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

作者：Helena T. Högberg, Rita de Cássia da Silveira e Sá, André Kleensang, Mounir Bouhifd, Özge Cemiloğlu Ülker, Lena Smirnova, Mamta Behl, Alexandra Maertens, Liang Zhao, Thomas Härtung · 发表于：Archives of Toxicology · 年份：2020 · DOI：10.1007/s00204-020-02903-2 · 被引用次数：78 · 研究领域：Toxic Organic Pollutants Impact、Neuroscience and Neuropharmacology Research、Pesticide Exposure and Toxicity

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,...