Abstract：
Poly(hexamethylenebicyanoguanide-hexamethylenediamine) hydrochloride (PHMB) is a biocide with a broad spectrum of antibacterial activity. Its use as a disinfectant and preservative in consumer products results in human exposure to PHMB. Toxicity studies on PHMB mainly focus on systemic toxicity or skin irritation; however, its effects on developmental neurotoxicity (DNT) and the underlying mechanisms are poorly understood. In this study, the DNT effects of PHMB were evaluated using IMR-32 and SH-SY5Y cell lines and zebrafish. In both cell lines, PHMB concentrations ≥ 10 µM reduced neurite outgrowth, and cytotoxicity was observed at concentrations up to 40 µM. PHMB regulated expression of neurodevelopmental genes and induced reactive oxygen species (ROS) production and mitochondrial dysfunction. Treatment with N-acetylcysteine reversed the toxic effects of PHMB. Toxicity tests on zebrafish embryos showed that PHMB reduced viability and heart rate and caused irregular hatching. PHMB concentrations of 1-4 µM reduced the width of the brain and spinal cord of transgenic zebrafish and attenuated myelination processes. Furthermore, PHMB modulated expression of neurodevelopmental genes in zebrafish and induced ROS accumulation. These results suggested that PHMB exerted DNT effects in vitro and in vivo through a ROS-dependent mechanism, highlighting the risk of PHMB exposure.
摘要：
聚(六亚甲基双胍-六亚甲基二胺)盐酸盐(PHMB)是具有广谱抗菌活性的杀生物剂。其在消费品中用作消毒剂和防腐剂导致人类暴露于PHMB。对PHMB的毒性研究主要集中在全身毒性或皮肤刺激;然而,其对发育神经毒性（DNT）的影响及其潜在机制知之甚少。在这项研究中,使用IMR-32和SH-SY5Y细胞系和斑马鱼评估PHMB的DNT效应。在两种细胞系中，PHMB浓度≥10µM可减少神经突生长，在高达40µM的浓度下观察到细胞毒性。PHMB调节神经发育基因的表达并诱导活性氧（ROS）的产生和线粒体功能障碍。用N-乙酰半胱氨酸处理逆转了PHMB的毒性作用。对斑马鱼胚胎的毒性测试表明，PHMB降低了活力和心率，并引起不规则的孵化。1-4µM的PHMB浓度降低了转基因斑马鱼的大脑和脊髓的宽度，并减弱了髓鞘形成过程。此外，PHMB调节斑马鱼神经发育基因的表达并诱导ROS积累。这些结果表明，PHMB通过ROS依赖性机制在体外和体内发挥DNT作用。强调PHMB暴露的风险。
