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Arch Toxicol. 2019 Jun;93(6):1649-1664. doi: 10.1007/s00204-019-02455-0. Epub 2019 Apr 16.

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

Author information

1
Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 7, 1005, Lausanne, Switzerland.
2
Swiss Centre for Applied Human Toxicology, Basel, Switzerland.
3
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
4
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
5
School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
6
Department of Neuroscience and Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
7
Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 7, 1005, Lausanne, Switzerland. Florianne.Tschudi-Monnet@unil.ch.
8
Swiss Centre for Applied Human Toxicology, Basel, Switzerland. Florianne.Tschudi-Monnet@unil.ch.

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:

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

PMID:
30993381
DOI:
10.1007/s00204-019-02455-0

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