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Karlsson, Oskar
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Publications (10 of 38) Show all publications
Pierozan, P. & Karlsson, O. (2019). Mitotically heritable effects of BMAA on striatal neural stem cell proliferation and differentiation. Cell Death and Disease, 10, Article ID 478.
Open this publication in new window or tab >>Mitotically heritable effects of BMAA on striatal neural stem cell proliferation and differentiation
2019 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 10, article id 478Article in journal (Refereed) Published
Abstract [en]

The widespread environmental contaminant beta-methylamino-L-alanine (BMAA) is a developmental neurotoxicant that can induce long-term learning and memory deficits. Studies have shown high transplacental transfer of 3H-BMAA and a significant uptake in fetal brain. Therefore, more information on how BMAA may influence growth and differentiation of neural stem cells is required for assessment of the risk to the developing brain. The aim of this study was to investigate direct and mitotically inherited effects of BMAA exposure using primary striatal neurons and embryonic neural stem cells. The neural stem cells were shown to be clearly more susceptible to BMAA exposure than primary neurons. Exposure to 250 mu M BMAA reduced neural stem cell proliferation through apoptosis and G2/M arrest. At lower concentrations (50-100 mu M), not affecting cell proliferation, BMAA reduced the differentiation of neural stem cells into astrocytes, oligodendrocytes, and neurons through glutamatergic mechanisms. Neurons that were derived from the BMAA-treated neuronal stem cells demonstrated morphological alterations including reduced neurite length, and decreased number of processes and branches per cell. Interestingly, the BMAA-induced changes were mitotically heritable to daughter cells. The results suggest that early-life exposure to BMAA impairs neuronal stem cell programming, which is vital for development of the nervous system and may result in long-term consequences predisposing for both neurodevelopmental disorders and neurodegenerative disease later in life. More attention should be given to the potential adverse effects of BMAA exposure on brain development.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-390201 (URN)10.1038/s41419-019-1710-2 (DOI)000472438300009 ()31209203 (PubMedID)
Funder
Swedish Research CouncilSwedish Research Council Formas
Available from: 2019-08-09 Created: 2019-08-09 Last updated: 2019-08-09Bibliographically approved
Ransome, Y., Slopen, N., Karlsson, O. & Williams, D. R. (2018). Elevated inflammation in association with alcohol abuse among Blacks but not Whites: results from the MIDUS biomarker study. Journal of behavioral medicine, 41(3), 374-384
Open this publication in new window or tab >>Elevated inflammation in association with alcohol abuse among Blacks but not Whites: results from the MIDUS biomarker study
2018 (English)In: Journal of behavioral medicine, ISSN 0160-7715, E-ISSN 1573-3521, Vol. 41, no 3, p. 374-384Article in journal (Refereed) Published
Abstract [en]

Some studies document racial disparities in self-reported health associated with alcohol use and abuse. However, few studies examined biomarkers that underlie the onset of alcohol-related chronic diseases. We investigated whether the association between alcohol abuse and five biomarkers of inflammation (CRP, IL-6, fibrinogen, E-selectin, sICAM-1) vary between Black and White Americans aged 35 to 84 (n = 1173) from the Midlife in the United States Biomarker Study. Multivariable Ordinary Least Squares regressions were used to assess Black-White differences in the association between alcohol abuse and the biomarkers. Race moderated the association between alcohol abuse and CRP (b = 0.56, SE = 0.28, p = 0.048), IL-6 (b = 0.65, SE = 0.22, p = 0.004), and a composite inflammation score (b = 0.014, SE = 0.07, p = 0.041). These findings potentially shed light for why alcohol has a stronger negative association with poorer health for Blacks compared to Whites. Analysis should be replicated in larger prospective cohorts.

Keywords
Alcohol abuse, Biological markers, Chronic disease, Inflammation, MIDUS, Race/ethnicity
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-342427 (URN)10.1007/s10865-017-9905-4 (DOI)000431113200010 ()29230616 (PubMedID)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-07-25Bibliographically approved
Sjöholm, L. K., Ransome, Y., Ekström, T. J. & Karlsson, O. (2018). Evaluation of Post-Mortem Effects on Global Brain DNA Methylation and Hydroxymethylation.. Basic & Clinical Pharmacology & Toxicology, 122(2), 208-213
Open this publication in new window or tab >>Evaluation of Post-Mortem Effects on Global Brain DNA Methylation and Hydroxymethylation.
2018 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 122, no 2, p. 208-213Article in journal (Refereed) Published
Abstract [en]

The number of epigenetic studies on brain functions and diseases are dramatically increasing, but little is known about the impact of post-mortem intervals and post-sampling effects on DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Here, we examined post-mortem-induced changes in global brain 5mC and 5hmC levels at post-mortem intervals up to 540 min., and studied effects of tissue heat stabilization, using LUMA and ELISA. The global 5mC and 5hmC levels were generally higher in the cerebellum of adult rats than neonates. When measured by ELISA, the global 5mC content in adults, but not neonates, decreased with the post-mortem interval reaching a significantly lower level in cerebellum tissue at the post-mortem interval 540 min. (2.9 ± 0.7%; mean ± S.E.M.) compared to control (3.7 ± 0.6%). The global 5hmC levels increased with post-mortem interval reaching a significantly higher level at 540 min. (0.29 ± 0.06%) compared to control (0.19 ± 0.03%). This suggests that the post-mortem interval may confound 5mC and 5hmC analysis in human brain tissues as the post-mortem handling could vary substantially. The reactive oxygen species (ROS) level in cerebellum also increased over time, in particular in adults, and may be part of the mechanism that causes the observed post-mortem changes in 5mC and 5hmC. The global 5mC and 5hmC states were unaffected by heat stabilization, allowing analysis of tissues that are stabilized to preserve more labile analytes. Further studies in human samples are needed to confirm post-mortem effects on DNA methylation/hydroxymethylation and elucidate details of the underlying mechanisms.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-342430 (URN)10.1111/bcpt.12875 (DOI)000429078500003 ()28834189 (PubMedID)
Funder
Swedish Research Council FormasCarl Tryggers foundation
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-06-04Bibliographically approved
Pierozan, P., Jernerén, F. & Karlsson, O. (2018). Perfluorooctanoic acid (PFOA) exposure promotes proliferation, migration and invasion potential in human breast epithelial cells. Archives of Toxicology, 92(5), 1729-1739
Open this publication in new window or tab >>Perfluorooctanoic acid (PFOA) exposure promotes proliferation, migration and invasion potential in human breast epithelial cells
2018 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 92, no 5, p. 1729-1739Article in journal (Refereed) Published
Abstract [en]

Despite significant advances in early detection and treatment, breast cancer remains a major cause of morbidity and mortality. Perfluorooctanoic acid (PFOA) is a suspected endocrine disruptor and a common environmental pollutant associated with various diseases including cancer. However, the effects of PFOA and its mechanisms of action on hormone-responsive cells remain unclear. Here, we explored the potential tumorigenic activity of PFOA (100 nM-1 mM) in human breast epithelial cells (MCF-10A). MCF-10A cells exposed to 50 and 100 mu M PFOA demonstrated a higher growth rate compared to controls. The compound promoted MCF-10A proliferation by accelerating G(0)/G(1) to S phase transition of the cell cycle. PFOA increased cyclin D1 and CDK4/6 levels, concomitant with a decrease in p27. In contrast to previous studies of perfluorooctane sulfate (PFOS), the estrogen receptor antagonist ICI 182,780 had no effect on PFOA-induced cell proliferation, whereas the PPAR alpha antagonist GW 6471 was able to prevent the MCF-10A proliferation, indicating that the underlying mechanisms involve PPAR alpha-dependent pathways. Interestingly, we also showed that PFOA is able to stimulate cell migration and invasion, demonstrating its potential to induce neoplastic transformation of human breast epithelial cells. These results suggest that more attention should be paid to the roles of PFOA in the development and progression of breast cancer.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2018
Keywords
Endocrine disrupting chemicals, EDCs, MCF-10A cells, Breast cancer, Cyclin D, P27
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-357023 (URN)10.1007/s00204-018-2181-4 (DOI)000432976700005 ()29502166 (PubMedID)
Funder
Swedish Research Council Formas
Available from: 2018-08-10 Created: 2018-08-10 Last updated: 2018-08-10Bibliographically approved
Pierozan, P. & Karlsson, O. (2018). PFOS induces proliferation, cell-cycle progression, and malignant phenotype in human breast epithelial cells. Archives of Toxicology, 92(2), 705-716
Open this publication in new window or tab >>PFOS induces proliferation, cell-cycle progression, and malignant phenotype in human breast epithelial cells
2018 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 92, no 2, p. 705-716Article in journal (Refereed) Published
Abstract [en]

Perfluorooctanesulfonic acid (PFOS) is a synthetic fluorosurfactant widely used in the industry and a prominent environmental toxicant. PFOS is persistent, bioaccumulative, and toxic to mammalian species. Growing evidence suggests that PFOS has the potential to interfere with estrogen homeostasis, posing a risk of endocrine-disrupting effects. Recently, concerns about a potential link between PFOS and breast cancer have been raised, but the mechanisms underlying its actions as a potential carcinogen are unknown. By utilizing cell proliferation assays, flow cytometry, immunocytochemistry, and cell migration/invasion assays, we examined the potentially tumorigenic activity of PFOS (100 nM–1 mM) in MCF-10A breast cell line. The results showed that the growth of MCF-10A cells exposed to 1 and 10 µM PFOS was higher compared to that of the control. Mechanistic studies using 10 µM PFOS demonstrated that the compound promotes MCF-10A proliferation through accelerating G0/G1-to-S phase transition of the cell cycle after 24, 48, and 72 h of treatment. In addition, PFOS exposure increased CDK4 and decreased p27, p21, and p53 levels in the cells. Importantly, treatment with 10 µM PFOS for 72 h also stimulated MCF-10A cell migration and invasion, illustrating its capability to induce neoplastic transformation of human breast epithelial cells. Our experimental results suggest that exposure to low levels of PFOS might be a potential risk factor in human breast cancer initiation and development.

Keywords
Breast cancer, Cell transformation, CDK4, p53, MCF-10A cells, Perfluorooctanesulfonic acid
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-342428 (URN)10.1007/s00204-017-2077-8 (DOI)000425526000013 ()29063134 (PubMedID)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-03-29Bibliographically approved
Machtinger, R., Zhong, J., Mansur, A., Adir, M., Racowsky, C., Hauser, R., . . . Baccarelli, A. A. (2018). Placental lncRNA Expression Is Associated With Prenatal Phthalate Exposure. Toxicological Sciences, 163(1), 116-122
Open this publication in new window or tab >>Placental lncRNA Expression Is Associated With Prenatal Phthalate Exposure
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2018 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 163, no 1, p. 116-122Article in journal (Refereed) Published
Abstract [en]

Phthalates are endocrine-disrupting chemicals that can cross the placenta and affect the fetal epigenome. Among various epigenetic regulators of gene expression, long noncoding RNAs (lncRNAs) are important players that may also be involved in the manifestation of endocrine-disrupting chemical toxicity. We sought to explore the association between maternal urinary phthalate metabolite concentrations and lncRNA expression in human placenta to better understand potential mechanisms through which lncRNAs participate in mediating phthalate toxicity. Ten patients with uncomplicated dichorionic diamniotic twin pregnancies at term were included in this study. Urinary (n = 10) and placenta samples (n = 20) were collected for all participants. Urinary samples were analyzed for 15 phthalate metabolites and 2 phthalate alternative metabolites. Real-time PCR arrays were used to identify and quantify 87 lncRNAs from the placental samples. We tested the Spearman correlation matrix to compare prenatal phthalate measures against placental lncRNA levels. lncRNA levels showed large variations across samples, with no significant differences in lncRNA expression within twin pairs. Mono-(carboxynonyl) phthalate demonstrated consistently strong correlations with most lncRNAs. The strongest correlation was observed between mono-hydroxyisobutyl phthalate and LOC91450 (Rspearman = 0.88, p < .001). This correlation remained significant after Bonferroni adjustment. Other strong correlations were observed between mono-isobutyl phthalate, DPP10 and HOTTIP (Rspearman = −0.91, p < .001). AIRN, DACT3.AS1, DLX6, DPP10, HOTTIP, LOC143666, and LOC91450 were strongly correlated with the greatest number of phthalate metabolites. Further studies are needed to validate these results and understand if the altered expression of lncRNAs in human placenta has clinical significance.

Keywords
imprinting genes, lncRNAs, phthalates, placenta, twins
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-342431 (URN)10.1093/toxsci/kfy013 (DOI)000432299900013 ()29385630 (PubMedID)
Funder
NIH (National Institute of Health), P30ES009089; R01ES021357; R21ES024236; P30ES00002
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-08-10Bibliographically approved
Pierozan, P., Andersson, M., Brandt, I. & Karlsson, O. (2018). The environmental neurotoxin beta-N-methylamino-L-alanine inhibits melatonin synthesis in primary pinealocytes and a rat model. Journal of Pineal Research, 65(1), Article ID e12488.
Open this publication in new window or tab >>The environmental neurotoxin beta-N-methylamino-L-alanine inhibits melatonin synthesis in primary pinealocytes and a rat model
2018 (English)In: Journal of Pineal Research, ISSN 0742-3098, E-ISSN 1600-079X, Vol. 65, no 1, article id e12488Article in journal (Refereed) Published
Abstract [en]

The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is a glutamate receptor agonist that can induce oxidative stress and has been implicated as a possible risk factor for neurodegenerative disease. Detection of BMAA in mussels, crustaceans, and fish illustrates that the sources of human exposure to this toxin are more abundant than previously anticipated. The aim of this study was to determine uptake of BMAA in the pineal gland and subsequent effects on melatonin production in primary pinealocyte cultures and a rat model. Autoradiographic imaging of 10-day-old male rats revealed a high and selective uptake in the pineal gland at 30minutes to 24hours after C-14-L-BMAA administration (0.68mg/kg). Primary pinealocyte cultures exposed to 0.05-3mmol/L BMAA showed a 57%-93% decrease in melatonin synthesis in vitro. Both the metabotropic glutamate receptor 3 (mGluR3) antagonist Ly341495 and the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate prevented the decrease in melatonin secretion, suggesting that BMAA inhibits melatonin synthesis by mGluR3 activation and PKC inhibition. Serum analysis revealed a 45% decrease in melatonin concentration in neonatal rats assessed 2weeks after BMAA administration (460mg/kg) and confirmed an inhibition of melatonin synthesis in vivo. Given that melatonin is a most important neuroprotective molecule in the brain, the etiology of BMAA-induced neurodegeneration may include mechanisms beyond direct excitotoxicity and oxidative stress.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
amyotrophic lateral sclerosis, parkinsonism-dementia complex, BMAA, developmental exposure, DOHaD, mGluR3, neurodegenerative disease, pineal gland, protein kinase C
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-360183 (URN)10.1111/jpi.12488 (DOI)000437132700009 ()29528516 (PubMedID)
Funder
Swedish Research Council FormasCarl Tryggers foundation
Available from: 2018-09-13 Created: 2018-09-13 Last updated: 2018-09-13Bibliographically approved
Andersson, M., Karlsson, O. & Brandt, I. (2018). The environmental neurotoxin β-N-methylamino-l-alanine (l-BMAA) is deposited into birds' eggs. Ecotoxicology and Environmental Safety, 147, 720-724
Open this publication in new window or tab >>The environmental neurotoxin β-N-methylamino-l-alanine (l-BMAA) is deposited into birds' eggs
2018 (English)In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 147, p. 720-724Article in journal (Refereed) Published
Abstract [en]

C-carboxyl-labeled BMAA were compared. The results revealed a pronounced incorporation of radioactivity in the eggs, predominantly in the yolk but also in the albumen. Imaging analysis showed that the concentrations of radioactivity in the liver decreased about seven times between the 24h and the 72h time points, while the concentrations in egg yolk remained largely unchanged. At 72h the egg yolk contained about five times the concentration of radioactivity in the liver. Both BMAA preparations gave rise to similar distribution pattern in the bird tissues and in the eggs, indicating metabolic stability of the labeled groups. The demonstrated deposition into eggs warrants studies of BMAAs effects on bird development. Moreover, birds' eggs may be a source of human BMAA exposure, provided that the laying birds are exposed to BMAA via their diet.

Keywords
Birds' eggs, Cyanobacterial neurotoxin, Developmental toxicity, Human exposure, Secretion
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-342429 (URN)10.1016/j.ecoenv.2017.09.032 (DOI)000416199700090 ()28942274 (PubMedID)
Funder
Swedish Research Council Formas
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-03-02Bibliographically approved
Zhong, J., Karlsson, O., Wang, G., Li, J., Guo, Y., Lin, X., . . . Baccarelli, A. A. (2017). B vitamins attenuate the epigenetic effects of ambient fine particles in a pilot human intervention trial. Proceedings of the National Academy of Sciences of the United States of America, 114(13), 3503-3508
Open this publication in new window or tab >>B vitamins attenuate the epigenetic effects of ambient fine particles in a pilot human intervention trial
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2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 13, p. 3503-3508Article in journal (Refereed) Published
Abstract [en]

Acute exposure to fine particle (PM2.5) induces DNA methylation changes implicated in inflammation and oxidative stress. We conducted a crossover trial to determine whether B-vitamin supplementation averts such changes. Ten healthy adults blindly received a 2-h, controlled-exposure experiment to sham under placebo, PM2.5 (250 μg/m(3)) under placebo, and PM2.5 (250 μg/m(3)) under B-vitamin supplementation (2.5 mg/d folic acid, 50 mg/d vitamin B6, and 1 mg/d vitamin B12), respectively. We profiled epigenome-wide methylation before and after each experiment using the Infinium HumanMethylation450 BeadChip in peripheral CD4(+) T-helper cells. PM2.5 induced methylation changes in genes involved in mitochondrial oxidative energy metabolism. B-vitamin supplementation prevented these changes. Likewise, PM2.5 depleted 11.1% [95% confidence interval (CI), 0.4%, 21.7%; P = 0.04] of mitochondrial DNA content compared with sham, and B-vitamin supplementation attenuated the PM2.5 effect by 102% (Pinteraction = 0.01). Our study indicates that individual-level prevention may be used to complement regulations and control potential mechanistic pathways underlying the adverse PM2.5 effects, with possible significant public health benefit in areas with frequent PM2.5 peaks.

Keywords
B vitamins, DNA methylation, air pollution, mitochondria
National Category
Occupational Health and Environmental Health Public Health, Global Health, Social Medicine and Epidemiology Medical Genetics Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-321813 (URN)10.1073/pnas.1618545114 (DOI)000397607300078 ()28289216 (PubMedID)
Funder
NIH (National Institute of Health), R21ES021895; R01ES015172; R01ES021733; R01ES020836; R01ES021357; P30ES009089; P30ES000002Multidisciplinary research focused on Parkinson’s disease - MultiPark
Note

See also Correction for Zhong et al., B vitamins attenuate the epigenetic effects of ambient fine particles in a pilot human intervention trial vol. 114 no. 16,  E3367, doi: 10.1073/pnas.1704438114

Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2018-01-13Bibliographically approved
Karlsson, O. & Hanrieder, J. (2017). Imaging mass spectrometry in drug development and toxicology. Archives of Toxicology, 91(6), 2283-2294
Open this publication in new window or tab >>Imaging mass spectrometry in drug development and toxicology
2017 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 91, no 6, p. 2283-2294Article, review/survey (Refereed) Published
Abstract [en]

During the last decades, imaging mass spectrometry has gained significant relevance in biomedical research. Recent advances in imaging mass spectrometry have paved the way for in situ studies on drug development, metabolism and toxicology. In contrast to whole-body autoradiography that images the localization of radiolabeled compounds, imaging mass spectrometry provides the possibility to simultaneously determine the discrete tissue distribution of the parent compound and its metabolites. In addition, imaging mass spectrometry features high molecular specificity and allows comprehensive, multiplexed detection and localization of hundreds of proteins, peptides and lipids directly in tissues. Toxicologists traditionally screen for adverse findings by histopathological examination. However, studies of the molecular and cellular processes underpinning toxicological and pathologic findings induced by candidate drugs or toxins are important to reach a mechanistic understanding and an effective risk assessment strategy. One of IMS strengths is the ability to directly overlay the molecular information from the mass spectrometric analysis with the tissue section and allow correlative comparisons of molecular and histologic information. Imaging mass spectrometry could therefore be a powerful tool for omics profiling of pharmacological/toxicological effects of drug candidates and toxicants in discrete tissue regions. The aim of the present review is to provide an overview of imaging mass spectrometry, with particular focus on MALDI imaging mass spectrometry, and its use in drug development and toxicology in general.

Keywords
6-OHDA, BMAA, Biologics, L-DOPA, MALDI IMS, Neurotoxicology, Preclinical, SIMS, Small-molecule drugs, Toxins
National Category
Medicinal Chemistry Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-321816 (URN)10.1007/s00204-016-1905-6 (DOI)000401338100001 ()27933369 (PubMedID)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2018-01-13Bibliographically approved
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