Role of Peroxisome Proliferator-activated Receptor-α in Hepatobiliary Injury Induced by Ammonium Perfluorooctanoate in Mouse Liver

Minata, Mutsuko; Harada, Kouji H.; Kärrman, Anna; Hitomi, Toshiaki; Hirosawa, Michi; Murata, Mariko; Gonzalez, Frank J.; Koizumi, Akio

doi:10.2486/indhealth.48.96

Cited by 38 publications

(47 citation statements)

References 35 publications

(29 reference statements)

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“…In addition, several reports have demonstrated that, unlike normal PPArα agonists, PFOA exposure increased hepatocyte hypertrophy and altered the liver gene expression profile in PPArα-null mice (Minata et al 2010;rosen et al 2008a, b;Wolf et al 2008). An in vitro study on the activation of multiple nuclear receptors, including PPArα, pregnane x receptor (Pxr), constitutive active receptor (cAr), lxr-α, and farnesoid x receptor (Fxr), in the primary hepatocytes of rats and humans exposed to PFOA or PFOS (Bjork et al 2011) demonstrated that PFOA and PFOS could activate nuclear receptors other than PPArα.…”

Section: Discussionmentioning

confidence: 96%

“…PPArα plays an important role in fatty acids β-oxidation, ketogenesis, and systemic lipid metabolism, and PPAr agonists reportedly induce hepatomegaly and hepatocarcinogenesis without genetic damage (Pyper et al 2010). Although PFOA-and PFOS-induced liver enlargement appears to result from acting as a PPAr ligand, liver weight increase was still observed in PFOA-exposed PPArα-null mice (Minata et al 2010;Wolf et al 2008). Fat accumulation and changes in genes related to fatty acid metabolism were also observed in PFOA-treated PPArα-null mice (Minata et al 2010;rosen et al 2008a, b), indicating that the activation of other alternate nuclear receptors may also be involved in lipid metabolism disturbance induced by PFOA.…”

Section: Introductionmentioning

confidence: 95%

“…Although PFOA-and PFOS-induced liver enlargement appears to result from acting as a PPAr ligand, liver weight increase was still observed in PFOA-exposed PPArα-null mice (Minata et al 2010;Wolf et al 2008). Fat accumulation and changes in genes related to fatty acid metabolism were also observed in PFOA-treated PPArα-null mice (Minata et al 2010;rosen et al 2008a, b), indicating that the activation of other alternate nuclear receptors may also be involved in lipid metabolism disturbance induced by PFOA. Several potential targets of PFOA and PFOS toxicity, which may be independent or indirectly controlled via cross talk with PPArα, were previously analyzed in vitro and seem to be activated in cells of rats more so than that of humans after exposure to PFOA or PFOS (Bjork et al 2011).…”

Section: Introductionmentioning

confidence: 95%

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Activation of sterol regulatory element-binding proteins in mice exposed to perfluorooctanoic acid for 28 days

2014

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Perfluoroalkyl acids are widely used in numerous industrial and commercial applications due to their unique physical and chemical characteristics. Although perfluorooctanoic acid (PFOA) is associated with hepatomegaly through peroxisome proliferator-activated receptor α (PPARα) activation, liver fat accumulation and changes in gene expression related to fatty acid metabolism could still be found in PPARα-null mice exposed to PFOA. To explore the potential effects of PFOA on sterol regulatory element-binding proteins (SREBPs) activity, male mice were dosed with either Milli-Q water or PFOA at doses of 0.08, 0.31, 1.25, 5, and 20 mg/kg/day by gavage for 28 days. Liver total cholesterol concentrations and PFOA contents showed a dose-dependent decrease and increase, respectively. Transcriptional activity of PPARα and SREBPs was significantly enhanced in livers. Protein expression analyzed by Western blotting showed that PFOA exposure stimulated SREBP maturation. Furthermore, proteins blocked SREBP precursor transport, insulin-induced gene 1 (INSIG1) and INSIG2 proteins, as well as a protein-mediated nuclear SREBP proteolysis, F-box and WD-40 domain protein 7, decreased in mouse liver exposed to PFOA. The expression levels of the miR-183-96-182 cluster, which is possibly involved in a regulatory loop intermediated by SREBPs maturation, were also increased in the mouse liver after PFOA exposure. We also observed that PFOA induced lipid content and PPARα in Hepa 1-6 cells after exposure to PFOA for 72 h but SREBPs were not activated in vitro. These results demonstrated that SREBPs were maturated by activating the miR-183-96-182 cluster-SREBP regulatory loop in PFOA-exposed mouse liver.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 95%

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Activation of sterol regulatory element-binding proteins in mice exposed to perfluorooctanoic acid for 28 days

2014

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“…This result indicated a species difference in the brain concentrations of PFCAs between human and mice. A previous study revealed that the bloodbrain barrier in both humans and mice is maintained by several organic anion transporters, such as organic anion transporter 3, which may actively transport PFCAs from the CSF into the serum 38) . However, there are some species differences in substance selectivity between mouse and human organic anion transporter 3 40) .…”

Section: Implications For Species Differencementioning

confidence: 99%

Toxicokinetics of perfluoroalkyl carboxylic acids with different carbon chain lengths in mice and humans

Fujii

Niisoe

Harada

et al. 2015

Journal of Occupational Health

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“…Fernán-dez Freire et al (2008) reported that high doses of PFOA caused oxidative stress in Vero cells, which was closely linked to cell cycle arrest at the G1 phase and induction of apoptosis. Minata et al (2010) reported that PFOA produced marked fat accumulation, severe cholangiopathy, hepatocellular damage and apoptotic cells especially in bile ducts in PPAR α-Null mice. Hu and Hu (2009) suggested that PFOA could induce apoptosis by overwhelming the homeostasis of antioxidative systems, increasing ROS, impacting mitochondria, and changing expression of apoptosis gene regulators in HepG2 cells.…”

Section: Further Considerationmentioning

confidence: 99%

Differential toxicity between perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA)

Tsuda

2016

J. Toxicol. Sci.

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-Perfluoroalkyl substances (PFASs) are persistent environmental contaminants. Perfluorooctane sulfonate (PFOS) and Perfluorooctanoic acid (PFOA) are representatives of PFASs. Recently, the U.S. Environmental Protection Agency (US EPA) set the health advisory level as 70 parts per trillion for lifetime exposure to PFOS and PFOA from drinking water, based on the EPA's 2016 Health Effects Support Documents. Then, a monograph on PFOA was made available online by the International Agency for Research on Cancer, where the agency classified PFOA as "possibly carcinogenic to humans" (Group 2B). The distinction between PFOS and PFOA, however, may not be easily understood from the above documents. This paper discussed differential toxicity between PFOS and PFOA focusing on neurotoxicity, developmental toxicity and carcinogenicity, mainly based on these documents. The conclusions are as follows: Further mechanistic studies may be necessary for ultrasonic-induced PFOS-specific neurotoxicity. To support the hypothesis for PFOS-specific neonatal death that PFOS interacts directly with components of natural lung surfactant, in vivo studies to relate the physicochemical effects to lung collapse may be required. PFOA-induced DNA damage secondary to oxidative stress may develop to mutagenicity under the condition where PFOA-induced apoptosis is not sufficient to remove the damaged cells. A study to find whether PFOA induces apoptosis in normal human cells may contribute to assessment of human carcinogenicity. Studies for new targets such as hepatocyte nuclear factor 4α (HNF4α) may help clarify the underlying mechanism for PFOA-induced carcinogenicity.

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Role of Peroxisome Proliferator-activated Receptor-α in Hepatobiliary Injury Induced by Ammonium Perfluorooctanoate in Mouse Liver

Cited by 38 publications

References 35 publications

Activation of sterol regulatory element-binding proteins in mice exposed to perfluorooctanoic acid for 28 days

Activation of sterol regulatory element-binding proteins in mice exposed to perfluorooctanoic acid for 28 days

Toxicokinetics of perfluoroalkyl carboxylic acids with different carbon chain lengths in mice and humans

Differential toxicity between perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA)

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