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- Bogdanska, Jasna, et al.
(author)
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Tissue distribution of (35)S-labelled perfluorooctane sulfonate in adult mice after oral exposure to a low environmentally relevant dose or a high experimental dose
- 2011
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In: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 284:1-3, s. 54-62
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Journal article (peer-reviewed)abstract
- The widespread environmental pollutant perfluorooctane sulfonate (PFOS), detected in most animal species including the general human population, exerts several effects on experimental animals, e.g., hepatotoxicity, immunotoxicity and developmental toxicity. However, detailed information on the tissue distribution of PFOS in mammals is scarce and, in particular, the lack of available information regarding environmentally relevant exposure levels limits our understanding of how mammals (including humans) may be affected. Accordingly, we characterized the tissue distribution of this compound in mice, an important experimental animal for studying PFOS toxicity. Following dietary exposure of adult male C57/BL6 mice for 1-5 days to an environmentally relevant (0.031 mg/kg/day) or a 750-fold higher experimentally relevant dose (23 mg/kg/day) of (35)S-PFOS, most of the radioactivity administered was recovered in liver, bone (bone marrow), blood, skin and muscle, with the highest levels detected in liver, lung, blood, kidney and bone (bone marrow). Following high daily dose exposure, PFOS exhibited a different distribution profile than with low daily dose exposure, which indicated a shift in distribution from the blood to the tissues with increasing dose. Both scintillation counting (with correction for the blood present in the tissues) and whole-body autoradiography revealed the presence of PFOS in all 19 tissues examined, with identification of thymus as a novel site for localization for PFOS and bone (bone marrow), skin and muscle as significant body compartments for PFOS. These findings demonstrate that PFOS leaves the bloodstream and enters most tissues in a dose-dependent manner.
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| 3. |
- Bogdanska, Jasna, et al.
(author)
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Tissue distribution of C-14-labelled perfluorooctanoic acid in adult mice after 1-5 days of dietary exposure to an experimental dose or a lower dose that resulted in blood levels similar to those detected in exposed humans
- 2020
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In: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 239
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Journal article (peer-reviewed)abstract
- Perfluorooctanoic acid (PFOA), a global environmental pollutant detected in both wildlife and human populations, has several pathophysiological effects in experimental animals, including hepatotoxicity, immunotoxicity, and developmental toxicity. However, details concerning the tissue distribution of PFOA, in particular at levels relevant to humans, are lacking, which limits our understanding of how humans, and other mammals, may be affected by this compound. Therefore, we characterized the tissue distribution of C-14-PFOA in mice in the same manner as we earlier examined its analogues perfluorooctanesulfonate (PFOS) and perfluorobutanesulfonate (PFBS) in order to allow direct comparisons. Following dietary exposure of adult male C57/BL6 mice for 1, 3 or 5 days to a low dose (0.06 mg/kg/day) or a higher experimental dose (22 mg/kg/day) of C-14-PFOA, both scintillation counting and whole-body autoradiography revealed the presence of PFOA in most of the 19 different tissues examined, demonstrating its ability to leave the bloodstream and enter tissues. There were no differences in the pattern of tissue distribution with the low and high dose and the tissue-to-blood ratios were similar. At both doses, PFOA levels were highest in the liver, followed by blood, lungs and kidneys. The body compartments estimated to contain the largest amounts of PFOA were the liver, blood, skin and muscle. In comparison with our identical studies on PFOS and PFBS, PFOA reached considerably higher tissue levels than PFBS, but lower than PFOS. Furthermore, the distribution of PFOA differed notably from that of PFOS, with lower tissue-to-blood ratios in the liver, lungs, kidneys and skin.
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| 4. |
- Bogdanska, Jasna, et al.
(author)
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Tissue distribution of S-35-labelled perfluorobutanesulfonic acid in adult mice following dietary exposure for 1-5 days
- 2014
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In: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 98, s. 28-36
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Journal article (peer-reviewed)abstract
- Perfluorobutanesulfonyl fluoride (PBSF) has been introduced as a replacement for its eight-carbon homolog perfluorooctanesulfonyl fluoride (POSF) in the manufacturing of fluorochemicals. Fluorochemicals derived from PBSF may give rise to perfluorobutanesulfonic acid (PFBS) as a terminal degradation product. Although basic mammalian toxicokinetic data exist for PFBS, information on its tissue distribution has only been reported in one study focused on rat liver. Therefore, here we characterized the tissue distribution of PFBS in mice in the same manner as we earlier examined its eight-carbon homolog perfluorooctanesulfonate (PFOS) to allow direct comparisons. Following dietary exposure of adult male C57/BL6 mice for 1,3 or 5 d to 16 mg S-35-PFBS kg(-1) d(-1), both scintillation counting and whole-body autoradiography (WBA) revealed the presence of PFBS in all of the 20 different tissues examined, demonstrating its ability to leave the bloodstream and enter tissues. After 5 d of treatment the highest levels were detected in liver, gastrointestinal tract, blood, kidney, cartilage, whole bone, lungs and thyroid gland. WBA revealed relatively high levels of PFBS in male genital organs as well, with the exception of the testis. The tissue levels increased from 1 to 3 d of exposure but appeared thereafter to level-off in most cases. The estimated major body compartments were whole bone, liver, blood, skin and muscle. This exposure to PFBS resulted in 5-40-fold lower tissue levels than did similar exposure to PFOS, as well as in a different pattern of tissue distribution, including lower levels in liver and lungs relative to blood.
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| 5. |
- Borg, Daniel, et al.
(author)
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Perinatal tissue distribution of perfluorooctane sulphonate (PFOS) in mice.
- 2009
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In: Abstracts of the 46th Congress of the European Societies of Toxicology. - : Elsevier BV. ; 189:SI, s. S147-S147
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Conference paper (peer-reviewed)abstract
- Perfluorooctane sulfonate (PFOS) is an industrial chemical that has been used as a surfactant and surface protector for more than fifty years. It has during the last decade emerged as an environmental contaminant due to its widespread presence in humans and wildlife and its persistant, bioaccumulative and toxic properties. PFOS is developmentally toxic and late in utero exposure in rodents affects neonatal survival and growth. Observed symptoms suggest impaired pulmonary function, but the cause of the mortality has not been clarified. The purpose of this study was to determine the perinatal tissue distribution of S35-labelled PFOS in mice using whole-body autoradiography (WBA) combined with liquid scintillation counting (LSC). Pregnant C57Bl/6 mice were dosed orally on gestation day (GD) 16 and sampled on GD18, GD20 and postnatal day (PND) 1 (dams + pups). The results from the WBA and the LSC were unequivocal. In dams, PFOS accumulated primarily in the liver, but also the lungs contained levels higher than the blood. PFOS was readily transferred to the fetus. At GD18 general PFOS levels were higher in the fetus than in the blood of the corresponding dam with accumulation in the liver. At GD20, general PFOS levels remained higher in the fetus than in the dam, with substantial accumulation also in the lung. The accumulation in the lung persisted at PND1. Our results show that the fetus is exposed to higher levels of PFOS than the dam and point towards the lung being the main perinatal target organ of PFOS.
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| 6. |
- Nobel, Stefan
(author)
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Thiol redox state in apoptosis : physiological and toxicant modulation
- 1997
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Doctoral thesis (other academic/artistic)abstract
- Apoptosis is a physiological type of cell death used to regulate the number of cells during development and in adult organs. However, apoptosis can also be inappropriately activated or inhibited under pathological conditions. One of the critical mechanisms of apoptosis is the activity of cysteine proteases belonging to the caspase family. The present study was designed to investigate the role of oxidative stress in apoptosis and how the apoptotic death program might be regulated by redox-active toxicants. We identified markers for oxidative stress in apoptotic rat thymocytes, assayed by the depletion of reduced glutathione (GSH), protein thiols, and a-tocopherol as compared to healthy control cells. Supporting a biological role for these events, we observed that different antioxidants could inhibit rat thymocyte apoptosis induced by a variety of non-oxidant stimuli. This suggests that in rat thymocytes the apoptotic program induces oxidative stress which might be critical for the process. We continued these studies in a human leukemic T cell line (Jurkat T cells), where it was found that apoptosis induced by anti-CD95 (Fas/APO-l) antibody (anti-CD95 Ab) dramatically depleted intracellular GSH, which agrees with the above findings. Interestingly, glutathione was found to be depleted through efflux of the reduced form of the molecule. The apoptotic GSH efflux was dependent on caspase activity and could be blocked by inhibitors specific for the hepatocyte canalicular GSH transporter. Investigating the role for apoptotic GSH efflux, it was found that preventing the GSH depletion did not inhibit CD95-mediated DNA fragmentation. Furthermore, we found that anti-CD95 Ab-treatment mediated caspase-dependent K+ efflux and caspase-dependent cell shrinkage in Jurkat T cells, which both also seemed to be independent on GSH efflux. Preliminary results indicate that none of the known K+-channels or K+-co-transporters were responsible for the CD95-mediated K+ efflux. However, Na+ / K+-ATPase activity of Jurkat T cells was inhibited by the anti CD95 Ab, suggesting that passive diffusion of K across the cell membrane might be responsible. Preliminary results show that inhibition of Na+/K+-ATPase might also be involved in apoptotic cell shrinkage. While screening antioxidants as inhibitors of apoptosis, it was found that pyrrolidine dithiocarbamate (PDTC) was the most potent inhibitor of thymocyte apoptosis then available. Surprisingly, at the same time, PDTC induced an oxidative stress, which was dependent upon its ability to transport extracellular copper into the cells. In longer incubations, PDTC was clearly toxic, inducing apoptosis or necrosis depending on the dose. Investigating the potent anti-apoptotic effect by dithiocarbamates (DCs), we found that it probably was the DC disulfides which mediated the inhibitory effect. The inhibition of CD95 mediated apoptosis by the DC disulfide disulfiram (DSF) was correlated to the inhibition of the processing of pro-caspase-3. This was confirmed with an in vitro activation model of this proenzyme. DSF was unable to inhibit the in vitro activation of pro-caspase-3 if dithiothreitol was included, suggesting thiol-disulfide exchange between the DC disulfide and its target(s). Since processing of pro-caspases may need activity of other caspases, studies on the interaction between active caspases and DSF were performed in vitro. DSF was found to be a potent inhibitor of both purified caspase-3 and caspase-1. The inhibition seemed to be competitive and was shown to be accomplished through thiol-disulfide exchange. This suggests that the anti-apoptotic effect of DC disulfides occurs by inhibition of some yet unidentified caspase, that is responsible for the activation of a caspase cascade subsequent to CD95 receptor clustering.
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| 10. |
- Sundström, Maria, 1980-
(author)
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Radiosynthesis of Perfluoroalkyl Substances : Chemical analysis, uptake, distribution, and partitioning studies
- 2012
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Doctoral thesis (other academic/artistic)abstract
- Perfluoroalkyl substances (PFASs) are widely utilized manmade chemicals. Their properties have made them highly appreciated in a variety of industrial and consumer product applications, including fire-fighting foams, hydraulic fluids, as well as in cookware and food contact papers.However, some of the PFASs are highly persistent in the environment and their toxicological profiles are of concern. Voluntary and regulatory efforts have been taken to reduce the environmental levels of PFASs. These actions have resulted in a reduction of PFASs in human milk from Stockholm as presented in this thesis.The radiosyntheses of 35S-PFOS, 35S-PFBS, and 14C-PFOA presented herein were applied for distribution studies in mice but also for solubility and adhesion experiments of common laboratory solvents and buffers. The radiosynthesis employed reactive Grignard reagents, perfluoroalkyliodides, and 35S-sulfur dioxide or 14C-carbon dioxide. The distribution studies were performed with 35S-PFOS on both pregnant mice and their offspring as well as on male mice. The mice were subjected to whole-body autoradiography and the tissues were analyzed by liquid scintillation counting. Liver and lungs were the target organs for 35S-PFOS in the dams. The fetuses and pups had remarkable high levels of 35S-PFOS in their lungs as well as in the brain. The male mice were given a high dose and a more environmental relevant dose of 35S-PFOS. PFOS was transferred from the blood to the tissues as the dose increased.In another study the distribution pattern of the shorter homologue PFBS was compared to PFOS. 35S-PFBS was utilized and demonstrated a 5-40 fold lower tissue levels in comparison to PFOS.The pharmacokinetic parameters determined for PFHxS in mice, rats, and monkeys will provide valuable insight in establishing a proper risk assessment for this compound. The study confirms the common species differences in serum elimination half-life that are associated with PFASs.
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