Asexual freshwater planarians are an attractive invertebrate model for high-throughput neurotoxicity screening, because they possess multiple quantifiable behaviors to assess distinct neuronal functions. Planarians uniquely allow direct comparisons between developing and adult animals to distinguish developmentally selective effects from general neurotoxicity. In this study, we used our automated planarian screening platform to compare the neurotoxicity of 15 flame retardants (FRs), consisting of representative phased-out brominated (BFRs) and replacement organophosphorus FRs (OPFRs). OPFRs have emerged as a proposed safer alternative to BFRs; however, limited information is available on their health effects. We found 11 of the 15 FRs (3/6 BFRs, 7/8 OPFRs, and Firemaster 550) caused adverse effects in both adult and developing planarians with similar nominal lowest-effect-levels for BFRs and OPFRs. This suggests that replacement OPFRs are comparably neurotoxic to the phased-out compounds. BFRs were primarily systemically toxic, whereas OPFRs, except Tris(2-chloroethyl) phosphate, shared a behavioral phenotype in response to noxious heat at sublethal concentrations, indicating specific neurotoxic effects. We found this behavioral phenotype was correlated with cholinesterase inhibition, thus linking behavioral outcomes to molecular targets. By directly comparing effects on adult and developing planarians, we further found that one BFR (3,3',5,5'-Tetrabromobisphenol A) caused a developmental selective defect. Together, these results demonstrate that our planarian screening platform yields high content data from various behavioral and morphological endpoints, allowing us to distinguish selective neurotoxic effects and effects specific to the developing nervous system. Ten of these 11 bioactive FRs were previously found to be bioactive in other models, including cell culture and alternative animal models (nematodes and zebrafish). This level of concordance across different platforms emphasizes the urgent need for further evaluation of OPFRs in mammalian systems.

中文翻译：

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使用淡水涡虫筛选 15 种阻燃剂的神经毒性潜力。

无性淡水涡虫是用于高通量神经毒性筛查的有吸引力的无脊椎动物模型，因为它们具有多种可量化的行为来评估不同的神经元功能。涡虫独特地允许在发育和成年动物之间进行直接比较，以区分发育选择性效应和一般神经毒性。在这项研究中，我们使用我们的自动涡虫筛选平台来比较 15 种阻燃剂 (FRs) 的神经毒性，这些阻燃剂由具有代表性的逐步淘汰溴化 (BFRs) 和替代有机磷 FRs (OPFRs) 组成。OPFR 已成为 BFR 的一种更安全的替代方案；然而，关于它们的健康影响的信息有限。我们发现了 15 个 FR 中的 11 个（3/6 BFR，7/8 OPFR，和 Firemaster 550）对成年涡虫和发育中的涡虫造成不利影响，BFR 和 OPFR 的标称最低效应水平相似。这表明替代 OPFR 与淘汰的化合物具有相当的神经毒性。BFRs 主要具有全身毒性，而 OPFRs，除磷酸三（2-氯乙基）酯外，在亚致死浓度下对有毒热有反应，具有共同的行为表型，表明具有特定的神经毒性作用。我们发现这种行为表型与胆碱酯酶抑制相关，从而将行为结果与分子目标联系起来。通过直接比较对成年涡虫和发育中的涡虫的影响，我们进一步发现一种 BFR (3,3',5,5'-四溴双酚 A) 会导致发育选择性缺陷。一起，这些结果表明，我们的涡虫筛选平台从各种行为和形态学端点产生高含量数据，使我们能够区分选择性神经毒性作用和特定于发育中的神经系统的作用。之前发现这 11 种生物活性 FR 中有 10 种在其他模型中具有生物活性，包括细胞培养和替代动物模型（线虫和斑马鱼）。不同平台之间的这种一致性水平强调迫切需要进一步评估哺乳动物系统中的 OPFR。包括细胞培养和替代动物模型（线虫和斑马鱼）。不同平台之间的这种一致性水平强调迫切需要进一步评估哺乳动物系统中的 OPFR。包括细胞培养和替代动物模型（线虫和斑马鱼）。不同平台之间的这种一致性水平强调迫切需要进一步评估哺乳动物系统中的 OPFR。