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In vitro models to study insulin and glucocorticoids modulation of trimethyltin (TMT)-induced neuroinflammation and neurodegeneration, and in vivo validation in db/db mice

  • Jenny Sandström
  • Denise V. Kratschmar
  • Alexandra Broyer
  • Olivier Poirot
  • Philippe Marbet
  • Boonrat Chantong
  • Fanny Zufferey
  • Tania Dos Santos
  • Julien Boccard
  • Roman Chrast
  • Alex Odermatt
  • Florianne Monnet-TschudiEmail author
Organ Toxicity and Mechanisms

Abstract

Brain susceptibility to a neurotoxic insult may be increased in a compromised health status, such as metabolic syndrome. Both metabolic syndrome and exposure to trimethyltin (TMT) are known to promote neurodegeneration. In combination the two factors may elicit additive or compensatory/regulatory mechanisms. Combined effects of TMT exposure (0.5–1 μM) and mimicked metabolic syndrome—through modulation of insulin and glucocorticoid (GC) levels—were investigated in three models: tridimensional rat brain cell cultures for neuron-glia effects; murine microglial cell line BV-2 for a mechanistic analysis of microglial reactivity; and db/db mice as an in vivo model of metabolic syndrome. In 3D cultures, low insulin condition significantly exacerbated TMT’s effect on GABAergic neurons and promoted TMT-induced neuroinflammation, with increased expression of cytokines and of the regulator of intracellular GC activity, 11β-hydroxysteroid dehydrogenase 1 (11β-Hsd1). Microglial reactivity increased upon TMT exposure in medium combining low insulin and high GC. These results were corroborated in BV-2 microglial cells where lack of insulin exacerbated the TMT-induced increase in 11β-Hsd1 expression. Furthermore, TMT-induced microglial reactivity seems to depend on mineralocorticoid receptor activation. In diabetic BKS db mice, a discrete exacerbation of TMT neurotoxic effects on GABAergic neurons was observed, together with an increase of interleukin-6 (IL-6) and of basal 11β-Hsd1 expression as compared to controls. These results suggest only minor additive effects of the two brain insults, neurotoxicant TMT exposure and metabolic syndrome conditions, where 11β-Hsd1 appears to play a key role in the regulation of neuroinflammation and of its protective or neurodegenerative consequences.

Keywords

Trimethyltin (TMT) 11β-Hydroxysteroid dehydrogenase (11β-hsd1) Insulin Glucocorticoid Interleukin-6 (IL-6) Neuron Astrocyte Microglial cell 

Abbreviations

3D

Tri-dimensional

11-DHC

11-Dihydrocorticosterone

11β-HSD1

11-β Hydroxysteroid dehydrogenase

AKT

Protein kinase B

ARG1

Arginase 1

CD16

Cluster of differentiation 16

CD32

Cluster of differentiation 32

CD68

Cluster of differentiation 68

CD 206

Cluster of differentiation 206

ChAT

Choline acetyltransferase

CORT

Corticosterone

CxCl1

C-X-C motif chemokine ligand 1

DEX

Dexamethasone

FBS

Fetal bovine serum

GAD

Glutamic acid decarboxylase

GC

Glucocorticoids

GFAP

Glial fibrillary acidic protein

GR

Glucocorticoid receptor

GS

Glutamine synthetase

hsp32

Heat shock protein 32

IB4

Isolectin B4 of Griffonia simplicifolia

IL-6

Interleukin-6

i-NOS

Inducible nitric oxide synthase

Ins

Insulin

Itgam

Integrin alpha M

LDH

Lactate dehydrogenase

LPS

Lipopolysaccharide

MAPK

Mitogen-activated protein kinase

MEK1/2

MEK1/2 dual specificity protein kinase

MR

Mineralocorticoid receptor

MRC1

Mannose receptor 1

NF-H

Neurofilament heavy chain

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

p38 MAPK

p38 Mitogen-activated protein kinase

PI3K

Phosphoinositol 3 kinase

Spirono

Spironolactone

TMT

Trimethyl tin

TNF-α

Tumor necrosis factor-α

Notes

Acknowledgements

The excellent technical assistance of Denise Tavel and Brigitte Delacuisine is greatly acknowledged. This work was supported by a grant from the Swiss Centre for Applied Human Toxicology to FMT and to AO and by the Swiss National Science Foundation (Grant 31003A_135735/1 to RC and 31003A-159454 to AO).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

Human and animal rights

Animal experiments were performed in accordance with the legal requirements of the University of Lausanne and of the Canton of Vaud.

Supplementary material

204_2019_2455_MOESM1_ESM.tif (67.8 mb)
Supplementary Figure 1 Effects of insulin and GC on 3D rat brain cell cultures. (A) Dose response of 0 to 1 mM insulin in normal versus high GC medium of 3D cell cultures. Effects were assessed at DIV31, after 10 day treatment. Effects on cell death were assessed, by total protein content and intracellular LDH, and effects on astrocytes, by GS activity measurement. (B) Effect of normal insulin versus no insulin in combination with TMT-treatment. Aggregates were treated with 0.1, 0.5, and 1 μM of TMT, and effects were assessed on cell death, by total protein content and intracellular LDH, on astrocytes, by GS activity measurement, and on neurons by activity measurement of ChAT and GAD.Data was generated from a minimum of three independent experiments with each value in biological triplicates (n=9). Statistical significance is indicated with * for effect of the TMT treatment as compared to the control (CTR/0), and with # for effects of the medium alone (TIFF 69387 kb)
204_2019_2455_MOESM2_ESM.tif (77.7 mb)
Supplementary Figure 2 Microglial phenotype markers in 3D rat brain cell model (A) and in brain of lean versus obese mice (B). (A) 3D rat brain cell cultures maintained in normal, low insulin, high GC and low insulin combined to high GC medium, respectively. Results are expressed as fold change of untreated cultures maintained under normal conditions. mRNA expression of markers of the pro-inflammatory phenotype, Integrin alpha M (Itgam) and Cluster of differentiation 86 (Cd86), and of markers of the alternative phenotype, Arginase 1 (Arg1) and Mannose receptor 1 (Mrc1). A significant effect of TMT was found for all four genes (P<0.007). No interaction was found between TMT and either of the other factors (insulin or GC levels). Microglial phenotype markers in BKS db mice. (B) microglial markers of the pro-inflammatory phenotype, Cluster of differentiation 16 and 32 (Cd16, Cd32), and markers of the alternative phenotype, Arginase 1 (Arg1) and cluster of differentiation 206 Cd206 at stages 24 h and 10 days post-TMT injection. Graph shows min-max distribution of expression determined in 4 animals of the vehicle group, and 7 animals of the TMT group, horizontal bar at mean. Tukey’s multiple comparison showed a tendency for Cd16 expression to be slightly higher in saline treated db/db as compared to db/+ (P=0.061 and 0.072 for 24h and 10d respectively), no such tendencies were present in the TMT-treated groups. Arg1 was upregulated (P=0.018) in 24 h TMT-treated db/db animals compared to db/+. No interaction was found between TMT and either of the other factors (genotype or time-point) (TIFF 79590 kb)
204_2019_2455_MOESM3_ESM.tif (78.2 mb)
Supplementary Figure 3 Concentration- and time-dependent effects of TMT in BV-2 microglial cells. (A-B) Cells were treated with TMT at concentrations ranging from 0.1 to 2 μM for 24 h. (A) Expression of Il-6, 11β-Hsd1 and iNos mRNA upregulated in a TMT concentration-dependent manner. (B) TMT concentration-dependent increased release of IL-6 in the culture medium as measured by ELISA, and increased 11β-HSD1 activity as assessed by the conversion of cortisone to cortisol (% E/F conversion). (C) BV-2 cells were treated either with TMT (1 μM) or LPS (10 ng/mL) for 0.25, 0.5, 1, 6, 12, 24 and 48 h. Expression and release of IL-6 was measured as above, revealing the peak at 18-24 h of exposure. Data was generated from three independent experiments with three biological triplicates in each experiment (n=9). Results are represented as means ± SEM. Significance was determined by two-way ANOVA followed by Tukey’s posttest, *p < 0.05. (TIFF 80105 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jenny Sandström
    • 1
    • 5
  • Denise V. Kratschmar
    • 2
    • 5
  • Alexandra Broyer
    • 1
  • Olivier Poirot
    • 3
  • Philippe Marbet
    • 2
  • Boonrat Chantong
    • 2
  • Fanny Zufferey
    • 1
    • 5
  • Tania Dos Santos
    • 1
  • Julien Boccard
    • 5
    • 6
  • Roman Chrast
    • 3
    • 4
  • Alex Odermatt
    • 2
    • 5
  • Florianne Monnet-Tschudi
    • 1
    • 5
    Email author
  1. 1.Department of Physiology, Faculty of Biology and MedicineUniversity of LausanneLausanneSwitzerland
  2. 2.Division of Molecular and Systems Toxicology, Department of Pharmaceutical SciencesUniversity of BaselBaselSwitzerland
  3. 3.Department of Medical GeneticsUniversity of LausanneLausanneSwitzerland
  4. 4.Department of Neuroscience and Department of Clinical NeuroscienceKarolinska InstituteStockholmSweden
  5. 5.Swiss Centre for Applied Human ToxicologyBaselSwitzerland
  6. 6.School of Pharmaceutical SciencesUniversity of GenevaGenevaSwitzerland

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