Parallel in vivo and in vitro transcriptomics analysis reveals calcium and zinc signalling in the brain as sensitive targets of HBCD neurotoxicity

V. Reffatto, J. D. Rasinger, T. S. Carroll, T. Ganay, A. K. Lundebye, I. Sekler, M. Hershfinkel, C. Hogstrand

نتاج البحث: نشر في مجلةمقالةمراجعة النظراء

ملخص

Hexabromocyclododecane (HBCD) is a brominated flame retardant (BFR) that accumulates in humans and affects the nervous system. To elucidate the mechanisms of HBCD neurotoxicity, we used transcriptomic profiling in brains of female mice exposed through their diet to HBCD (199 mg/kg body weight per day) for 28 days and compared with those of neuronal N2A and NSC-19 cell lines exposed to 1 or 2 µM HBCD. Similar pathways and functions were affected both in vivo and in vitro, including Ca 2+ and Zn 2+ signalling, glutamatergic neuron activity, apoptosis, and oxidative stress. Release of cytosolic free Zn 2+ by HBCD was confirmed in N2A cells. This Zn 2+ release was partially quenched by the antioxidant N-acetyl cysteine indicating that, in accordance with transcriptomic analysis, free radical formation is involved in HBCD toxicity. To investigate the effects of HBCD in excitable cells, we isolated mouse hippocampal neurons and monitored Ca 2+ signalling triggered by extracellular glutamate or zinc, which are co-released pre-synaptically to trigger postsynaptic signalling. In control cells application of zinc or glutamate triggered a rapid rise of intracellular [Ca 2+ ]. Treatment of the cultures with 1 µM of HBCD was sufficient to reduce the glutamate-dependent Ca 2+ signal by 50%. The effect of HBCD on zinc-dependent Ca 2+ signalling was even more pronounced, resulting in the reduction of the Ca 2+ signal with 86% inhibition at 1 µM HBCD. Our results show that low concentrations of HBCD affect neural signalling in mouse brain acting through dysregulation of Ca 2+ and Zn 2+ homeostasis.

اللغة الأصليةإنجليزيّة أمريكيّة
الصفحات (من إلى)1189-1203
عدد الصفحات15
دوريةArchives of Toxicology
مستوى الصوت92
رقم الإصدار3
المعرِّفات الرقمية للأشياء
حالة النشرنُشِر - 1 مارس 2018

All Science Journal Classification (ASJC) codes

  • !!Toxicology
  • !!Health, Toxicology and Mutagenesis

بصمة

أدرس بدقة موضوعات البحث “Parallel in vivo and in vitro transcriptomics analysis reveals calcium and zinc signalling in the brain as sensitive targets of HBCD neurotoxicity'. فهما يشكلان معًا بصمة فريدة.

قم بذكر هذا