| 1. |
- Hyötyläinen, Tuulia, 1971-, et al.
(författare)
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Lipidomic Analyses Reveal Modulation of Lipid Metabolism by the PFAS Perfluoroundecanoic Acid (PFUnDA) in Non-Obese Diabetic Mice
- 2021
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Ingår i: Frontiers in Genetics. - : Frontiers Media S.A.. - 1664-8021. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to Per- and polyfluoroalkyl substances (PFAS) has been linked to multiple undesirable health outcomes across a full lifespan, both in animal models as well as in human epidemiological studies. Immunosuppressive effects of PFAS have been reported, including increased risk of infections and suppressed vaccination responses in early childhood, as well as association with immunotoxicity and diabetes. On a mechanistic level, PFAS exposure has been linked with metabolic disturbances, particularly in lipid metabolism, but the underlying mechanisms are poorly characterized. Herein we explore lipidomic signatures of prenatal and early-life exposure to perfluoroundecanoic acid (PFUnDA) in non-obese diabetic (NOD) mice; an experimental model of autoimmune diabetes. Female NOD mice were exposed to four levels of PFUnDA in drinking water at mating, during gestation and lactation, and during the first weeks of life of female offspring. At offspring age of 11-12 weeks, insulitis and immunological endpoints were assessed, and serum samples were collected for comprehensive lipidomic analyses. We investigated the associations between exposure, lipidomic profile, insulitis grade, number of macrophages and apoptotic, active-caspase-3-positive cells in pancreatic islets. Dose-dependent changes in lipidomic profiles in mice exposed to PFUnDA were observed, with most profound changes seen at the highest exposure levels. Overall, PFUnDA exposure caused downregulation of phospholipids and triacylglycerols containing polyunsaturated fatty acids. Our results show that PFUnDA exposure in NOD mice alters lipid metabolism and is associated with pancreatic insulitis grade. Moreover, the results are in line with those reported in human studies, thus suggesting NOD mice as a suitable model to study the impacts of environmental chemicals on T1D.
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| 2. |
- Lindeman, Birgitte, et al.
(författare)
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Does the food processing contaminant acrylamide cause developmental neurotoxicity? A review and identification of knowledge gaps
- 2021
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Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238 .- 1873-1708. ; 101, s. 93-114
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Forskningsöversikt (refereegranskat)abstract
- There is a worldwide concern on adverse health effects of dietary exposure to acrylamide (AA) due to its presence in commonly consumed foods. AA is formed when carbohydrate rich foods containing asparagine and reducing sugars are prepared at high temperatures and low moisture conditions. Upon oral intake, AA is rapidly absorbed and distributed to all organs. AA is a known human neurotoxicant that can reach the developing foetus via placental transfer and breast milk. Although adverse neurodevelopmental effects have been observed after prenatal AA exposure in rodents, adverse effects of AA on the developing brain has so far not been studied in humans. However, epidemiological studies indicate that gestational exposure to AA impair foetal growth and AA exposure has been associated with reduced head circumference of the neonate. Thus, there is an urgent need for further research to elucidate whether pre- and perinatal AA exposure in humans might impair neurodevelopment and adversely affect neuronal function postnatally. Here, we review the literature with emphasis on the identification of critical knowledge gaps in relation to neurodevelopmental toxicity of AA and its mode of action and we suggest research strategies to close these gaps to better protect the unborn child.
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| 3. |
- McGlinchey, Aidan J, 1984-, et al.
(författare)
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Prenatal exposure to perfluoroalkyl substances modulates neonatal serum phospholipids, increasing risk of type 1 diabetes
- 2020
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 143
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Tidskriftsartikel (refereegranskat)abstract
- In the last decade, increasing incidence of type 1 diabetes (T1D) stabilized in Finland, a phenomenon that coincides with tighter regulation of perfluoroalkyl substances (PFAS). Here, we quantified PFAS to examine their effects, during pregnancy, on lipid and immune-related markers of T1D risk in children. In a mother-infant cohort (264 dyads), high PFAS exposure during pregnancy associated with decreased cord serum phospholipids and progression to T1D-associated islet autoantibodies in the offspring. This PFAS-lipid association appears exacerbated by increased human leukocyte antigen-conferred risk of T1D in infants. Exposure to a single PFAS compound or a mixture of organic pollutants in non-obese diabetic mice resulted in a lipid profile characterized by a similar decrease in phospholipids, a marked increase of lithocholic acid, and accelerated insulitis. Our findings suggest that PFAS exposure during pregnancy contributes to risk and pathogenesis of T1D in offspring.
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| 4. |
- Sinioja, Tim, 1983-, et al.
(författare)
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Exposure to persistent organic pollutants alters the serum metabolome in non-obese diabetic mice
- 2022
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Ingår i: Metabolomics. - : Springer-Verlag New York. - 1573-3882 .- 1573-3890. ; 18:11
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Autoimmune disorders such as type 1 diabetes (T1D) are believed to be caused by the interplay between several genetic and environmental factors. Elucidation of the role of environmental factors in metabolic and immune dysfunction leading to autoimmune disease is not yet well characterized.OBJECTIVES: Here we investigated the impact of exposure to a mixture of persistent organic pollutants (POPs) on the metabolome in non-obese diabetic (NOD) mice, an experimental model of T1D. The mixture contained organochlorides, organobromides, and per- and polyfluoroalkyl substances (PFAS).METHODS: Analysis of molecular lipids (lipidomics) and bile acids in serum samples was performed by UPLC-Q-TOF/MS, while polar metabolites were analyzed by GC-Q-TOF/MS.RESULTS: Experimental exposure to the POP mixture in these mice led to several metabolic changes, which were similar to those previously reported as associated with PFAS exposure, as well as risk of T1D in human studies. This included an increase in the levels of sugar derivatives, triacylglycerols and lithocholic acid, and a decrease in long chain fatty acids and several lipid classes, including phosphatidylcholines, lysophosphatidylcholines and sphingomyelins.CONCLUSION: Taken together, our study demonstrates that exposure to POPs results in an altered metabolic signature previously associated with autoimmunity.
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| 5. |
- Tal, Tamara, et al.
(författare)
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New approach methods to assess developmental and adult neurotoxicity for regulatory use : a PARC work package 5 project
- 2024
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Ingår i: Frontiers in Toxicology. - : Frontiers Media S.A.. - 2673-3080. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- In the European regulatory context, rodent in vivo studies are the predominant source of neurotoxicity information. Although they form a cornerstone of neurotoxicological assessments, they are costly and the topic of ethical debate. While the public expects chemicals and products to be safe for the developing and mature nervous systems, considerable numbers of chemicals in commerce have not, or only to a limited extent, been assessed for their potential to cause neurotoxicity. As such, there is a societal push toward the replacement of animal models with in vitro or alternative methods. New approach methods (NAMs) can contribute to the regulatory knowledge base, increase chemical safety, and modernize chemical hazard and risk assessment. Provided they reach an acceptable level of regulatory relevance and reliability, NAMs may be considered as replacements for specific in vivo studies. The European Partnership for the Assessment of Risks from Chemicals (PARC) addresses challenges to the development and implementation of NAMs in chemical risk assessment. In collaboration with regulatory agencies, Project 5.2.1e (Neurotoxicity) aims to develop and evaluate NAMs for developmental neurotoxicity (DNT) and adult neurotoxicity (ANT) and to understand the applicability domain of specific NAMs for the detection of endocrine disruption and epigenetic perturbation. To speed up assay time and reduce costs, we identify early indicators of later-onset effects. Ultimately, we will assemble second-generation developmental neurotoxicity and first-generation adult neurotoxicity test batteries, both of which aim to provide regulatory hazard and risk assessors and industry stakeholders with robust, speedy, lower-cost, and informative next-generation hazard and risk assessment tools.
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| 6. |
- Vryonidis, Efstathios, 1989-, et al.
(författare)
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Dietary intake of acrylamide in the Norwegian EuroMix biomonitoring study : Comparing probabilistic dietary estimates with haemoglobin adduct measurements
- 2023
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Ingår i: Food and Chemical Toxicology. - 0278-6915 .- 1873-6351. ; 180
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Tidskriftsartikel (refereegranskat)abstract
- Acrylamide is a probable human carcinogen with widespread exposure via food. The present study compared acrylamide intake measurements obtained from haemoglobin adduct levels and self-registered dietary consumption data in a group of 144 Norwegian healthy adults. Acrylamide adducts to N-terminal valine in haemoglobin were measured and used to estimate the intake via the internal dose approach which showed a median (interquartile range) of 0.24 (0.19–0.30) μg/kg bw/day. Data from weighed food records and food frequency questionnaires from the same individuals were used for probabilistic modelling of the intake of acrylamide. The median acrylamide intake was calculated to be 0.26 (0.16–0.39) and 0.30 (0.23–0.39) μg/kg bw/day, respectively from the two sources of self-registered dietary consumption data. Overall, a relatively good agreement was observed between the methods in pairwise comparison in Bland-Altman plots, with the methods disagreeing with 7% or less of the values. The intake estimates obtained with the two dietary consumption methods and one biomarker method are in line with earlier dietary estimates in the Norwegian population. The Margin of Exposure indicate a possible health risk concern from dietary acrylamide. This is the first study with a comparison in the same individuals of acrylamide intake estimates obtained with these methods.
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| 7. |
- Zlatev, Jordan, et al.
(författare)
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Polysemy or generality? Mu
- 2003
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Ingår i: Cognitive Approaches to Lexical Semantics. - 3110177099 ; 23, s. 447-494
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Bokkapitel (refereegranskat)abstract
- This chapter proposes a conception of lexical meaning as use-potential, in contrast to prevailing atomistic and reificational views. The issues are illustrated on the example of spatial expressions, pre-eminently prepositions. It is argued that the dichotomy between polysemy and semantic generality is a false one, with expressions occupying points on a continuum from full homonymy to full monosemy, and with typical cases of polysemy falling in between. The notion of use-potential is explored in connectionist models of spatial categorization. Some possible objections to the use-potential approach are also addressed.
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