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Philippot, G., Stenerlöw, B., Fredriksson, A., Sundell-Bergman, S., Eriksson, P. & Buratovic, S. (2019). Developmental effects of neonatal fractionated co-exposure to low-dose gamma radiation and paraquat on behaviour in adult mice. Journal of Applied Toxicology, 39(4), 582-589
Open this publication in new window or tab >>Developmental effects of neonatal fractionated co-exposure to low-dose gamma radiation and paraquat on behaviour in adult mice
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2019 (English)In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 39, no 4, p. 582-589Article in journal (Refereed) Published
Abstract [en]

Radiological methods for screening, diagnostics and therapy are often used in healthcare; however, it has recently been reported that developmental exposure to low-dose ionizing radiation (IR) causes neurotoxicity. Environmental chemicals also have the potential to affect the developing brain and the concomitant effects caused by IR and chemicals are of high interest today. We therefore aim to investigate if low-dose IR can interact with the known neurotoxicant paraquat to induce neurotoxicity in the neonatal mouse model. Using the same model, we also aim to investigate if fractionated low-dose IR can be as neurotoxic as higher acute doses. Male mice were exposed to a single dose of paraquat (0.2 or 0.02 mg/kg) on postnatal day 10 and 11. Two hours following paraquat exposure, mice were whole body irradiated with 100 or 300 mGy gamma radiation (Cs-137). Behavioural observations were performed at 2 and 3 months of age. Following behavioural testing, we evaluated striatal dopaminergic gene transcription. Animals co-exposed to IR and paraquat generally displayed altered spontaneous behaviour compared to controls and single agent exposed mice. Stronger effects by combined exposure were also observed on adult memory and learning. However, dopaminergic gene transcript levels remained unchanged by treatment. Co-exposure to low-dose IR and paraquat can interact to exacerbate neurotoxic effects and to impair cognitive function. Furthermore, fractionation of the radiation dose was observed to be as potent as higher acute exposure for induction of developmental neurotoxicity.

National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-282374 (URN)10.1002/jat.3748 (DOI)000461835200003 ()30426514 (PubMedID)
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2019-04-05Bibliographically approved
Philippot, G., Hallgren, S., Gordh, T., Fredriksson, A., Fredriksson, R. & Viberg, H. (2018). A Cannabinoid Receptor Type 1 (CB1R) Agonist Enhances the Developmental Neurotoxicity of Acetaminophen (Paracetamol). Toxicological Sciences, 166(1), 203-212
Open this publication in new window or tab >>A Cannabinoid Receptor Type 1 (CB1R) Agonist Enhances the Developmental Neurotoxicity of Acetaminophen (Paracetamol)
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2018 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 166, no 1, p. 203-212Article in journal (Refereed) Published
Abstract [en]

Acetaminophen (AAP; also known as paracetamol) is the most used and only recommended analgesic and antipyretic among pregnant women and young children. However, recent findings in both humans and rodents suggest a link between developmental exposure to AAP and adverse neurobehavioral effects later in life. We hypothesized that the cannabinoid receptor type 1 (CB1R) may be involved in the developmental neurotoxicity of AAP, owing to its interaction with the endocannabinoid system. Here we test if CB1R agonist WIN 55 212-2 (WIN) and AAP can interact when exposure occurs during a neurodevelopmental stage known for increased growth rate and for its vulnerability to AAP exposure. We exposed male NMRI mice on postnatal day 10 to different combinations of AAP and WIN. Adult mice, neonatally co-exposed to AAP and WIN, displayed a significant lack of habituation in the spontaneous behavior test, when compared with controls and single agent exposed mice. These adult adverse effects may at least in part be explained by a reduction of transcript levels of hippocampal synaptophysin (Syp) and tropomyosin receptor kinase B (Trkb), and cerebral cortical fatty acid amide hydroxylase (Faah), 24h after exposure. These findings are consistent with our hypothesis that AAP and WIN can interact when exposure occurs during early postnatal brain development in mice. Assuming our results are relevant for humans, they raise concerns on AAP safety because it is the only recommended analgesic and antipyretic during pregnancy and early life.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
Keywords
developmental toxicity, acetaminophen (paracetamol), CB1R, spontaneous behavior, habituation
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-372828 (URN)10.1093/toxsci/kfy199 (DOI)000453585900016 ()30165669 (PubMedID)
Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2019-01-09Bibliographically approved
Philippot, G., Gordh, T., Fredriksson, A. & Viberg, H. (2017). Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period. Journal of Applied Toxicology, 37(10), 1174-1181
Open this publication in new window or tab >>Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period
2017 (English)In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 37, no 10, p. 1174-1181Article in journal (Refereed) Published
Abstract [en]

Paracetamol (acetaminophen) is a widely used non-prescription drug with analgesic and antipyretic properties. Among pregnant women and young children, paracetamol is one of the most frequently used drugs and is considered the first-choice treatment for pain and/or fever. Recent findings in both human and animal studies have shown associations between paracetamol intake during brain development and adverse behavioral outcomes later in life. The present study was undertaken to investigate if the induction of these effects depend on when the exposure occurs during a critical period of brain development and if male and female mice are equally affected. Mice of both sexes were exposed to two doses of paracetamol (30 + 30 mg kg – 1 , 4 h apart) on postnatal days (PND) 3, 10 or 19. Spontaneous behavior, when introduced to a new home environment, was observed at the age of 2 months. We show that adverse effects on adult behavior and cognitive function occurred in both male and female mice exposed to paracetamol on PND 3 and 10, but not when exposed on PND 19. These neurodevelopmental time points in mice correspond to the beginning of the third trimester of pregnancy and the time around birth in humans, supporting existing human data. Considering that paracetamol is the first choice treatment for pain and/or fever during pregnancy and early life, these results may be of great importance for future research and, ultimately, for clinical practice

Keywords
Paracetamol (acetaminophen), developmental neurotoxicity, neonatal mice, critical period, spontaneous behavior, habituation, cognitive impairments
National Category
Neurosciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-334493 (URN)10.1002/jat.3473 (DOI)000409913500005 ()28448685 (PubMedID)
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-01-13Bibliographically approved
Gaetan, P., Fredriksson, A. & Viberg, H. (2016). Neonatal exposure to acetamiophen (paracetamol) and CB1R agonist shos an additive adverese neurodevelopmental effects. In: : . Paper presented at The 55th Annual Meeting of the Society of Toxicology,New Orleans, March 13–17, 2016. (pp. 55-55). , 150
Open this publication in new window or tab >>Neonatal exposure to acetamiophen (paracetamol) and CB1R agonist shos an additive adverese neurodevelopmental effects
2016 (English)Conference paper, Poster (with or without abstract) (Refereed)
Series
The Toxicologist: Supplement to Toxicological Sciences, ISSN 1096-6080 ; 150 (1)
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-289271 (URN)
Conference
The 55th Annual Meeting of the Society of Toxicology,New Orleans, March 13–17, 2016.
Available from: 2016-04-29 Created: 2016-04-29 Last updated: 2016-05-03Bibliographically approved
Gaetan, P., Nyberg, F., Gordh, T., Fredriksson, A. & Viberg, H. (2016). Short-term exposure and long-term consequences of neonatal exposure to Δ9-tetrahydrocannabinol (THC) and ibuprofen in mice. Behavioural Brain Research, 307, 137-144
Open this publication in new window or tab >>Short-term exposure and long-term consequences of neonatal exposure to Δ9-tetrahydrocannabinol (THC) and ibuprofen in mice
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2016 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 307, p. 137-144Article in journal (Refereed) Published
Abstract [sv]

Both Δ9-tetrahydrocannabinol (THC) and ibuprofen have analgesic properties by interacting with the cannabinoid receptor type 1 (CB1R) and the cyclooxygenase (COX) systems, respectively. Evaluation of these analgesics is important not only clinically, since they are commonly used during pregnancy and lactation, but also to compare them with acetaminophen, with a known interaction with both CB1R and the COX systems. Short-term exposure of neonatal rodents to acetaminophen during the first weeks of postnatal life, which is comparable with a period from the third trimester of pregnancy to the first years of postnatal life in humans, induces long-term behavioral disturbances. This period, called the brain growth spurt (BGS) and is characterized by series of rapid and fundamental changes and increased vulnerability, peaks around postnatal day (PND) 10 in mice. We therefore exposed male NMRI mice to either THC or ibuprofen on PND 10. At 2 months of age, the mice were subjected to a spontaneous behavior test, consisting of a 60 min recording of the variables locomotion, rearing and total activity. Mice exposed to THC, but not ibuprofen, exhibited altered adult spontaneous behavior and habituation capability in a dose-dependent manner. This highlights the potency of THC as a developmental neurotoxicant, since a single neonatal dose of THC was enough to affect adult cognitive function. The lack of effect from ibuprofen also indicates that the previously seen developmental neurotoxicity of acetaminophen is non-COX-mediated. These results might be of importance in future research as well as in the ongoing risk/benefit assessment of THC.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-289311 (URN)10.1016/j.bbr.2016.04.001 (DOI)000376549000016 ()27058925 (PubMedID)
External cooperation:
Available from: 2016-04-29 Created: 2016-04-29 Last updated: 2017-11-30Bibliographically approved
Eriksson, A., Williams, M. J., Voisin, S., Hansson, I., Krishnan, A., Philippot, G., . . . Schiöth, H. B. (2015). Implication of coronin 7 in body weight regulation in humans, mice and flies. BMC neuroscience (Online), 16, Article ID 13.
Open this publication in new window or tab >>Implication of coronin 7 in body weight regulation in humans, mice and flies
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2015 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 16, article id 13Article in journal (Refereed) Published
Abstract [en]

Background: Obesity is a growing global concern with strong associations with cardiovascular disease, cancer and type-2 diabetes. Although various genome-wide association studies have identified more than 40 genes associated with obesity, these genes cannot fully explain the heritability of obesity, suggesting there may be other contributing factors, including epigenetic effects. Results: We performed genome wide DNA methylation profiling comparing normal-weight and obese 9-13 year old children to investigate possible epigenetic changes correlated with obesity. Of note, obese children had significantly lower methylation levels at a CpG site located near coronin 7 (CORO7), which encodes a tryptophan-aspartic acid dipeptide (WD)-repeat containing protein most likely involved in Golgi complex morphology and function. Anatomical profiling of coronin 7 (Coro7) mRNA expression in mice revealed that it is highly expressed in appetite and energy balance regulating regions, including the hypothalamus, striatum and locus coeruleus, the main noradrenergic brain site. Interestingly, we found that food deprivation in mice downregulates hypothalamic Coro7 mRNA levels, and injecting ethanol, an appetite stimulant, increased the number of Coro7 expressing cells in the locus coeruleus. Finally, by employing the genetically-tractable Drosophila melanogaster model we were able to demonstrate an evolutionarily conserved metabolic function for the CORO7 homologue pod1. Knocking down the pod1 in the Drosophila adult nervous system increased their resistance to starvation. Furthermore, feeding flies a high-calorie diet significantly increased pod1 expression. Conclusion: We conclude that coronin 7 is involved in the regulation of energy homeostasis and this role stems, to some degree, from the effect on feeding for calories and reward.

Keywords
Coronin 7, Obesity, Homeostatic control, Gene expression
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-251425 (URN)10.1186/s12868-015-0151-9 (DOI)000351126000001 ()
Available from: 2015-04-23 Created: 2015-04-17 Last updated: 2018-01-11Bibliographically approved
Philippot, G., Fredriksson, A. & Viberg, H. (2015). Neonatal paracetamol (acetaminophen) exposure during a defined and critical period of brain development causes altered spontaneous behavior in both male and female adult mice. In: : . Paper presented at 54th Annual Meeting and ToxExpo,San Diego, California, March 22–26, 2015 (pp. 383). Oxford University Press, 144
Open this publication in new window or tab >>Neonatal paracetamol (acetaminophen) exposure during a defined and critical period of brain development causes altered spontaneous behavior in both male and female adult mice
2015 (English)Conference paper, Poster (with or without abstract) (Other academic)
Place, publisher, year, edition, pages
Oxford University Press, 2015
Series
The Toxicologist: supplement to Toxicological Sciences, ISSN 1096-6080 ; 144(1)
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-289275 (URN)
Conference
54th Annual Meeting and ToxExpo,San Diego, California, March 22–26, 2015
Available from: 2016-04-29 Created: 2016-04-29 Last updated: 2016-07-01Bibliographically approved
Viberg, H., Gaetan, P. & Fredriksson, A. (2015). Substances with analgesic properties, tetrahydrocannabinol (THC) and Ibuprofen, affect behaviour and cognitive function differently after developmental exposure. In: : . Paper presented at 54th Annual Meeting and ToxExpo,San Diego, California, March 22–26, 2015 (pp. 382-383). Oxford University Press, 144
Open this publication in new window or tab >>Substances with analgesic properties, tetrahydrocannabinol (THC) and Ibuprofen, affect behaviour and cognitive function differently after developmental exposure
2015 (English)Conference paper, Poster (with or without abstract) (Refereed)
Place, publisher, year, edition, pages
Oxford University Press, 2015
Series
The Toxicologist: supplement to to Toxicological Sciences, ISSN 1096-6080 ; 144(1)
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-289274 (URN)
Conference
54th Annual Meeting and ToxExpo,San Diego, California, March 22–26, 2015
Available from: 2016-04-29 Created: 2016-04-29 Last updated: 2016-07-01Bibliographically approved
Hägglund, M. G., Hellsten, S. V., Bagchi, S., Philippot, G., Löfqvist, E., Nilsson, V. C., . . . Fredriksson, R. (2015). Transport of L-glutamine, L-alanine, L-arginine and L-histidine by the neuron-specific Slc38a8 (SNAT8) in CNS. Journal of Molecular Biology, 427(6), 1495-1512
Open this publication in new window or tab >>Transport of L-glutamine, L-alanine, L-arginine and L-histidine by the neuron-specific Slc38a8 (SNAT8) in CNS
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2015 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 427, no 6, p. 1495-1512Article in journal (Refereed) Published
Abstract [en]

Glutamine transporters are important for regulating levels of glutamate and GABA in the brain. To date, six members of the SLC38 family (SNATs) have been characterized and functionally subdivided into System A (SNAT1, SNAT2 and SNAT4) and System N (SNAT3, SNAT5 and SNAT7). Here we present a first functional characterization of SLC38A8, one of the previous orphan transporters from the family and we suggest that the encoded protein should be named SNAT8 to adhere with the SNAT nomenclature. We show that SLC38A8 have preference for transporting L-glutamine, L-alanine, L-arginine, L-histidine, and L-aspartate using a Na(+)-dependent transport mechanism and that the functional characteristics of SNAT8 has highest similarity to the known System A transporters. We also provide a comprehensive CNS expression profile in mouse brain for the Slc38a8 gene and the SNAT8 protein. We show that Slc38a8 (SNAT8) is expressed in all neurons, both excitatory and inhibitory, in mouse brain using in situ hybridization and immunohistochemistry. Furthermore, proximity ligation assay show highly similar subcellular expression of SNAT7 and SNAT8. In conclusion, the neuronal SLC38A8 have a broad amino acid transport profile and is the first identified neuronal System A transporter. This suggests a key role of SNAT8 in the glutamine/glutamate(GABA) cycle in the brain.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-238741 (URN)10.1016/j.jmb.2014.10.016 (DOI)000351798700021 ()25451601 (PubMedID)
Available from: 2014-12-16 Created: 2014-12-16 Last updated: 2017-12-05Bibliographically approved
Rask-Andersen, M., Philippot, G., Moschonis, G., Dedoussis, G., Manios, Y., Marcus, C., . . . Schiöth, H. B. (2014). CDKAL1-Related Single Nucleotide Polymorphisms Are Associated with Insulin Resistance in a Cross-Sectional Cohort of Greek Children. PLoS ONE, 9(4), e93193
Open this publication in new window or tab >>CDKAL1-Related Single Nucleotide Polymorphisms Are Associated with Insulin Resistance in a Cross-Sectional Cohort of Greek Children
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e93193-Article in journal (Refereed) Published
Abstract [en]

Five novel loci recently found to be associated with body mass in two GWAS of East Asian populations were evaluated in two cohorts of Swedish and Greek children and adolescents. These loci are located within, or in the proximity of: CDKAL1, PCSK1, GP2, PAX6 and KLF9. No association with body mass has previously been reported for these loci in GWAS performed on European populations. The single nucleotide polymorphisms ( SNPs) with the strongest association at each loci in the East Asian GWAS were genotyped in two cohorts, one obesity case control cohort of Swedish children and adolescents consisting of 496 cases and 520 controls and one cross-sectional cohort of 2293 nine-to-thirteen year old Greek children and adolescents. SNPs were surveyed for association with body mass and other phenotypic traits commonly associated with obesity, including adipose tissue distribution, insulin resistance and daily caloric intake. No association with body mass was found in either cohort. However, among the Greek children, association with insulin resistance could be observed for the two CDKAL1-related SNPs: rs9356744 (beta = 0.018, p = 0.014) and rs2206734 (beta = 0.024, p = 0.001). CDKAL1-related variants have previously been associated with type 2 diabetes and insulin response. This study reports association of CDKAL1-related SNPs with insulin resistance, a clinical marker related to type 2 diabetes in a cross-sectional cohort of Greek children and adolescents of European descent.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-224744 (URN)10.1371/journal.pone.0093193 (DOI)000334103000046 ()
Available from: 2014-05-20 Created: 2014-05-19 Last updated: 2017-12-05Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2024-1824

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