Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model

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Hogberg H. T., da Silveira E Sa R. d. C., Kleensang A., Bouhifd M., Cemiloglu Ulker Ö., Smirnova L., ...Daha Fazla

ARCHIVES OF TOXICOLOGY, cilt.95, sa.1, ss.207-228, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 95 Sayı: 1
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1007/s00204-020-02903-2
  • Dergi Adı: ARCHIVES OF TOXICOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, Environment Index, MEDLINE, Pollution Abstracts, Veterinary Science Database
  • Sayfa Sayıları: ss.207-228
  • Anahtar Kelimeler: Developmental neurotoxicity, Flame retardants, 3D in vitro model, New approach methodologies, Metabolomics, Transcriptomics, CENTRAL-NERVOUS-SYSTEM, MYELIN-ASSOCIATED GLYCOPROTEIN, FIBRILLARY ACIDIC PROTEIN, MESSENGER-RNA EXPRESSION, PLURIPOTENT STEM-CELLS, N-ACETYLASPARTATE, NITRIC-OXIDE, ZEBRAFISH LARVAE, OXIDATIVE STRESS, PRIMARY CULTURES
  • Ankara Üniversitesi Adresli: Hayır

Özet

Due to regulatory bans and voluntary substitutions, halogenated polybrominated diphenyl ether (PBDE) flame retardants (FR) are increasingly substituted by mainly organophosphorus FR (OPFR). Leveraging a 3D rat primary neural organotypic in vitro model (rat brainsphere), we compare developmental neurotoxic effects of BDE-47-the most abundant PBDE congener-with four OPFR (isopropylated phenyl phosphate-IPP, triphenyl phosphate-TPHP, isodecyl diphenyl phosphate-IDDP, and tricresyl phosphate (also known as trimethyl phenyl phosphate)-TMPP). Employing mass spectroscopy-based metabolomics and transcriptomics, we observe at similar human-relevant non-cytotoxic concentrations (0.1-5 mu M) stronger developmental neurotoxic effects by OPFR. This includes toxicity to neurons in the low mu M range; all FR decrease the neurotransmitters glutamate and GABA (except BDE-47 and TPHP). Furthermore,n-acetyl aspartate (NAA), considered a neurologic diagnostic molecule, was decreased by all OPFR. At similar concentrations, the FR currently in use decreased plasma membrane dopamine active transporter expression, while BDE-47 did not. Several findings suggest astrogliosis induced by the OPFR, but not BDE-47. At the 5 mu M concentrations, the OPFR more than BDE-47 interfered with myelination. An increase of cytokine gene and receptor expressions suggests that exposure to OPFR may induce an inflammatory response. Pathway/category overrepresentation shows disruption in 1) transmission of action potentials, cell-cell signaling, synaptic transmission, receptor signaling, (2) immune response, inflammation, defense response, (3) cell cycle and (4) lipids metabolism and transportation. Taken together, this appears to be a case of regretful substitution with substances not less developmentally neurotoxic in a primary rat 3D model.