn, Cheshire, United Kingdom). GW7647 (CASRN 265129-71-3; ≥98% purity) was purchased from Cayman Chemical Company (Ann Arbor, MI). Rosiglitazone (CASRN 122320-73-4; 98.9% purity), acetaminophen (APAP; CASRN 103-90-2; ≥99% purity), dimethyl sulfoxide (DMSO; CASRN 67-68-5; >99.9% purity), and carboxylmethylcellulose sodium salt (CASRN 9004-32-4; Product No. C4888) were purchased from Sigma Aldrich (St. Louis, MO). HFPO-DA dosing solutions were prepared in deionized water; GW7647 and rosiglitazone dosing solutions were prepared in 5% DMSO suspended in 0.1% carboxymethylcellulose in deionized water. APAP dosing solutions were prepared in warm 0.9% saline.
Animal Husbandry and Exposure
The study was conducted at The Jackson Laboratory (JAX) (Sacramento, CA) under the supervision and approval of the Institutional Animal Care an..., , # Supplementary data for: Comparison of phenotypic and transcriptomic profiles between HFPO-DA and prototypical PPARα, PPARγ, and cytotoxic agents in wild-type and Ppara-null mouse livers

[https://doi.org/10.5061/dryad.hx3ffbgq5](https://doi.org/10.5061/dryad.hx3ffbgq5)

To further inform the mode of action (MOA) of HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate) and evaluate the PPARa-dependence of HFPO-DA-mediated liver effects *in vivo*, 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 PPARa (GW7647) and PPARg (rosiglitazone), or cytotoxic agent (acetaminophen [APAP]). This Dryad dataset contains the supplementary data pertaining to the transcriptomic results of this study; supplementary data for phenotypic findings (i.e., clinical observations)  are provided in Supplementary Files S1-S3 available with the main publication.

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近期针对短链全氟和多氟烷基物质（per- and polyfluoroalkyl substances, PFAS）开展的体外转录组学分析显示，全氟(2-甲基-3-氧杂己酸)铵（HFPO-DA，化学名称：2,3,3,3-四氟-2-(七氟丙氧基)丙酸铵）相关的证据权重进一步支持了其通过过氧化物酶体增殖物激活受体α（peroxisome proliferator-activated receptor alpha, PPARα）激活诱导肝细胞癌发生的作用模式（mode of action, MOA），该模式是啮齿类动物中HFPO-DA介导肝脏毒性的核心机制。值得注意的是，PPARα介导的关键事件（key events, KEs）——包括肿瘤发生前已被证实的肝细胞肥大与增殖——具有啮齿类特异性，大概率与人类无关。为进一步阐明HFPO-DA的作用模式并评估其他假说中的作用模式，本研究对野生型（wild-type, WT）及Ppara基因敲除小鼠在短期暴露于HFPO-DA、PPARα原型激动剂（GW7647）、PPARγ原型激动剂（罗格列酮）或细胞毒性剂（对乙酰氨基酚）后的表型与转录组响应进行了探究。小鼠肝脏的表型与转录组学评估总体呈现出……[原文截断]
化学品与配制溶液：
全氟(2-甲基-3-氧杂己酸)铵（HFPO-DA；CAS登记号：62037-80-3；纯度95%）购自英国曼彻斯特有机化学品有限公司（Manchester Organics Ltd.，柴郡朗科恩）。GW7647（CAS登记号：265129-71-3；纯度≥98%）购自美国凯曼化学公司（Cayman Chemical Company，密歇根州安阿伯）。罗格列酮（CAS登记号：122320-73-4；纯度98.9%）、对乙酰氨基酚（APAP；CAS登记号：103-90-2；纯度≥99%）、二甲基亚砜（DMSO；CAS登记号：67-68-5；纯度>99.9%）及羧甲基纤维素钠盐（CAS登记号：9004-32-4；产品编号C4888）购自美国西格玛奥德里奇公司（Sigma Aldrich，密苏里州圣路易斯）。HFPO-DA的给药溶液以去离子水配制；GW7647与罗格列酮的给药溶液以5%二甲基亚砜悬浮于0.1%羧甲基纤维素的去离子水溶液中配制；对乙酰氨基酚的给药溶液以温热的0.9%生理盐水配制。
动物饲养与暴露：
本研究在美国杰克逊实验室（The Jackson Laboratory, JAX，加州萨克拉门托）开展，实验方案经机构动物护理与使用委员会监督批准……[原文截断]
# 补充数据集：《野生型与Ppara基因敲除小鼠肝脏中HFPO-DA与原型PPARα、PPARγ激动剂及细胞毒性剂的表型与转录组谱比较》
数据集DOI：https://doi.org/10.5061/dryad.hx3ffbgq5
为进一步阐明HFPO-DA（化学名称：2,3,3,3-四氟-2-(七氟丙氧基)丙酸铵）的作用模式（MOA）并验证其介导肝脏毒性的PPARα依赖性，本研究对野生型（WT）及Ppara基因敲除小鼠在短期暴露于HFPO-DA、PPARα原型激动剂（GW7647）、PPARγ原型激动剂（罗格列酮）或细胞毒性剂（对乙酰氨基酚[APAP]）后的表型与转录组响应进行了探究。本Dryad数据集包含本研究转录组学结果相关的补充数据；表型结果（即临床观察结果）的补充数据已随主出版物一并提供于补充文件S1-S3中。
### 文件列表……[原文截断]