Perfluorooctanoic acid induces oxidative damage and mitochondrial dysfunction in pancreatic β-cells

Suh, Kwang Sik; Choi, Eun Mi; Kim, Yu Jin; Hong, Soo Min; Park, So Yong; Rhee, Sang Youl; Oh, Seungjoon; Kim, Sung Woon; Pak, Youngmi Kim; Choe, Wonchae; Chon, Suk

doi:10.3892/mmr.2017.6452

Cited by 54 publications

(45 citation statements)

References 63 publications

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“…While no remarkable changes were observed in earlier stage hearts, a significant increase in the ROS level was observed in ED19 chicken embryo hearts exposed to PFOA, suggesting the role of ROS in PFOA-induced developmental cardiotoxicity. This result is consistent with previous studies with PFOA [22,31]. Meanwhile, co-treatment with l -carnitine significantly decreased the ROS level in ED19 hearts, suggesting the anti-oxidant effects of l -carnitine, which may help to explain the protective effects exerted by l -carnitine.…”

Section: Discussionsupporting

confidence: 92%

“…It has been reported that PFOA could induce ROS in various cell types and organisms [22,31], which might contribute to its toxicity. l -carnitine has been reported to possess anti-oxidant effects in multiple studies [20,32]; however, it may also promote ROS generation since it facilitates β-oxidation [23].…”

Section: Discussionmentioning

confidence: 99%

“…Elevated oxidative stress could damage cardiomyocytes, alter the heart morphology and function, and deteriorate the prognosis of patients with cardiovascular diseases [21]. PFOA has been reported to elevate ROS and NO levels, which is believed to be part of its mechanism of toxicity [22]. On the other hand, l -carnitine has mixed roles in ROS and NO generation: technically, the presence of l -carnitine could promote fatty acid β-oxidation, which suggests that it may increase ROS generation, as reported in Moraes et al [23].…”

Section: Introductionmentioning

confidence: 99%

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The Roles of Reactive Oxygen Species and Nitric Oxide in Perfluorooctanoic Acid-Induced Developmental Cardiotoxicity and l-Carnitine Mediated Protection

Zhao

Jiang

Wang

et al. 2017

IJMS

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Perfluorooctanoic acid (PFOA) is an environmental contaminant that could induce developmental cardiotoxicity in a chicken embryo, which may be alleviated by l-carnitine. To explore the roles of reactive oxygen species (ROS) and nitric oxide (NO) in such changes and the potential effects of l-carnitine, fertile chicken eggs were exposed to PFOA via an air cell injection, with or without l-carnitine co-treatment. The ROS and NO levels in chicken embryo hearts were determined with electron spin resonance (ESR), and the protein levels of the nuclear factor κ-light chain-enhancer of activated B cells (NF-κB) p65 and inducible nitric oxide synthase (iNOS) in chicken embryo hearts were assessed with western blotting. The results of ESR indicated that PFOA exposure induced an elevation in the ROS levels in ED19 chicken embryo hearts and hatchling chicken hearts, while l-carnitine could alleviate such changes. Meanwhile, increased NO levels were observed in ED19 embryo hearts and hatchling hearts following PFOA exposure, while l-carnitine co-treatment exerted modulatory effects. Western blotting revealed that p65 translocation in ED19 embryo hearts and hatchling hearts was enhanced by PFOA, while l-carnitine co-treatment alleviated such changes. iNOS expression levels in ED19 embryo hearts followed the same pattern as NO levels, while a suppression of expression was observed in hatchling hearts exposed to PFOA. ROS/NF-κB p65 and iNOS/NO seem to be involved in the late stage (ED19 and post hatch) of PFOA-induced developmental cardiotoxicity in a chicken embryo. l-carnitine could exert anti-oxidant and NO modulatory effects in the developing chicken embryo hearts, which likely contribute to its cardioprotective effects.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Roles of Reactive Oxygen Species and Nitric Oxide in Perfluorooctanoic Acid-Induced Developmental Cardiotoxicity and l-Carnitine Mediated Protection

Zhao

Jiang

Wang

et al. 2017

IJMS

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“…Several studies have demonstrated that PFOA is able to generate oxidative stress in various cell types and organisms . In our study, it was found that ROS levels increased significantly and in a concentration‐dependent manner in PFOA‐exposed ovaries ex vivo.…”

Section: Discussionsupporting

confidence: 90%

Perfluorooctanoic acid disrupts gap junction intercellular communication and induces reactive oxygen species formation and apoptosis in mouse ovaries

López-Arellano

Luna

et al. 2018

Environmental Toxicology

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Perfluorooctanoic acid (PFOA) is a member of the perfluoroalkyl acid family of compounds. Due to the presence of strong carbon-fluorine bonds, it is practically nonbiodegradable and highly persistent in the environment. PFOA has been detected in the follicular fluid of women, and positively associated with reduced fecundability and infertility. However, there are no reports concerning the experimental evaluation of PFOA on oocyte toxicity in mammals. The aim of the present study was to determine if PFOA is able to induce oxidative stress in fetal ovaries and cause apoptosis in oocytes in vitro. In addition, since inhibition of the gap junction intercellular communication (GJIC) by PFOA has been demonstrated in liver cells in vivo and in vitro, the effect of PFOA on the GJIC between the oocyte and its supportive cumulus cells was studied.Results show that PFOA induced oocyte apoptosis and necrosis in vitro (medium lethal concentration, LC 50 = 112.8 μM), as evaluated with Annexin-V-Alexa 508 in combination with BOBO-1 staining. Reactive oxygen species (ROS) levels, as assessed by DCFH-DA, increased significantly in fetal ovaries exposed to ¼ LC 50 (28.2 μM, a noncytotoxic and relevant occupational exposure concentration) and LC 50 PFOA ex vivo. This perfluorinated compound also caused the blockage of GJIC in cumulus cells-oocyte complexes (COCs) obtained from female mice exposed in vivo, as evaluated by calcein transfer from cumulus cells to the oocyte. The ability of PFOA of disrupting the GJIC in COCs, generating ROS in the fetal ovary and causing apoptosis and necrosis in mammal's oocytes, might account for the reported association between increasing maternal plasma concentrations of PFOA with reduced fertility in women.

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“…In mouse testis, the lowest dose tested of 2.5 mg/kg/day PFOA increased MDA and hydrogen peroxide levels, decreased the expression of the oxidant-sensitive transcription factor, Nrf2, and inhibited the activities of antioxidant enzymes (superoxide dismutase and catalase) [91]. PFOA also induces oxidative stress in a dose-dependent manner from 0.5 to 5 mg/kg/day in the mouse liver and pancreas [25], and a variety of tissues including rat pancreatic β-cells [92], mouse testes and epididymis [93], and mouse ovary [94]. Similarly, in vivo and in vitro studies have demonstrated that PFOS exposure results in oxidative stress, evidenced by the production of ROS, changes in antioxidant enzymes, elevation of lipid peroxidation products and changes in Nrf2 [32,[95][96][97].…”

Section: Induces Oxidative Stressmentioning

confidence: 95%

Application of the Key Characteristics of Carcinogens to Per and Polyfluoroalkyl Substances

Temkin

Hocevar

Andrews

et al. 2020

IJERPH

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Per- and polyfluoroalkyl substances (PFAS) constitute a large class of environmentally persistent chemicals used in industrial and consumer products. Human exposure to PFAS is extensive, and PFAS contamination has been reported in drinking water and food supplies as well as in the serum of nearly all people. The most well-studied member of the PFAS class, perfluorooctanoic acid (PFOA), induces tumors in animal bioassays and has been associated with elevated risk of cancer in human populations. GenX, one of the PFOA replacement chemicals, induces tumors in animal bioassays as well. Using the Key Characteristics of Carcinogens framework for cancer hazard identification, we considered the existing epidemiological, toxicological and mechanistic data for 26 different PFAS. We found strong evidence that multiple PFAS induce oxidative stress, are immunosuppressive, and modulate receptor-mediated effects. We also found suggestive evidence indicating that some PFAS can induce epigenetic alterations and influence cell proliferation. Experimental data indicate that PFAS are not genotoxic and generally do not undergo metabolic activation. Data are currently insufficient to assess whether any PFAS promote chronic inflammation, cellular immortalization or alter DNA repair. While more research is needed to address data gaps, evidence exists that several PFAS exhibit one or more of the key characteristics of carcinogens.

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Perfluorooctanoic acid induces oxidative damage and mitochondrial dysfunction in pancreatic β-cells

Cited by 54 publications

References 63 publications

The Roles of Reactive Oxygen Species and Nitric Oxide in Perfluorooctanoic Acid-Induced Developmental Cardiotoxicity and l-Carnitine Mediated Protection

The Roles of Reactive Oxygen Species and Nitric Oxide in Perfluorooctanoic Acid-Induced Developmental Cardiotoxicity and l-Carnitine Mediated Protection

Perfluorooctanoic acid disrupts gap junction intercellular communication and induces reactive oxygen species formation and apoptosis in mouse ovaries

Application of the Key Characteristics of Carcinogens to Per and Polyfluoroalkyl Substances

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