Perfluorinated compounds (PFCs) and particularly two of them, perfluoroctanoate (PFOA) and perfluorooctanesulfonate (PFOS), have been widely produced and used since 1950. They both persist in the environment and accumulate in wildlife and humans. The toxicity of PFOS and PFOA has been studied extensively in rodents with several adverse effects mainly a hepatocarcinogenic potential. Carcinogenic effects are not highlighted in humans' studies. In this study, we investigated the cytotoxic and genotoxic effects of PFOA and PFOS using human HepG2 cells after 1 or 24h of exposure. The cytotoxic and genotoxic potential was evaluated by MTT assay, single cell gel electrophoresis (SCGE) assay and micronucleus assay respectively. We measured the intracellular generation of reactive oxygen species (ROS) using dichlorofluorescein diacetate to identify a potential mechanism of toxicity. We observed a cytotoxic effect of PFOA and PFOS after 24h of exposure starting from a concentration of 200 μM (MTT: -14.6%) and 300 μM (MTT: -51.2%) respectively. We did not observe an increase of DNA damage with the comet assay or micronucleus with the micronucleus assay after exposure to the two PFCs. After 24h of exposure, both PFOA and PFOS highlight a decrease of ROS generation (-5.9% to -23%). We did not find an effect after an hour of exposure. Our findings show that PFOA and PFOS exert a cytotoxic effect on the human cells line HepG2 but nor PFOA or PFOS could induce an increase of DNA damage (DNA strand breaks and micronucleus) or reactive oxygen species at the range concentration tested. Our results do not support that oxidative stress and DNA damage are relevant for potential adverse effects of PFOA and PFOS. These results tend to support epidemiological studies that do not show evidence of carcinogenicity.
"General toxicological findings associated with exposure to PFOS and PFOA include hepatotoxicity (Malinverno et al., 2005), hepatomegaly (Elcombe et al., 2012), hepatocellular adenoma (Butenhoff et al., 2012), peroxisomal proliferation (Berthiaume and Wallace, 2002), congestion and thickened epithelial walls in lungs (Cui et al., 2009), reproductive toxicity (Luebker et al., 2005), immunotoxicity (Peden-Adams et al., 2008; Keil et al., 2008; Hu et al., 2010; Fair et al., 2011; Grandjean et al., 2012), and neurotoxicity (Johansson et al., 2008; Mariussen, 2012). In vitro studies show that PFOS and PFOA exert cytotoxic effects on hepatoma HepG2 cells (Florentin et al., 2011). These compounds also exhibit capacity to interfere with the hepatic enzyme activity (Narimatsu et al., 2011) and to exert anti-inflammatory effects modulating the secretion of pro-inflammatory cytokines in blood cells (Brieger et al., 2011; Corsini et al., 2011). "
"Conversely, irradiation or drugs, which result in DNA damage in some cells, can also induce apoptotic death through a p53-dependent pathway  . So far, studies regarding the mutagenicity and carcinogenicity of PFOS are quite conflicting   . Using the sensitive A L cell system, we reported previously that 16 days of PFOA exposure had the mutagenic effect on A L cells . "
[Show abstract][Hide abstract] ABSTRACT: Perfluorooctane sulfonate (PFOS) was listed as one of the persistent organic pollutants (POPs) in Stockholm Convention in 2009. Recent evidence showed that PFOS could induce apoptosis both in vivo and in vitro. However, the apoptotic mechanisms induced by PFOS as well as the possible relationship between apoptosis and other PFOS-induced endpoints, remain unclear. In the present study, normal human-hamster hybrid (AL) cells and mtDNA-depleted (ρ(0) AL) cells were exposed to PFOS, and assayed for cytotoxicity, mutagenicity, and apoptosis (caspase-3/7, -9 activities). Our results showed that PFOS decreased cell viability in a time- and concentration-dependent manner in AL cells, but not in ρ(0) AL cells. However, long-term exposure to PFOS failed to induce the mutagenic effects at the CD59 locus in AL cells. Exposure to 200 (M PFOS significantly increased the activities of caspase-3/7 and caspase-9 in AL cells, but the activities of these caspases were not affected in ρ(0) AL cells. In addition, PFOS increased the levels of reactive oxygen species (ROS), superoxide anion (O2(.-)), as well as nitric oxide (NO), and decreased mitochondrial membrane potential (MMP) at the concentrations of 100 and 200μM in AL cells. On the other hand, exposure to PFOS had no effect on intracellular ROS, O2(.-), and NO production in ρ(0) AL cells. Caspase-3/7 activity, which was increased by 200 (M PFOS, could be suppressed by ROS/O2(.-) scavengers and nitric oxide synthases (NOSs) inhibitors in AL cells. These results implicate that PFOS-induced apoptosis and oxidative stress is mediated by a mitochondria-dependent pathway and that the induction of apoptosis might be a protective function against mutagenesis in AL cells exposed to PFOS.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 04/2013; 754(1-2). DOI:10.1016/j.mrgentox.2013.04.004 · 3.68 Impact Factor
"Oxidative stress, including oxidative DNA lesions, which may be associated with the activation of PPARα and peroxisomal proliferation, is controversial. Production of reactive oxygen species (ROS) and oxidative effects were reported in human hepatoma HepG2 cells (Panaretakis et al. 2001; Yao and Zhong 2005; Hu and Hu 2009), but DNA damage was not confirmed in other studies on the same cells (Eriksen et al. 2010; Florentin et al. 2011). Carcinogenicity of PFOA was suspected. "
[Show abstract][Hide abstract] ABSTRACT: Perfluorooctane sulfonate (PFOS) (C(8)F(17)SO(3)) and perfluorooctanoic acid (PFOA) (C(8)HF(15)O(2)) are synthetic chemicals widely used in industrial applications for their hydrophobic and oleophobic properties. They are persistent, bioaccumulative, and toxic to mammalian species. Their widespread distribution on earth and contamination of human serum raised concerns about long-term side effects. They are suspected to be carcinogenic through a nongenotoxic mode of action, a mechanism supported by recent findings that PFOS induced cell transformation but no genotoxicity in Syrian hamster embryo (SHE) cells. In the present study, we evaluated carcinogenic potential of PFOA using the cell transformation assay on SHE cells. The chemical was applied alone or in combination with a nontransformant concentration of benzo[a]pyrene (BaP, 0.4 μM) in order to detect PFOA ability to act as tumor initiator or tumor promoter. The results showed that PFOA tested alone in the range 3.7 × 10(-5) to 300 μM did not induce SHE cell transformation frequency in a 7-day treatment. On the other side, the combination BaP/PFOA induced cell transformation at all PFOA concentrations tested, which revealed synergistic effects. No genotoxicity of PFOA on SHE cells was detected using the comet assay after 5 and 24 h of exposure. No significant increase in DNA breakage was found in BaP-initiated cells exposed to PFOA in a 7-day treatment. The whole results showed that PFOA acts as a tumor promoter and a nongenotoxic carcinogen. Cell transformation in initiated cells was observed at concentrations equivalent to the ones found in human serum of nonoccupationally and occupationally exposed populations. An involvement of PFOA in increased incidence of cancer recorded in occupationally exposed population cannot be ruled out.
Environmental Science and Pollution Research 08/2011; 19(7):2537-49. DOI:10.1007/s11356-012-0968-z · 2.83 Impact Factor
M. Cassien, V. Tassistro, M. Culcasi, E. Ricquebourg, S. Thétiot-Laurent, A. Mercier, T. Orsière, S. Pietri
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