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  • 1.
    Andersson, Maria A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Petersson Grawé, Kierstin
    Karlsson, Oskar M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Abramsson-Zetterberg, Lilianne A-G
    Hellman, Björn E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Evaluation of the potential genotoxicity of chromium picolinate in mammalian cells in vivo and in vitro2007In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 45, no 7, p. 1097-1106Article in journal (Refereed)
    Abstract [en]

    Chromium picolinate (CrPic) is a synthetic nutritional supplement primarily used for weight loss and muscle building. Recent studies have indicated that CrPic might be genotoxic and these findings together with the wide-spread consumer use, have increased the concern about its safety. In the present study we investigated the potential genotoxicity of CrPic in mice given a single intraperitoneal injection (up to 3 mg/kg b.wt.) by evaluating the frequency of micronucleated polychromatic erythrocytes (fMNPCE) in peripheral blood, and DNA damage in lymphocytes and hepatocytes. The fMNPCE was evaluated after 42 h and DNA damage after 16 h. Using the Comet assay DNA damage was also monitored in extended-term cultures of human lymphocytes and in L5178Y mouse lymphoma cells that had been exposed for 3 h to 500 μM CrPic under different exposure conditions.

    A slight, but significant CrPic-induced increase in DNA damage (P < 0.001) was observed in the human lymphocytes, but only when these cells were exposed in the absence of serum. In all other experiments CrPic was found to be without genotoxic effects, both in vivo and in vitro. Taken together, our results suggest that a high concentration of CrPic might be DNA damaging, but only under non-physiological conditions.

  • 2.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, SE-17176 Stockholm, Sweden.
    Banack, Sandra
    Inst Ethnomed, POB 3464, Jackson, WY 83001 USA.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Transfer of developmental neurotoxin beta-N-methylamino-L-alanine (BMAA) via milk to nursed offspring: Studies by mass spectrometry and image analysis2016In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 258, p. 108-114Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial non-proteinogenic amino acid beta-N-methylamino-L-alanine (BMAA) is proposed to be involved in the etiology of amyotrophic lateral sclerosis/parkinsonism dementia complex. When administered as single doses to neonatal rats, BMAA gives rise to cognitive and neurodegenerative impairments in the adult animal. Here, we employed mass spectrometry (LC-MS/MS) and autoradiographic imaging to examine the mother-to-pup transfer of BMAA in rats. The results show that unchanged BMAA was secreted into the milk and distributed to the suckling pups. The concentration of BMAA in pup stomach milk and the neonatal liver peaked after 8 h, while the concentration in the pup brain increased throughout the study period. About 1 and 6% of the BMAA recovered from adult liver and brain were released following hydrolysis, suggesting that this fraction was associated with protein. No association to milk protein was observed. Injection of rat pups with [methyl-C-14]-L-BMAA or [carboxyl-C-14]-L-BMAA resulted in highly similar distribution patterns, indicating no or low metabolic elimination of the methylamino- or carboxyl groups. In conclusion, BMAA is transported as a free amino acid to rat milk and suckling pups. The results strengthen the proposal that mothers' milk could be a source of exposure for BMAA in human infants. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

  • 3.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Correction: Maternal Transfer of the Cyanobacterial Neurotoxin β-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 10, article id e78133Article in journal (Refereed)
  • 4.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Maternal Transfer of the Cyanobacterial Neurotoxin beta-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 10, p. e78133-Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial neurotoxin beta-N-methylamino-L-alanine (BMAA) has been implicated in the etiology of neurodegenerative disease and proposed to be biomagnified in terrestrial and aquatic food chains. We have previously shown that the neonatal period in rats, which in humans corresponds to the last trimester of pregnancy and the first few years of age, is a particularly sensitive period for exposure to BMAA. The present study aimed to examine the secretion of C-14-labeled L-and D-BMAA into milk in lactating mice and the subsequent transfer of BMAA into the developing brain. The results suggest that secretion into milk is an important elimination pathway of BMAA in lactating mothers and an efficient exposure route predominantly for L-BMAA but also for D-BMAA in suckling mice. Following secretion of [C-14] L-BMAA into milk, the levels of [C-14] L-BMAA in the brains of the suckling neonatal mice significantly exceeded the levels in the maternal brains. In vitro studies using the mouse mammary epithelial HC11 cell line confirmed a more efficient influx and efflux of L-BMAA than of D-BMAA in cells, suggesting enantiomer-selective transport. Competition experiments with other amino acids and a low sodium dependency of the influx suggests that the amino acid transporters LAT1 and LAT2 are involved in the transport of L-BMAA into milk. Given the persistent neurodevelopmental toxicity following injection of L-BMAA to neonatal rodent pups, the current results highlight the need to determine whether BMAA is enriched mother's and cow's milk.

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  • 5.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    The environmental neurotoxin β-N-methylamino-l-alanine (l-BMAA) is deposited into birds' eggs2018In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 147, p. 720-724Article in journal (Refereed)
    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.

  • 6.
    Brittebo, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Anna-Lena
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hanrieder, Jörg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurotoxin-induced fibril formation and protein changes in rodents2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no Suppl., p. S193-193Article in journal (Other academic)
  • 7.
    Engskog, Mikael K R
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Elmsjö, Albert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    The cyanobacterial amino acid beta-N-methylamino-L-alanine perturbs the intermediary metabolism in neonatal rats2013In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 49, no 5, p. 905-919, article id 10.1007/s00726-017-2391-8Article in journal (Refereed)
    Abstract [en]

    The neurotoxic amino acid β-N-methylamino-l-alanine (BMAA) is produced by most cyanobacteria. BMAA is considered as a potential health threat because of its putative role in neurodegenerative diseases. We have previously observed cognitive disturbances and morphological brain changes in adult rodents exposed to BMAA during the development. The aim of this study was to characterize changes of major intermediary metabolites in serum following neonatal exposure to BMAA using a non-targeted metabolomic approach. NMR spectroscopy was used to obtain serum metabolic profiles from neonatal rats exposed to BMAA (40, 150, 460mg/kg) or vehicle on postnatal days 9-10. Multivariate data analysis of binned NMR data indicated metabolic pattern differences between the different treatment groups. In particular five metabolites, d-glucose, lactate, 3-hydroxybutyrate, creatine and acetate, were changed in serum of BMAA-treated neonatal rats. These metabolites are associated with changes in energy metabolism and amino acid metabolism. Further statistical analysis disclosed that all the identified serum metabolites in the lowest dose group were significantly (p<0.05) decreased. The neonatal rat model used in this study is so far the only animal model that displays significant biochemical and behavioral effects after a low short-term dose of BMAA. The demonstrated perturbation of intermediary metabolism may contribute to BMAA-induced developmental changes that result in long-term effects on adult brain function.

  • 8. Hanrieder, Jorg
    et al.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Malmberg, Per
    Ewing, Andrew G.
    Probing the lipid chemistry of neurotoxin-induced hippocampal lesions using multimodal imaging mass spectrometry2014In: Surface and Interface Analysis, ISSN 0142-2421, E-ISSN 1096-9918, Vol. 46, no 1, p. 375-378Article in journal (Refereed)
    Abstract [en]

    The environmental toxin -N-methylamino-l-alanine (BMAA) has been causatively linked to neurodegenerative disease pathology. In a rat model, neonatal BMAA resulted in selective uptake in the hippocampal formation and caused learning and memory impairments in adult animals. Moreover, high dose neonatal BMAA exposure resulted in formation of histopathological lesions in the CA1 region of the adult hippocampus; however, the mechanism underlying BMAA induced neuropathology remains elusive. Imaging mass spectrometry (IMS) is a powerful method for spatial interrogation of biochemical distribution in biological tissue with high chemical specificity. The aim of this study was to therefore characterize the lipid microenvironment of BMAA-induced hippocampal lesions in adult rats using matrix-assisted laser desorption/ionization (MALDI) and time-of-flight SIMS (ToF-SIMS imaging). Multimodal imaging was carried out by ToF-SIMS scans of the hippocampal formation followed by whole tissue scans using MALDI imaging. Multivariate analysis was performed on the SIMS data in order to delineate the spatial biochemistry surrounding the lesions. The data show lesion-specific localization of phosphatidylcholine fragments, suggesting neuroinflammatory glial cell activation. Complementary MALDI imaging data showed increased levels of phosphoethanolamines colocalizing with the proteopathic lesions pointing to macroautophagic mechanisms associated with neurotoxin-induced protein accumulation. Multimodal IMS by means of ToF-SIMS and MALDI mass spectrometry proved to be a powerful technique for neurotoxicological research. 

  • 9. Hanrieder, Jörg
    et al.
    Gerber, Lorenz
    Persson Sandelius, Asa
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ewing, Andrew G
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    High resolution metabolite imaging in the hippocampus following neonatal exposure to the environmental toxin BMAA using ToF-SIMS2014In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 5, no 7, p. 568-575Article in journal (Refereed)
    Abstract [en]

    The environmental neurotoxin β-N-methylamino-l-alanine (BMAA) is suggested to be linked with neurodegenerative disease. In a rat model, neonatal exposure to BMAA induced selective uptake in the hippocampus and caused cell loss, mineralization and astrogliosis as well as learning and memory impairments in adulthood. Moreover, neonatal exposure resulted in increased protein ubiquitination in the cornus ammonis 1 (CA1) region of the adult hippocampus indicating that BMAA may induce protein aggregation. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) based imaging is a powerful technology for spatial profiling of small molecular weight compounds in biological tissues with high chemical specificity and high spatial resolution. The aim of this study was to characterize neurochemical changes in the hippocampus of six month-old rats treated neonatally (postnatal days 9-10) with BMAA. Multivariate data analysis of whole section ToF-SIMS scans was performed to delineate anatomical regions of interest based on their chemical distribution pattern. Further analysis of spectral data obtained from the outlined anatomical regions, including CA1 and dentate gyrus (DG) revealed BMAA-induced long-term changes. Increased levels of phospholipids and protein fragments in the histopathologically altered CA1 region as well as phosphate depletion in the DG were observed. Moreover, high resolution SIMS imaging revealed a specific localization of phosphatidylcholine lipids, protein signals and potassium in the histopathologically altered CA1. These findings demonstrate that ToF-SIMS based imaging is a powerful approach for probing biochemical changes in situ and might serve as promising technique for investigating neurotoxin-induced brain pathology.

  • 10.
    Jernerén, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Söderquist, Marcus
    Karlsson, Oskar
    Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, 17176 Stockholm, Sweden.
    Post-sampling release of free fatty acids -: effects of heat stabilization and methods of euthanasia2015In: Journal of pharmacological and toxicological methods, ISSN 1056-8719, E-ISSN 1873-488X, Vol. 71, p. 13-20Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The field of lipid research has made progress and it is now possible to study the lipidome of cells and organelles. A basic requirement of a successful lipid study is adequate pre-analytical sample handling, as some lipids can be unstable and postmortem changes can cause substantial accumulation of free fatty acids (FFAs).

    METHODS: The aim of the present study was to investigate the effects of conductive heat stabilization and euthanasia methods on FFA levels in the rat brain and liver using liquid chromatography tandem mass spectrometry.

    RESULTS: The analysis of brain homogenates clearly demonstrated phospholipase activity and time-dependent post-sampling changes in the lipid pool of snap frozen non-stabilized tissue. There was a significant increase in FFAs already at 2min, which continued over time. Heat stabilization was shown to be an efficient method to reduce phospholipase activity and ex vivo lipolysis. Post-sampling effects due to tissue thawing and sample preparation induced a massive release of FFAs (up to 3700%) from non-stabilized liver and brain tissues compared to heat stabilized tissue. Furthermore, the choice of euthanasia method significantly influenced the levels of FFAs in the brain. The FFAs were decreased by 15-44% in the group of animals euthanized by pentobarbital injection compared with CO2 inhalation or decapitation.

    DISCUSSION: Our results highlight the importance of considering euthanasia methods and pre-analytical treatment in lipid analysis, factors which may otherwise interfere with the outcome of the experiments.

  • 11.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Distribution and Long-term Effects of the Environmental Neurotoxin β-N-methylamino-L-alanine (BMAA): Brain changes and behavioral impairments following developmental exposure2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Many cyanobacteria are reported to produce the nonprotein amino acid β-N-methylamino-L-alanine (BMAA). Cyanobacteria are extensively distributed in terrestrial and aquatic environments and recently BMAA was detected in temperate aquatic ecosystems, e.g. the Baltic Sea. Little is known about developmental effects of the mixed glutamate receptor agonist BMAA. Brain development requires an optimal level of glutamate receptor activity as the glutamatergic system modulates many vital neurodevelopmental processes.

    The aim of this thesis was to investigate the developmental neurotoxicity of BMAA, and its interaction with the pigment melanin. Autoradiography was utilized to determine the tissue distribution of 3H-labelled BMAA in experimental animals. Behavioral studies and histological techniques were used to study short and long-term changes in the brain following neonatal exposure to BMAA. Long-term changes in protein expression in the brain was also investigated using matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS).

    A notable targeting of 3H-BMAA to discrete brain regions e.g. hippocampus and striatum in mouse fetuses and neonates was determined by autoradiography. BMAA treatment of neonatal rats on postnatal days 9–10 induced acute but transient ataxia and hyperactivity. Postnatal exposure to BMAA also gave rise to reduced spatial learning and memory abilities in adulthood. Neonatal rat pups treated with BMAA at 600 mg/kg showed early neuronal cell death in the hippocampus, retrosplenial and cingulate cortices. In adulthood the CA1 region of the hippocampus displayed neuronal loss and astrogliosis. Lower doses of BMAA (50 and 200 mg/kg) caused impairments in learning and memory function without any acute or long-term morphological changes in the brain. The MALDI IMS studies, however, revealed changes in protein expression in the hippocampus and striatum suggesting more subtle effects on neurodevelopmental processes. The studies also showed that BMAA was bound and incorporated in melanin and neuromelanin, suggesting that pigmented tissues such as in the substantia nigra and eye may be sequestering BMAA.

    In conclusion, the findings in this thesis show that BMAA is a developmental neurotoxin in rodents. The risks posed by BMAA as a potential human neurotoxin merits further consideration, particularly if the proposed biomagnifications in the food chain are confirmed.

    List of papers
    1. Retention of the cyanobacterial neurotoxin beta-N-methylamino-l-alanine in melanin and neuromelanin-containing cells: a possible link between Parkinson-dementia complex and pigmentary retinopathy
    Open this publication in new window or tab >>Retention of the cyanobacterial neurotoxin beta-N-methylamino-l-alanine in melanin and neuromelanin-containing cells: a possible link between Parkinson-dementia complex and pigmentary retinopathy
    2009 (English)In: Pigment cell & melanoma research, ISSN 1755-1471, Vol. 22, no 1, p. 120-130Article in journal (Refereed) Published
    Abstract [en]

    beta-N-methylamino-l-alanine (BMAA), a neurotoxic amino acid produced by cyanobacteria, has been suggested to be involved in the etiology of a neurodegenerative disease complex which includes Parkinson-dementia complex (PDC). In PDC, neuromelanin-containing neurons in substantia nigra are degenerated. Many PDC patients also have an uncommon pigmentary retinopathy. The aim of this study was to investigate the distribution of (3)H-BMAA in mice and frogs, with emphasis on pigment-containing tissues. Using autoradiography, a distinct retention of (3)H-BMAA was observed in melanin-containing tissues such as the eye and neuromelanin-containing neurons in frog brain. Analysis of the binding of (3)H-BMAA to Sepia melanin in vitro demonstrated two apparent binding sites. In vitro-studies with synthetic melanin revealed a stronger interaction of (3)H-BMAA with melanin during synthesis than the binding to preformed melanin. Long-term exposure to BMAA may lead to bioaccumulation in melanin- and neuromelanin-containing cells causing high intracellular levels, and potentially changed melanin characteristics via incorporation of BMAA into the melanin polymer. Interaction of BMAA with melanin may be a possible link between PDC and pigmentary retinopathy.

    Keywords
    BMAA, neuromelanin, melanin, frog, Parkinson, ALS/PDC
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-102429 (URN)10.1111/j.1755-148X.2008.00508.x (DOI)000262513500016 ()19154235 (PubMedID)
    Available from: 2010-03-31 Created: 2009-05-07 Last updated: 2018-01-13Bibliographically approved
    2. Selective Brain Uptake and Behavioral Effects of the Cyanobacterial Toxin BMAA (β-N-Methylamino-L-alanine) following Neonatal Administration to Rodents
    Open this publication in new window or tab >>Selective Brain Uptake and Behavioral Effects of the Cyanobacterial Toxin BMAA (β-N-Methylamino-L-alanine) following Neonatal Administration to Rodents
    2009 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 109, no 2, p. 286-295Article in journal (Refereed) Published
    Abstract [en]

    Cyanobacteria are extensively distributed in terrestrial and aquatic environments all over the world. Most cyanobacteria can produce the neurotoxin ss-N-methylamino-L-alanine (BMAA), which has been detected in several water systems and could accumulate in food chains. The aim of the study was to investigate the transfer of BMAA to fetal and neonatal brains and the effects of BMAA on the development of behavioral characteristics during the brain growth spurt (BGS) in rodents Pregnant and neonatal mice were given an injection of (3)H-BMAA on gestational day 14 and postnatal day (PND) 10, respectively, and processed for tape-section autoradiography. The study revealed transplacental transfer of (3)H-BMAA and a significant uptake in fetal mouse. The radioactivity was specifically located in the hippocampus, striatum, brainstem, spinal cord and cerebellum of 10-day-old mice. The effect of repeated BMAA treatment (200 or 600 mg/kg sc) during BGS on rat behavior was also studied. BMAA treatment on PND 9-10 induced acute alterations, such as impaired locomotor ability and hyperactivity, in the behavior of neonatal rats. Furthermore, rats given the high dose of BMAA failed to habituate to the test environment when tested at juvenile age. In conclusion, the results demonstrated that BMAA was transferred to the neonatal brain and induced significant changes in the behavior of neonatal rats following administration during BGS. The observed behavioral changes suggest possible cognitive impairment. Increased information on the long-term effects of BMAA on cognitive function following fetal and neonatal exposure is required for assessment of the risk to children's health.

    Keywords
    neurotoxin, ALS, PDC, hippocampus, striatum, brain growth spurt, seizure
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-102428 (URN)10.1093/toxsci/kfp062 (DOI)000266357900013 ()19321797 (PubMedID)
    Available from: 2010-03-31 Created: 2009-05-07 Last updated: 2018-01-13Bibliographically approved
    3. Long-term cognitive impairments in adult rats treated neonatally with beta-N-Methylamino-L-Alanine
    Open this publication in new window or tab >>Long-term cognitive impairments in adult rats treated neonatally with beta-N-Methylamino-L-Alanine
    2009 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 112, no 1, p. 185-195Article in journal (Refereed) Published
    Abstract [en]

    Most cyanobacteria (blue-green algae) can produce the neurotoxin beta-N-methylamino-L-alanine (BMAA). Dietary exposure to BMAA has been suggested to be involved in the etiology of the neurodegenerative disease amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC). Little is known about BMAA-induced neurotoxicity following neonatal administration. Our previous studies have revealed an uptake of BMAA in the hippocampus and striatum of neonatal mice. Furthermore, rats treated with BMAA during the neonatal period displayed acute but transient motoric disturbances and failed to show habituation at juvenile age suggesting impairments in learning functions. In the present study, the aim was to investigate long-term behavioral effects of BMAA administration in neonatal rats. BMAA was administered on postnatal days 9-10 (200 or 600 mg/kg; subcutaneous injection). Spatial learning and memory was investigated in adulthood using the radial arm maze test. The results revealed impaired learning but not memory in BMAA-treated animals. The observed impairments were not due to alterations in motoric capacity, general activity, or behavioral profiles, as assessed in the multivariate concentric square field (MCSF) and open field tests. An aversive stimulus in the MCSF test revealed impairments in avoidance learning and/or memory. There was no difference in basal serum corticosterone levels in BMAA-treated animals, indicating that the observed long-term effects were not secondary to an altered basal hypothalamic-pituitary-adrenal axis function. The present data demonstrated long-term learning impairments following neonatal BMAA administration. Further studies on biochemical effects in various brain regions and subsequent behavioral alterations are needed to elucidate the mechanisms of BMAA-induced developmental neurotoxicity.

    Keywords
    cyanobacteria, ALS, PDC, brain growth spurt, multivariate concentric square field, behavior, developmental neurotoxicity
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-121807 (URN)10.1093/toxsci/kfp196 (DOI)000271387900018 ()19692667 (PubMedID)
    Available from: 2010-03-31 Created: 2010-03-30 Last updated: 2018-01-12Bibliographically approved
    4. Early hippocampal cell death, and late learning and memory deficits in rats exposed to the environmental toxin BMAA (β-N-methylamino-l-alanine) during the neonatal period
    Open this publication in new window or tab >>Early hippocampal cell death, and late learning and memory deficits in rats exposed to the environmental toxin BMAA (β-N-methylamino-l-alanine) during the neonatal period
    2011 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 219, no 2, p. 310-320Article in journal (Refereed) Published
    Abstract [en]

    We have reported previously that exposure to the cyanobacterial neurotoxin β-N-methylamino-l-alanine (BMAA) during the neonatal period causes cognitive impairments in adult rats. The aim of this study was to investigate the long-term effects of neonatal BMAA exposure on learning and memory mechanisms and to identify early morphological changes in the neonatal brain. BMAA was injected subcutaneously in rat pups on postnatal days 9-10. BMAA (50 and 200mg/kg) caused distinct deficits in spatial learning and memory in adult animals but no morphological changes. No impairment of recognition memory was detected, suggesting that neonatal exposure to BMAA preferentially affects neuronal systems that are important for spatial tasks. Histopathological examination revealed early neuronal cell death as determined by TUNEL staining in the hippocampus 24h after a high dose (600mg/kg) of BMAA whereas no changes were observed at lower doses (50 and 200mg/kg). In addition, there was a low degree of neuronal cell death in the retrosplenial and cingulate cortices, areas that are also important for cognitive function. Taken together, these results indicate that BMAA is a developmental neurotoxin inducing long-term changes in cognitive function. The risk posed by BMAA as a potential human neurotoxin merits further consideration, particularly if the proposed biomagnifications in the food chain are confirmed.

    Keywords
    ALS/PDC, Apoptosis, Behavior, Brain growth spurt, Cyanobacteria, Developmental neurotoxicity, Excitotoxicity, Nonprotein amino acid
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-140782 (URN)10.1016/j.bbr.2011.01.056 (DOI)000289703700018 ()21315110 (PubMedID)
    Available from: 2011-01-09 Created: 2011-01-09 Last updated: 2018-01-12Bibliographically approved
    5. LONG-TERM MORPHOLOGICAL AND PROTEIN CHANGES IN THE BRAIN OF ADULT RATS NEONATALLY TREATED WITH THE ENVIRONMENTAL TOXIN β-N-METHYLAMINO-L-ALANINE (BMAA)
    Open this publication in new window or tab >>LONG-TERM MORPHOLOGICAL AND PROTEIN CHANGES IN THE BRAIN OF ADULT RATS NEONATALLY TREATED WITH THE ENVIRONMENTAL TOXIN β-N-METHYLAMINO-L-ALANINE (BMAA)
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    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-140784 (URN)
    Available from: 2011-01-09 Created: 2011-01-09 Last updated: 2011-03-21
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  • 12.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Berg, Anna-Lena
    Hanrieder, Jörg
    Arnerup, Gunnel
    Lindström, Anna-Karin
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Intracellular fibril formation, calcification, and enrichment of chaperones, cytoskeletal, and intermediate filament proteins in the adult hippocampus CA1 following neonatal exposure to the nonprotein amino acid BMAA2015In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 89, no 3, p. 423-436Article in journal (Refereed)
    Abstract [en]

    The environmental neurotoxin β-N-methylamino-L-alanine (BMAA) has been implicated in the etiology of neurodegenerative disease, and recent studies indicate that BMAA can be misincorporated into proteins. BMAA is a developmental neurotoxicant that can induce long-term learning and memory deficits, as well as regionally restricted neuronal degeneration and mineralization in the hippocampal CA1. The aim of the study was to characterize long-term changes (2 weeks to 6 months) further in the brain of adult rats treated neonatally (postnatal days 9-10) with BMAA (460 mg/kg) using immunohistochemistry (IHC), transmission electron microscopy, and laser capture microdissection followed by LC-MS/MS for proteomic analysis. The histological examination demonstrated progressive neurodegenerative changes, astrogliosis, microglial activation, and calcification in the hippocampal CA1 3-6 months after exposure. The IHC showed an increased staining for α-synuclein and ubiquitin in the area. The ultrastructural examination revealed intracellular deposition of abundant bundles of closely packed parallel fibrils in neurons, axons, and astrocytes of the CA1. Proteomic analysis of the affected site demonstrated an enrichment of chaperones (e.g., clusterin, GRP-78), cytoskeletal and intermediate filament proteins, and proteins involved in the antioxidant defense system. Several of the most enriched proteins (plectin, glial fibrillar acidic protein, vimentin, Hsp 27, and ubiquitin) are known to form complex astrocytic inclusions, so-called Rosenthal fibers, in the neurodegenerative disorder Alexander disease. In addition, TDP-43 and the negative regulator of autophagy, GLIPR-2, were exclusively detected. The present study demonstrates that neonatal exposure to BMAA may offer a novel model for the study of hippocampal fibril formation in vivo.

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  • 13.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Anna-Lena
    Lindström, Anna-Karin
    Hanrieder, Jorg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arnerup, Gunnel
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neonatal Exposure to the Cyanobacterial Toxin BMAA Induces Changes in Protein Expression and Neurodegeneration in Adult Hippocampus2012In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 130, no 2, p. 391-404Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial toxin -N-methylamino-l-alanine (BMAA) has been proposed to contribute to neurodegenerative disease. We have previously reported a selective uptake of BMAA in the mouse neonatal hippocampus and that exposure during the neonatal period causes learning and memory impairments in adult rats. The aim of this study was to characterize effects in the brain of 6-month-old rats treated neonatally (postnatal days 910) with the glutamatergic BMAA. Protein changes were examined using the novel technique Matrix-Assisted Laser Desorption Ionization (MALDI) imaging mass spectrometry (IMS) for direct imaging of proteins in brain cryosections, and histological changes were examined using immunohistochemistry and histopathology. The results showed long-term changes including a decreased expression of proteins involved in energy metabolism and intracellular signaling in the adult hippocampus at a dose (150mg/kg) that gave no histopathological lesions in this brain region. Developmental exposure to a higher dose (460mg/kg) also induced changes in the expression of S100, histones, calcium- and calmodulin-binding proteins, and guanine nucleotide-binding proteins. At this dose, severe lesions in the adult hippocampus including neuronal degeneration, cell loss, calcium deposits, and astrogliosis were evident. The data demonstrate subtle, sometimes dose-dependent, but permanent effects of a lower neonatal dose of BMAA in the adult hippocampus suggesting that BMAA could potentially disturb many processes during the development. The detection of BMAA in seafood stresses the importance of evaluating the magnitude of human exposure to this neurotoxin.

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  • 14.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Retention of the cyanobacterial neurotoxin beta-N-methylamino-l-alanine in melanin and neuromelanin-containing cells: a possible link between Parkinson-dementia complex and pigmentary retinopathy2009In: Pigment cell & melanoma research, ISSN 1755-1471, Vol. 22, no 1, p. 120-130Article in journal (Refereed)
    Abstract [en]

    beta-N-methylamino-l-alanine (BMAA), a neurotoxic amino acid produced by cyanobacteria, has been suggested to be involved in the etiology of a neurodegenerative disease complex which includes Parkinson-dementia complex (PDC). In PDC, neuromelanin-containing neurons in substantia nigra are degenerated. Many PDC patients also have an uncommon pigmentary retinopathy. The aim of this study was to investigate the distribution of (3)H-BMAA in mice and frogs, with emphasis on pigment-containing tissues. Using autoradiography, a distinct retention of (3)H-BMAA was observed in melanin-containing tissues such as the eye and neuromelanin-containing neurons in frog brain. Analysis of the binding of (3)H-BMAA to Sepia melanin in vitro demonstrated two apparent binding sites. In vitro-studies with synthetic melanin revealed a stronger interaction of (3)H-BMAA with melanin during synthesis than the binding to preformed melanin. Long-term exposure to BMAA may lead to bioaccumulation in melanin- and neuromelanin-containing cells causing high intracellular levels, and potentially changed melanin characteristics via incorporation of BMAA into the melanin polymer. Interaction of BMAA with melanin may be a possible link between PDC and pigmentary retinopathy.

  • 15.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Quality measures of imaging mass spectrometry aids in revealing long-term striatal protein changes induced by neonatal exposure to the cyanobacterial toxin β-N-methylamino-L-alanine (BMAA)2014In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 13, p. 93-104Article in journal (Refereed)
    Abstract [en]

    Many pathological processes are not directly correlated to dramatic alterations in protein levels. The changes in local concentration of important proteins in a subset of cells or at specific loci is likely to play a significant role in the disease etiologies, but the precise location might be unknown or too small to be adequately sampled for the purpose of traditional proteomic techniques. In this respect, matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) is a unique analytical method that combines analysis of multiple molecular species and their distribution in one single platform. As reproducibility is essential for successful biomarker discovery it is important to systemically assess data quality in biologically relevant MALDI IMS experiments. In the present study, we applied four simple tools to study the reproducibility for individual sections, within group variation and between group variations of data acquired from brain sections of 21 animals divided into three treatment groups. We also characterized protein changes in distinct regions of the striatum from six month-old rats treated neonatally (PND; postnatal days 9-10) with the cyanobacterial toxin β-N-methylamino-L-alanine (BMAA) that has been implicated in neurodegenerative diseases. The results showed that optimized experimental settings can render high quality MALDI IMS data with relatively low variation (14-15 %CV) that allows characterization of subtle changes in protein expression in various subregions of the brain. This was further exemplified by the dose-dependent reduction of MBP (myelin basic protein) in the caudate putamen and the nucleus accumbens of adult rats neonatally treated with BMAA (150 and 460 mg/kg). The MBP reduction was confirmed with immunohistochemistryand indicates that developmental exposure to BMAA may induce structural effects on axonal growth and/or directly on proliferation of oligodendrocytes and myelination, which might be important for the previously shown BMAA-induced long-term cognitive impairments.

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  • 16.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Colombo, Giancarlo
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Low copulatory activity in selectively bred Sardinian alcohol-nonpreferring (sNP) relative to alcohol-preferring (sP) rats2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 3, p. 181-189Article in journal (Refereed)
    Abstract [en]

    Background. There is a growing consensus that similar neural mechanisms are involved in the reinforcing properties of natural rewards, like food and sex, and drugs of abuse. Rat lines selectively bred for high and low oral alcohol intake and preference have been useful for understanding factors contributing to excessive alcohol intake and may constitute proper animal models for investigating the neurobiological basis of natural rewarding stimuli. Methods. The present study evaluated copulatory behavior in alcohol and sexually naive Sardinian alcohol-preferring (sP) and -nonpreferring (sNP) male rats in three consecutive copulatory behavior tests. Results. The main finding was that, under the conditions used in this study, sNP rats were sexually inactive relative to sP rats. To gain more information about the sexual behavior in sP rats, Wistar rats were included as an external reference strain. Only minor differences between sP and Wistar rats were revealed. Conclusions. The reason behind the low copulatory activity of sNP rats remains to be elucidated, but may in part be mediated by innate differences in brain transmitter systems. The comparison between sP and Wistar rats may also suggest that the inherent proclivity to excessive alcohol drinking in sP rats may mainly be dependent on its anxiolytic properties, as previously proposed, and not changes in the reward system.

  • 17.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hanrieder, Jörg
    Imaging mass spectrometry in drug development and toxicology2017In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 91, no 6, p. 2283-2294Article, review/survey (Refereed)
    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.

  • 18.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Jiang, Liying
    Andersson, Marie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Ilag, Leopold L.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Protein association of the neurotoxin and non-protein amino acid BMAA (beta-N-methylamino-L-alanine) in the liver and brain following neonatal administration in rats2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 226, no 1, p. 1-5Article in journal (Refereed)
    Abstract [en]

    The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is not an amino acid that is normally found in proteins. Our previous autoradiographic study of H-3-labeled BMAA in adult mice unexpectedly revealed a tissue distribution similar to that of protein amino acids. The aim of this study was to characterize the distribution of free and protein-bound BMAA in neonatal rat tissues following a short exposure using autoradiographic imaging and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The autoradiographic imaging of C-14-L-BMAA demonstrated a distinct uptake of radioactivity that was retained following acid extraction in tissues with a high rate of cell turnover and/or protein synthesis. The UHPLC-MS/MS analysis conclusively demonstrated a dose-dependent increase of protein-associated BMAA in neonatal rat tissues. The level of protein-associated BMAA in the liver was more than 10 times higher than that in brain regions not fully protected by the blood-brain barrier which may be due to the higher rate of protein synthesis in the liver. In conclusion, this study demonstrated that BMAA was associated with rat proteins suggesting that BMAA may be mis-incorporated into proteins. However, protein-associated BMAA seemed to be cleared over time, as none of the samples from adult rats had any detectable free or protein-associated BMAA.

  • 19.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jiang, Liying
    Stockholm Univ, Dept Environm Sci & Analyt Chem, SE-10691 Stockholm, Sweden..
    Ersson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Malmstrom, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ilag, Leopold L.
    Stockholm Univ, Dept Environm Sci & Analyt Chem, SE-10691 Stockholm, Sweden..
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Environmental neurotoxin interaction with proteins: Dose-dependent increase of free and protein-associated BMAA (beta-N-methylamino-L-alanine) in neonatal rat brain2015In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, article id 15570Article in journal (Refereed)
    Abstract [en]

    beta-Methylamino-L-alanine (BMAA) is implicated in the aetiology of neurodegenerative disorders. Neonatal exposure to BMAA induces cognitive impairments and progressive neurodegenerative changes including intracellular fibril formation in the hippocampus of adult rats. It is unclear why the neonatal hippocampus is especially vulnerable and the critical cellular perturbations preceding BMAA-induced toxicity remains to be elucidated. The aim of this study was to compare the level of free and protein-associated BMAA in neonatal rat brain and peripheral tissues after different exposures to BMAA. Ultra-high performance liquid chromatography-tandem mass spectrometry analysis revealed that BMAA passed the neonatal blood-brain barrier and was distributed to all studied brain areas. BMAA was also associated to proteins in the brain, especially in the hippocampus. The level in the brain was, however, considerably lower compared to the liver that is not a target organ for BMAA. In contrast to the liver there was a significantly increased level of protein-association of BMAA in the hippocampus and other brain areas following repeated administration suggesting that the degradation of BMAA-associated proteins may be lower in neonatal brain than in the liver. Additional evidence is needed in support of a role for protein misincorporation in the neonatal hippocampus for long-term effects of BMAA.

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  • 20.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wadensten, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurotoxin-Induced Neuropeptide Perturbations in Striatum of Neonatal Rats2013In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 12, no 4, p. 1678-1690Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial toxin β-N-methylamino-l-alanine (BMAA) is suggested to play a role in neurodegenerative disease. We have previously shown that although the selective uptake of BMAA in the rodent neonatal striatum does not cause neuronal cell death, exposure during the neonatal development leads to cognitive impairments in adult rats. The aim of the present study was to characterize the changes in the striatal neuropeptide systems of male and female rat pups treated neonatally (postnatal days 9-10) with BMAA (40-460 mg/kg). The label-free quantification of the relative levels of endogenous neuropeptides using mass spectrometry revealed that 25 peptides from 13 neuropeptide precursors were significantly changed in the rat neonatal striatum. The exposure to noncytotoxic doses of BMAA induced a dose-dependent increase of neurosecretory protein VGF-derived peptides, and changes in the relative levels of cholecystokinin, chromogranin, secretogranin, MCH, somatostatin and cortistatin-derived peptides were observed at the highest dose. In addition, the results revealed a sex-dependent increase in the relative level of peptides derived from the proenkephalin-A and protachykinin-1 precursors, including substance P and neurokinin A, in female pups. Because several of these peptides play a critical role in the development and survival of neurons, the observed neuropeptide changes might be possible mediators of BMAA-induced behavioral changes. Moreover, some neuropeptide changes suggest potential sex-related differences in susceptibility toward this neurotoxin. The present study also suggests that neuropeptide profiling might provide a sensitive characterization of the BMAA-induced noncytotoxic effects on the developing brain.

  • 21.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Melanin affinity and its possible role in neurodegeneration2013In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 120, no 12, p. 1623-1630Article, review/survey (Refereed)
    Abstract [en]

    Certain drugs with melanin affinity are known to have caused pigmentary lesions in the eye and skin. This was the basis for the hypothesis that compounds with melanin affinity may cause damage also in other melanin-bearing tissues such as the substantia nigra. The heterogeneity of compounds that binds to melanin is large. Toxins, drugs, and several other compounds have melanin affinity. Compounds showing the highest affinity are mainly organic amines and metal ions. The binding of toxicants to melanin probably protects the cells initially. However, the binding is normally, slowly reversible and melanin may accumulate the toxicant and gradually release it into the cytosol. Several studies indicate that neuromelanin may play a significant role both in the initiation and in the progression of neurodegeneration. MPTP/MPP(+) that has been causally linked with Parkinsonism has high affinity for neuromelanin, and the induced dopaminergic denervation correlates with the neuromelanin content in the cells. This shows that the toxicological implications of the accumulation of toxicants in pigmented neurons and its possible role in neurodegeneration should not be neglected. Extracellular neuromelanin has been reported to activate dendritic cells and microglia. An initial neuronal damage induced by a neurotoxicant that leaks neuromelanin from the cells may therefore lead to a vicious cycle of neuroinflammation and further neurodegeneration. Although there are many clues to the particular vulnerability of dopaminergic neurons of substantia nigra in Parkinson's disease, the critical factors are not known. Further studies to determine the importance of neuromelanin in neurodegeneration and Parkinson's disease are warranted.

  • 22.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, S-17176 Stockholm, Sweden..
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Melanin and neuromelanin binding of drugs and chemicals: toxicological implications2016In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 90, no 8, p. 1883-1891Article, review/survey (Refereed)
    Abstract [en]

    Melanin is a polyanionic pigment that colors, e.g., the hair, skin and eyes. The pigment neuromelanin is closely related to melanin and is mainly produced in specific neurons of the substantia nigra. Certain drugs and chemicals bind to melanin/neuromelanin and are retained in pigment cells for long periods. This specific retention is thought to protect the cells but also to serve as a depot that slowly releases accumulated compounds and may cause toxicity in the eye and skin. Moreover, neuromelanin and compounds with high neuromelanin affinity have been suggested to be implicated in the development of adverse drug reactions in the central nervous system (CNS) as well as in the etiology of Parkinson's disease (PD). Epidemiologic studies implicate the exposure to pesticides, metals, solvents and other chemicals as risk factors for PD. Neuromelanin interacts with several of these toxicants which may play a significant part in both the initiation and the progression of neurodegeneration. MPTP/MPP+ that has been casually linked with parkinsonism has high affinity for neuromelanin, and the induced dopaminergic denervation correlates with the neuromelanin content in the cells. Recent studies have also reported that neuromelanin may interact with alpha-synuclein as well as activate microglia and dendritic cells. This review aims to provide an overview of melanin binding of drugs and other compounds, and possible toxicological implications, with particular focus on the CNS and its potential involvement in neurodegenerative disorders.

  • 23.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Selective Brain Uptake and Behavioral Effects of the Cyanobacterial Toxin BMAA (β-N-Methylamino-L-alanine) following Neonatal Administration to Rodents2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 109, no 2, p. 286-295Article in journal (Refereed)
    Abstract [en]

    Cyanobacteria are extensively distributed in terrestrial and aquatic environments all over the world. Most cyanobacteria can produce the neurotoxin ss-N-methylamino-L-alanine (BMAA), which has been detected in several water systems and could accumulate in food chains. The aim of the study was to investigate the transfer of BMAA to fetal and neonatal brains and the effects of BMAA on the development of behavioral characteristics during the brain growth spurt (BGS) in rodents Pregnant and neonatal mice were given an injection of (3)H-BMAA on gestational day 14 and postnatal day (PND) 10, respectively, and processed for tape-section autoradiography. The study revealed transplacental transfer of (3)H-BMAA and a significant uptake in fetal mouse. The radioactivity was specifically located in the hippocampus, striatum, brainstem, spinal cord and cerebellum of 10-day-old mice. The effect of repeated BMAA treatment (200 or 600 mg/kg sc) during BGS on rat behavior was also studied. BMAA treatment on PND 9-10 induced acute alterations, such as impaired locomotor ability and hyperactivity, in the behavior of neonatal rats. Furthermore, rats given the high dose of BMAA failed to habituate to the test environment when tested at juvenile age. In conclusion, the results demonstrated that BMAA was transferred to the neonatal brain and induced significant changes in the behavior of neonatal rats following administration during BGS. The observed behavioral changes suggest possible cognitive impairment. Increased information on the long-term effects of BMAA on cognitive function following fetal and neonatal exposure is required for assessment of the risk to children's health.

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  • 24.
    Karlsson, Oskar
    et al.
    Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, Stockholm, Sweden; Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA.
    Rodosthenous, Rodosthenis S
    Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA.
    Jara, Calvin
    Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA.
    Brennan, Kasey J
    Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA.
    Wright, Robert O
    Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA; Icahn Sch Med Mt Sinai, Dept Pediat, Kravis Childrens Hosp, New York, NY 10029 USA.
    Baccarelli, Andrea A
    Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA.
    Wright, Rosalind J
    Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA; Icahn Sch Med Mt Sinai, Dept Pediat, Kravis Childrens Hosp, New York, NY 10029 USA.
    Detection of long non-coding RNAs in human breastmilk extracellular vesicles: Implications for early child development.2016In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 11, no 10, p. 721-729Article in journal (Refereed)
    Abstract [en]

    Breastmilk has many documented beneficial effects on the developing human infant, but the components of breastmilk that influence these developmental pathways have not been fully elucidated. Increasing evidence suggests that non-coding RNAs encapsulated in extracellular vesicles (EVs) represent an important mechanism of communication between the mother and child. Long non-coding RNAs (lncRNAs) are of particular interest given their key role in gene expression and development. However, it is not known whether breastmilk EVs contain lncRNAs. We used qRT-PCR to determine whether EVs isolated from human breastmilk contain lncRNAs previously reported to be important for developmental processes. We detected 55 of the 87 screened lncRNAs in EVs from the 30 analyzed breastmilk samples, and CRNDE, DANCR GAS5, SRA1 and ZFAS1 were detected in >90% of the samples. GAS5, SNHG8 and ZFAS1 levels were highly correlated (Spearman's rho>0.9; P<0.0001), which may indicate that the loading of these lncRNAs into breastmilk EVs is regulated by the same pathways. The detected lncRNAs are important epigenetic regulators involved in processes such as immune cell regulation and metabolism. They may target a repertoire of recipient cells in offspring and could be essential for child development and health. Further experimental and epidemiological studies are warranted to determine the impact of breastmilk EV-encapsulated lnRNAs in mother to child signaling.

  • 25.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dose-dependent effects of alcohol administration on behavioral profiles in the MCSF test.2016In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 50, p. 51-56Article in journal (Refereed)
    Abstract [en]

    The acute effects of alcohol administration are age-, dose-, time- and task-dependent. Although generally considered to be a sedative drug, alcohol has both stimulatory and depressant effects on behavior, depending on dose and time. Alcohol-induced motor activating effects are consistently shown in mice but rarely demonstrated in adult, outbred rats using conventional behavioral tests. The aim of the present experiment was to study acute alcohol-induced effects on behavioral profiles in a more complex environment using the novel multivariate concentric square field™ (MCSF) test, designed for assessing different behaviors in the same trial including locomotor activity. Adult male Wistar rats (Sca:WI) were administered one intraperitoneal (i.p.) injection of alcohol (0.0 g/kg, 0.5 g/kg, 1.0 g/kg, or 1.5 g/kg) 5 min prior to the 30-min MCSF test. The two highest doses induced marked motor-suppressing effects. A significant interaction between group and time was found in general activity when comparing rats exposed to alcohol at 0.0 g/kg and 0.5 g/kg. In contrast to the 0.0 g/kg dose that increased the activity over time, animals administered the low dose (0.5 g/kg) demonstrated an initial high activity followed by a decline over time. No indications for acute alcohol-induced anxiolytic-like effects were found. The multivariate setting in the MCSF test appears to be sensitive for detecting motor-activating effects of low doses of alcohol as well as reduced locomotion at doses lower than in other behavioral tasks. The detection of subtle changes in behavior across time and dose is important for understanding alcohol-induced effects. This approach may be useful in evaluating alcohol doses that correspond to different degrees of intoxication in humans.

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  • 26.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Anna-Lena
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Early hippocampal cell death, and late learning and memory deficits in rats exposed to the environmental toxin BMAA (β-N-methylamino-l-alanine) during the neonatal period2011In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 219, no 2, p. 310-320Article in journal (Refereed)
    Abstract [en]

    We have reported previously that exposure to the cyanobacterial neurotoxin β-N-methylamino-l-alanine (BMAA) during the neonatal period causes cognitive impairments in adult rats. The aim of this study was to investigate the long-term effects of neonatal BMAA exposure on learning and memory mechanisms and to identify early morphological changes in the neonatal brain. BMAA was injected subcutaneously in rat pups on postnatal days 9-10. BMAA (50 and 200mg/kg) caused distinct deficits in spatial learning and memory in adult animals but no morphological changes. No impairment of recognition memory was detected, suggesting that neonatal exposure to BMAA preferentially affects neuronal systems that are important for spatial tasks. Histopathological examination revealed early neuronal cell death as determined by TUNEL staining in the hippocampus 24h after a high dose (600mg/kg) of BMAA whereas no changes were observed at lower doses (50 and 200mg/kg). In addition, there was a low degree of neuronal cell death in the retrosplenial and cingulate cortices, areas that are also important for cognitive function. Taken together, these results indicate that BMAA is a developmental neurotoxin inducing long-term changes in cognitive function. The risk posed by BMAA as a potential human neurotoxin merits further consideration, particularly if the proposed biomagnifications in the food chain are confirmed.

  • 27.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Long-term cognitive impairments in adult rats treated neonatally with beta-N-Methylamino-L-Alanine2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 112, no 1, p. 185-195Article in journal (Refereed)
    Abstract [en]

    Most cyanobacteria (blue-green algae) can produce the neurotoxin beta-N-methylamino-L-alanine (BMAA). Dietary exposure to BMAA has been suggested to be involved in the etiology of the neurodegenerative disease amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC). Little is known about BMAA-induced neurotoxicity following neonatal administration. Our previous studies have revealed an uptake of BMAA in the hippocampus and striatum of neonatal mice. Furthermore, rats treated with BMAA during the neonatal period displayed acute but transient motoric disturbances and failed to show habituation at juvenile age suggesting impairments in learning functions. In the present study, the aim was to investigate long-term behavioral effects of BMAA administration in neonatal rats. BMAA was administered on postnatal days 9-10 (200 or 600 mg/kg; subcutaneous injection). Spatial learning and memory was investigated in adulthood using the radial arm maze test. The results revealed impaired learning but not memory in BMAA-treated animals. The observed impairments were not due to alterations in motoric capacity, general activity, or behavioral profiles, as assessed in the multivariate concentric square field (MCSF) and open field tests. An aversive stimulus in the MCSF test revealed impairments in avoidance learning and/or memory. There was no difference in basal serum corticosterone levels in BMAA-treated animals, indicating that the observed long-term effects were not secondary to an altered basal hypothalamic-pituitary-adrenal axis function. The present data demonstrated long-term learning impairments following neonatal BMAA administration. Further studies on biochemical effects in various brain regions and subsequent behavioral alterations are needed to elucidate the mechanisms of BMAA-induced developmental neurotoxicity.

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  • 28.
    Machtinger, Ronit
    et al.
    Tel Aviv Univ, Ramat Gan & Sackler Sch Med, Sheba Med Ctr, Tel Aviv, Israel.
    Zhong, Jia
    Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA.
    Mansur, Abdallah
    Tel Aviv Univ, Ramat Gan & Sackler Sch Med, Sheba Med Ctr, Tel Aviv, Israel.
    Adir, Michal
    Tel Aviv Univ, Ramat Gan & Sackler Sch Med, Sheba Med Ctr, Tel Aviv, Israel.
    Racowsky, Catherine
    Brigham & Womens Hosp, Boston, MA USA; Harvard Med Sch, Boston, MA USA.
    Hauser, Russ
    Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA.
    Brennan, Kasey
    Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci, Stockholm, Sweden.
    Baccarelli, Andrea A
    Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA.
    Placental lncRNA Expression Is Associated With Prenatal Phthalate Exposure2018In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 163, no 1, p. 116-122Article in journal (Refereed)
    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.

  • 29.
    Pierozan, Paula
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Marie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The environmental neurotoxin beta-N-methylamino-L-alanine inhibits melatonin synthesis in primary pinealocytes and a rat model2018In: Journal of Pineal Research, ISSN 0742-3098, E-ISSN 1600-079X, Vol. 65, no 1, article id e12488Article in journal (Refereed)
    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.

  • 30.
    Pierozan, Paula
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jernerén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Perfluorooctanoic acid (PFOA) exposure promotes proliferation, migration and invasion potential in human breast epithelial cells2018In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 92, no 5, p. 1729-1739Article in journal (Refereed)
    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.

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  • 31.
    Pierozan, Paula
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Stockholm Univ, Dept Environm Sci & Analyt Chem, Sci Life Lab, S-11418 Stockholm, Sweden.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Stockholm Univ, Dept Environm Sci & Analyt Chem, Sci Life Lab, S-11418 Stockholm, Sweden.
    Mitotically heritable effects of BMAA on striatal neural stem cell proliferation and differentiation2019In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 10, article id 478Article in journal (Refereed)
    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.

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    FULLTEXT01
  • 32.
    Pierozan, Paula
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    PFOS induces proliferation, cell-cycle progression, and malignant phenotype in human breast epithelial cells2018In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 92, no 2, p. 705-716Article in journal (Refereed)
    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.

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  • 33.
    Pierozan, Paula
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Stockholm Univ, Dept Environm Sci, Sci Life Lab, S-11418 Stockholm, Sweden.
    Piras, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Stockholm Univ, Dept Environm Sci, Sci Life Lab, S-11418 Stockholm, Sweden.
    The cyanobacterial neurotoxinbeta-N-methylamino-L-alanine (BMAA) targets the olfactory bulb region2020In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 94, no 8, p. 2799-2808Article in journal (Refereed)
    Abstract [en]

    Olfactory dysfunction is implicated in neurodegenerative disorders and typically manifests years before other symptoms. The cyanobacterial neurotoxin beta-N-methylamino-l-alanine (BMAA) is suggested as a risk factor for neurodegenerative disease. Detection of BMAA in air filters has increased the concern that aerosolization may lead to human BMAA exposure through the air. The aim of this study was to determine if BMAA targets the olfactory system. Autoradiographic imaging showed a distinct localization of radioactivity in the right olfactory mucosa and bulb following a unilateral intranasal instillation of H-3-BMAA (0.018 mu g) in mice, demonstrating a direct transfer of BMAA via the olfactory pathways to the brain circumventing the blood-brain barrier, which was confirmed by liquid scintillation. Treatment of mouse primary olfactory bulb cells with 100 mu M BMAA for 24 h caused a disruption of the neurite network, formation of dendritic varicosities and reduced cell viability. The NMDA receptor antagonist MK-801 and the metabotropic glutamate receptor antagonist MCPG protected against the BMAA-induced alterations, demonstrating the importance of glutamatergic mechanisms. The ionotropic non-NMDA receptor antagonist CNQX prevented the BMAA-induced decrease of cell viability in mixed cultures containing both neuronal and glial cells, but not in cultures with neurons only, suggesting a role of neuron-glial interactions and glial AMPA receptors in the BMAA-induced toxicity. The results show that the olfactory region may be a target for BMAA following inhalation exposure. Further studies on the relations between environmental olfactory toxicants and neurodegenerative disorders are warranted.

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    BMAA olfactory
  • 34.
    Ransome, Yusuf
    et al.
    Department of Social and Behavioral Sciences, Yale School of Public Health, New Haven, USA.
    Slopen, Natalie
    Department of Epidemiology and Biostatistics, University of Maryland School of Public Health, USA.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Center for Molecular Medicine, Karolinska Institute, Solna, Sweden.
    Williams, David R
    Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, USA.
    Elevated inflammation in association with alcohol abuse among Blacks but not Whites: results from the MIDUS biomarker study2018In: Journal of behavioral medicine, ISSN 0160-7715, E-ISSN 1573-3521, Vol. 41, no 3, p. 374-384Article in journal (Refereed)
    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.

  • 35.
    Ransome, Yusuf
    et al.
    Yale Sch Publ Hlth, New Haven, CT USA..
    Slopen, Natalie
    Univ Maryland, Sch Publ Hlth, College Pk, MD 20742 USA..
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Yale Sch Publ Hlth, New Haven, CT USA.;Karolinska Inst, Ctr Mol Med, Solna, Sweden.
    Williams, David R.
    Harvard Sch Publ Hlth, Boston, MA USA..
    The association between alcohol abuse and neuroendocrine system dysregulation: Race differences in a National sample2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 66, p. 313-321Article in journal (Refereed)
    Abstract [en]

    Objectives: Health outcomes, including chronic disease and mortality, attributed to or associated with alcohol abuse are discrepant between African Americans and Whites. To date, the topic is not fully understood and few studies conducted have used biomarker indicators of health. We investigated whether the association between alcohol abuse and biomarkers of the neuroendocrine system vary between black or African American and White respondents aged 34-84 from the Midlife in the United States Study (MIDUS) II (2004-2006) (n = 1129). Alcohol abuse was assessed with a modified version of the Michigan Alcohol Screening Test. Ordinary least squared (OLS) regression was used to evaluate whether race moderated the associations between alcohol abuse and four biomarkers-urinary cortisol and serum dehydroepiandrosterone sulfate (DHEA-S), epinephrine and norepinephrine-and two composite summary scores, each consisting of two components that characterize the hypothalamic pituitary adrenal (HPA)-axis and sympathetic nervous systems (SNS), respectively. Covariates included age, sex, education, income, current drinking, smoking, exercise, fast food consumption, heart disease, blood pressure, diabetes, body mass index, medication use, anxiety/depression, sleep duration, and cholesterol markers. Race significantly moderated the associations between alcohol abuse and norepinephrine concentration (chi(2) [1] = 4.48, p = 0.034) and the SNS composite score (chi(2) [1] = 5.83, p = 0.016). Alcohol abuse was associated with higher mean norepinephrine levels (b = 0.26, standard error (SE) = 0.12, p = 0.034) and SNS composite score (b = 0.23, SE = 0.11, p = 0.016) for African Americans compared to Whites. Interestingly, for Whites a paradoxical association between alcohol abuse, norepinephrine and SNS levels was observed; those who abused alcohol had lower mean norepinephrine levels than non-abusers. Race differences in neuroendocrine response could be biological pathways that contribute the excess risk of chronic disease and mortality attributed to alcohol abuse among African Americans compared to Whites. Replication of these analyses in larger cohorts are warranted in addition to further studies of underlying mechanisms among Blacks and Whites separately.

  • 36.
    Roman, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Increased anxiety-like behavior but no cognitive impairments in adult rats exposed to constant light conditions during perinatal development2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 4, p. 222-227Article in journal (Refereed)
    Abstract [en]

    Background

    Shift-work is suggested to affect fetal development negatively. In particular, maternal hormonal disturbance arising from sleep deprivation or circadian rhythm changes may disturb fetal growth or lead to complications during pregnancy. Exposure to constant light is an environmental stressor that can affect the circadian system and has been shown to induce neurochemical and behavioral changes when used during the prenatal and/or postnatal period in experimental animals. However, studies investigating long-term effects of constant light in the offspring are sparse.

    Methods

    An accidental power outage resulted in pregnant females being housed under constant light (LL) conditions for seven days of the offspring perinatal development (embryonic day 20 to postnatal day 4). The long-term effects of constant light on the behavior in the adult offspring were assessed by means of open field, object recognition, and water maze tests.

    Results

    In adulthood, LL-animals displayed an intact recognition memory and no deficits in spatial learning or memory. In the open field test, LL-animals exhibited higher anxiety-like behavior, observed as significantly more thigmotaxis and less ambulation. These results were confirmed in the other behavioral tests as the LL-animals spent less time exploring the objects in the object recognition test, and showed thigmotactic behavior also in the water maze test.

    Conclusion

    The results confirm that early life experience can cause changes in brain development that shape brain function and add to the sparse literature on long-term effects of constant light conditions during perinatal development on specific behaviors in adulthood.

  • 37. Shariatgorji, Mohammadreza
    et al.
    Nilsson, Anna
    Kallback, Patrik
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhang, Xiaoqun
    Svenningsson, Per
    Andren, Per E.
    Pyrylium Salts as Reactive Matrices for MALDI-MS Imaging of Biologically Active Primary Amines2015In: Journal of the American Society for Mass Spectrometry, ISSN 1044-0305, E-ISSN 1879-1123, Vol. 26, no 6, p. 934-939Article in journal (Refereed)
    Abstract [en]

    Many neuroactive substances, including endogenous biomolecules, environmental compounds, and pharmaceuticals possess primary amine functional groups. Among these are catecholamine neurotransmitters (e.g., dopamine), many substituted phenethylamines (e.g., amphetamine), as well as amino acids and neuropeptides. In most cases, mass spectrometric (ESI and MALDI) analyses of trace amounts of such compounds are challenging because of their poor ionization properties. We present a method for chemical derivatization of primary amines by reaction with pyrylium salts that facilitates their detection by MALDI-MS and enables the imaging of primary amines in brain tissue sections. A screen of pyrylium salts revealed that the 2,4-diphenyl-pyranylium ion efficiently derivatizes primary amines and can be used as a reactive MALDI-MS matrix that induces both derivatization and desorption. MALDI-MS imaging with such matrix was used to map the localization of dopamine and amphetamine in brain tissue sections and to quantitatively map the distribution of the neurotoxin beta-N-methylamino-L-alanine.

  • 38.
    Sjöholm, Louise K
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Ransome, Yusuf
    Harvard T.H. Chan School of Public Health, Boston, USA.
    Ekström, Tomas J
    Karolinska Institute, Stockholm, Sweden.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Evaluation of Post-Mortem Effects on Global Brain DNA Methylation and Hydroxymethylation.2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 122, no 2, p. 208-213Article in journal (Refereed)
    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.

  • 39. Stingl, Christoph
    et al.
    Söderquist, Marcus
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Borén, Mats
    Luider, Theo M
    Uncovering Effects of Ex Vivo Protease Activity during Proteomics and Peptidomics Sample Extraction in Rat Brain Tissue by Oxygen-18 Labeling2014In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, no 6, p. 2807-2817Article in journal (Refereed)
    Abstract [en]

    In biological samples, proteins and peptides are altered by proteolytic activity. The actual ex vivo form of the peptidome or proteome analyzed, therefore, does not always reflect the natural in vivo state. Sample stabilization and sample treatment are thereby decisive for how far these two states diverge. To assess ex vivo formation of peptides, we used enzymatic incorporation of oxygen-18 water during proteolysis (PALeO approach) to label ex-vivo-formed peptides in rodent brain tissue. Rates of ex-vivo-formed peptides were determined in 25 samples that were stabilized and treated by six different protocols, whereby samples were subjected to different conditions such as temperature, urea concentration, and duration of treatment. Samples were measured by nano LC-Orbitrap-MS, and incorporation of oxygen-18 was determined by MS/MS database search and analysis of the precursor isotope pattern. Extent of ex vivo degradations was affected relevantly by the sample treatment protocol applied and stopped almost completely by heat stabilization. Determination of the formation state by oxygen-18 incorporation by MS/MS database search correlated well to more elaborate analysis of the MS isotope pattern. Overall, oxygen-18 labeling in combination with shotgun data-acquisition and MS/MS database search offers an adjuvant and easily applicable tool to monitor sample quality and fidelity in peptide and neuropeptide sample preparations.

  • 40. Zhong, Jia
    et al.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Wang, Guan
    Li, Jun
    Guo, Yichen
    Lin, Xinyi
    Zemplenyi, Michele
    Sanchez-Guerra, Marco
    Trevisi, Letizia
    Urch, Bruce
    Speck, Mary
    Liang, Liming
    Coull, Brent A
    Koutrakis, Petros
    Silverman, Frances
    Gold, Diane R
    Wu, Tangchun
    Baccarelli, Andrea A
    B vitamins attenuate the epigenetic effects of ambient fine particles in a pilot human intervention trial2017In: 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)
    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.

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