1 Ocak 2021 Dergi makalesi Açık Erişim

Hogberg, Helena T.; da Silveira E Sa, Rita de Cassia; Kleensang, Andre; Bouhifd, Mounir; Cemiloglu Ulker, Ozge; Smirnova, Lena; Behl, Mamta; Maertens, Alexandra; Zhao, Liang; Hartung, Thomas

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{
  "DOI": "10.1007/s00204-020-02903-2", 
  "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 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.", 
  "author": [
    {
      "family": "Hogberg", 
      "given": " Helena T."
    }, 
    {
      "family": "da Silveira E Sa", 
      "given": " Rita de Cassia"
    }, 
    {
      "family": "Kleensang", 
      "given": " Andre"
    }, 
    {
      "family": "Bouhifd", 
      "given": " Mounir"
    }, 
    {
      "family": "Cemiloglu Ulker", 
      "given": " Ozge"
    }, 
    {
      "family": "Smirnova", 
      "given": " Lena"
    }, 
    {
      "family": "Behl", 
      "given": " Mamta"
    }, 
    {
      "family": "Maertens", 
      "given": " Alexandra"
    }, 
    {
      "family": "Zhao", 
      "given": " Liang"
    }, 
    {
      "family": "Hartung", 
      "given": " Thomas"
    }
  ], 
  "container_title": "ARCHIVES OF TOXICOLOGY", 
  "id": "3667", 
  "issue": "1", 
  "issued": {
    "date-parts": [
      [
        2021, 
        1, 
        1
      ]
    ]
  }, 
  "page": "207-228", 
  "title": "Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model", 
  "type": "article-journal", 
  "volume": "95"
}