Clinical Research Branch, Public Health and Integrated Toxicology Division, CPHEA/ORD, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Neurological and Endocrine Toxicology Branch, Public Health and Integrated Toxicology Division, CPHEA/ORD, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Toxicol In Vitro. 2020 Dec;69:104989. doi: 10.1016/j.tiv.2020.104989. Epub 2020 Sep 1.
The Hard-Soft Acid and Base hypothesis can be used to predict the potential bio-reactivity (electrophilicity) of a chemical with intracellular proteins, resulting in neurotoxicity. Twelve chemicals predicted to be neurotoxic were evaluated in vitro in rat dorsal root ganglia (DRG) for effects on cytotoxicity (%LDH), neuronal structure (total neurite length/neuron, NLPN), and neurophysiology (mean firing rate, MFR). DRGs were treated acutely on days in vitro (DIV) 7 (1-100 μM) with test chemical; %LDH and NLPN were measured after 48 h. 4-cyclohexylhexanone (4-C) increased %LDH release at 50 (29%) and 100 μM (56%), citronellal (Cit) and 1-bromopropane increased %LDH at 100 μM (22% and 26%). 4-C, Cit, 2,5 Hexanedione (2,5Hex), phenylacetylaldehyde (PAA) and 2-ethylhexanal decreased mean NLPN at 48 h; 50 and 100 μM for 4-C (28% and 60%), 100 μM Cit (52%), 100 μM 2,5- Hex (37%) 100 μM PAA (41%) and 100 μM for 2-ethylhexanal (23%). Separate DRG cultures were treated on DIV 14 and changes in MFR measured. Four compounds decreased MFR at 50 or 100 μM: Acrylamide (-83%), 3,4-dichloro-1-butene (-93%), 4-C (-89%) and hexane (-79%, 50 μM). Changes in MFR and NLPN occurred in absence of cytotoxicity. While the current study showed little cytotoxicity, it gave insight to initial changes in MFR. Results provide insight for future chronic exposure experiments to evaluate neurotoxicity.
硬-软酸碱理论可以用来预测化学物质与细胞内蛋白质的潜在生物反应性（亲电性），从而导致神经毒性。有 12 种被预测为具有神经毒性的化学物质在大鼠背根神经节（DRG）中进行了体外评估，以研究它们对细胞毒性（%LDH）、神经元结构（总神经突长度/神经元，NLPN）和神经生理学（平均放电率，MFR）的影响。DRG 在体外培养的第 7 天（DIV）急性处理（1-100μM）测试化学物质；48 小时后测量 %LDH 和 NLPN。4-环己基己酮（4-C）在 50μM（29%）和 100μM（56%）时增加 LDH 释放，柠檬醛（Cit）和 1-溴丙烷在 100μM 时增加 LDH 释放（22%和 26%）。4-C、Cit、2,5 己二酮（2,5Hex）、苯乙酮（PAA）和 2-乙基己醛在 48 小时时降低 NLPN 的平均值；4-C 在 50 和 100μM 时（28%和 60%），Cit 在 100μM 时（52%），2,5-Hex 在 100μM 时（37%），PAA 在 100μM 时（41%）和 2-乙基己醛在 100μM 时（23%）。分离的 DRG 培养物在 DIV 14 时进行处理，并测量 MFR 的变化。四种化合物在 50 或 100μM 时降低 MFR：丙烯酰胺（-83%）、3,4-二氯-1-丁烯（-93%）、4-C（-89%）和己烷（-79%，50μM）。在没有细胞毒性的情况下，MFR 和 NLPN 发生了变化。虽然本研究显示出很小的细胞毒性，但它为 MFR 的初始变化提供了一些见解。结果为未来的慢性暴露实验提供了神经毒性评估的见解。
