Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
Food Chem Toxicol. 2020 Mar;137:111173. doi: 10.1016/j.fct.2020.111173. Epub 2020 Feb 3.
We attempted to identify cellular mechanisms as an approach to screen chemicals for the potential to cause developmental neurotoxicity. We examine, in SH-SY5Y cells, whether apoptosis and oxidative stress via reactive oxygen species (ROS) generation, caspase 3/7 activation, gene expression (Bax, Bcl-2, Casp-3, BNIP3, p53 and Nrf2) alterations and necrosis by release of cytosolic adenylate kinase (AK), underlie direct effects of the pyrethroids cyfluthrin and alpha-cypermethrin. We also determined transcriptional alterations of genes (TUBB3, NEFL, NEFH, GAP43, CAMK2A, CAMK2B, WNT3A, WNT5A, WNT7A, SYN1 and PIK3C3) linked to neuronal development and maturation. Our results indicate that cyfluthrin and alpha-cypermethrin have the ability to elicit concentration-dependent increases in AK release, cellular ROS production, caspase 3/7 activity and gene expression of apoptosis and oxidative stress mediators. Both pyrethroids caused changes in mRNA expression of key target genes linked to neuronal development. These changes might reflect in a subsequent neuronal dysfunction. Our study shows that SH-SY5Y cell line is a valuable in vitro model for predicting development neurotoxicity. Our research provides evidence that cyfluthrin and alpha-cypermethrin have the potential to act as developmental neurotoxic compounds. Additional information is needed to improve the utility of this in vitro model and/or better understand its predictive capability.
我们试图确定细胞机制，作为筛选具有潜在发育神经毒性的化学物质的方法。我们在 SH-SY5Y 细胞中研究了拟除虫菊酯氯氟氰菊酯和α-氯氰菊酯是否通过活性氧 (ROS) 生成、caspase 3/7 激活、基因表达 (Bax、Bcl-2、Casp-3、BNIP3、p53 和 Nrf2) 改变以及细胞溶质腺苷酸激酶 (AK) 释放导致坏死，从而产生直接影响。我们还确定了与神经元发育和成熟相关的基因 (TUBB3、NEFL、NEFH、GAP43、CAMK2A、CAMK2B、WNT3A、WNT5A、WNT7A、SYN1 和 PIK3C3) 的转录改变。我们的结果表明，氯氟氰菊酯和α-氯氰菊酯具有引发 AK 释放、细胞 ROS 产生、caspase 3/7 活性和细胞凋亡和氧化应激介质基因表达浓度依赖性增加的能力。两种拟除虫菊酯都导致与神经元发育相关的关键靶基因的 mRNA 表达发生变化。这些变化可能反映在随后的神经元功能障碍中。我们的研究表明，SH-SY5Y 细胞系是一种预测发育神经毒性的有价值的体外模型。我们的研究结果表明，氯氟氰菊酯和α-氯氰菊酯具有作为发育神经毒性化合物的潜力。需要更多的信息来提高这种体外模型的实用性或更好地理解其预测能力。
