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Effects of perfluorooctanoic acid (PFOA) on gene expression profiles via nuclear receptors in HepaRG cells: Comparative study with in vitro transactivation assays

孕烷X受体 交易激励 雄激素受体 核受体 全氟辛酸 法尼甾体X受体 过氧化物酶体增殖物激活受体 受体 肝细胞核因子4 化学 生物 转录因子 内分泌学 内科学 生物化学 基因 医学
作者
Wataru Murase,Atsuhito Kubota,Atsuko Ikeda‐Araki,Masaru Terasaki,Koji Nakagawa,Ryota Shizu,Kouichi Yoshinari,Hiroyuki Kojima
出处
期刊:Toxicology [Elsevier]
卷期号:494: 153577-153577 被引量:1
标识
DOI:10.1016/j.tox.2023.153577
摘要

Perfluorooctanoic acid (PFOA), a synthetic perfluorinated eight-carbon organic chemical, induces hepatotoxicity in rodents, indicated increased liver weight, hepatocellular hypertrophy, necrosis, and peroxisome proliferation. Epidemiological studies have demonstrated the association between serum PFOA levels and various adverse effects. In this study, we investigated the gene expression profiles of human HepaRG cells exposed to 10 and 100 μM PFOA for 24 h. Treatment with 10 and 100 μM PFOA significantly modulated the expression of 190 and 996 genes, respectively. Genes upregulated or downregulated by 100 µM PFOA included peroxisome proliferator-activated receptor (PPAR) signaling genes related to lipid metabolism, adipocyte differentiation, and gluconeogenesis. Moreover, we identified the "Nuclear receptors-meta pathways" following the activation of other nuclear receptors: constitutive androstane receptor (CAR), pregnane X receptor (PXR) and farnesoid X receptor (FXR), as well as the transcription factor nuclear factor E2-related factor 2 (Nrf2). The expression levels of some target genes (CYP4A11, CYP2B6, CYP3A4, CYP7A1, and GPX2) of these nuclear receptors and Nrf2 were confirmed using quantitative reverse transcription polymerase chain reaction. Next, we performed transactivation assays using COS-7 and HEK293 cells to investigate whether these signaling-pathways were activated by the direct effects of PFOA on human PPARα, CAR, PXR, FXR and Nrf2. PFOA concentration-dependently activated PPARα, but not CAR, PXR, FXR, or Nrf2. Taken together, these results suggest that PFOA affects the hepatic transcriptomic responses of HepaRG cells through the direct activation of PPARα and indirect activation of CAR, PXR, FXR, and Nrf2. Our finding indicates that PPARα activation in the "Nuclear receptors-meta pathways" functions as a molecular initiating event for PFOA, and indirect activation of alternative nuclear receptors and Nrf2 also induce important molecular mechanisms in PFOA-induced human hepatotoxicity.
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