Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model.
Arch Toxicol
; 95(1): 207-228, 2021 01.
Article
en En
| MEDLINE
| ID: mdl-33078273
ABSTRACT
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 µM) stronger developmental neurotoxic effects by OPFR. This includes toxicity to neurons in the low µM 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 µM 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Organofosfatos
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Encéfalo
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Síndromes de Neurotoxicidad
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Retardadores de Llama
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Neuronas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Pregnancy
Idioma:
En
Revista:
Arch Toxicol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
ALEMANHA
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ALEMANIA
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DE
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DEUSTCHLAND
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GERMANY