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Title

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

Authors
Kratschmar, Denise V.
Broyer, Alexandra
Poirot, Olivier
Marbet, Philippe
Chantong, Boonrat
Zufferey, Fanny
Dos Santos, Tania
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Published in Archives of Toxicology. 2019, vol. 93, no. 6, p. 1649-1664
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)InsulinGlucocorticoidInterleukin-6NeuronAstrocyteMicroglial cell
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PMID: 30993381
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Other version: http://link.springer.com/10.1007/s00204-019-02455-0
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SANDSTROM VON TOBEL, Jenny et al. In vitro models to study insulin and glucocorticoids modulation of trimethyltin (TMT)-induced neuroinflammation and neurodegeneration, and in vivo validation in db/db mice. In: Archives of Toxicology, 2019, vol. 93, n° 6, p. 1649-1664. doi: 10.1007/s00204-019-02455-0 https://archive-ouverte.unige.ch/unige:134655

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Deposited on : 2020-04-16

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