有机磷农药被广泛使用;然而,由于神经毒性,它们的使用受到限制,在较小程度上,人类的心脏毒性。考虑到心肌的高能量需求,其特征是线粒体密集,对这些细胞器的任何损害都会加剧心脏毒性。这项研究旨在阐明有机磷农药的心脏毒性作用是否源于线粒体功能障碍。为了调查这一点,使用各种工具进行硅中毒基因组分析,例如比较毒理学数据库,遗传狂躁症,STRING,和Cytoscape。结果显示,WHO推荐的13种Ia类有机磷农药中有11种靶向与心脏毒性相关的基因。值得注意的是,其中三个基因是线粒体的,过氧化氢酶(CAT)是对硫磷中常见的差异表达基因,甲基对硫磷,和Phorate。此外,蛋白质-蛋白质相互作用分析表明CAT和超氧化物歧化酶2线粒体(SOD2)之间有很强的关联。随后,分离的心脏线粒体用于体外评估CAT和超氧化物歧化酶(SOD)活性。研究结果表明,在浓度为7.5ng/µL时,甲基对硫磷和甲硫磷均使CAT活性显着降低约35%。此外,甲拌磷将总SOD和SOD2活性降低17%和19%,分别,在相同的浓度。相比之下,三种有机磷农药均未诱导线粒体通透性过渡孔的开放。这些结果表明,CAT和SOD2活性的减少,关键的抗氧化酶,导致线粒体内活性氧的积累,最终导致线粒体损伤。这种机制可能是观察到的由这些有机磷酸酯农药诱导的心脏毒性的基础。
Organophosphate pesticides are widely used; however, their use is limited due to neurotoxicity and, to a lesser extent, cardiotoxicity in humans. Given the high energy demands of cardiac muscle, which is characterized by a dense population of mitochondria, any damage to these organelles can exacerbate cardiotoxicity. This study aims to elucidate whether the cardiotoxic effects of organophosphate pesticides originate from mitochondrial dysfunction. To investigate this, in silico toxicogenomic analyses were performed using various tools, such as the Comparative Toxicogenomic Database, GeneMANIA, STRING, and Cytoscape. Results revealed that 11 out of the 13 WHO-recommended Class Ia organophosphate pesticides target genes associated with cardiotoxicity. Notably, three of these genes were mitochondrial, with catalase (CAT) being the common differentially expressed gene among parathion, methyl parathion, and phorate. Furthermore, protein-protein interaction analysis indicated a strong association between CAT and superoxide dismutase 2, mitochondrial (SOD2). Subsequently, isolated heart mitochondria were utilized to assess CAT and superoxide dismutase (SOD) activities in vitro. The findings demonstrated that at a concentration of 7.5 ng/µL, both methyl parathion and phorate significantly decreased CAT activity by approximately 35%. Moreover, phorate reduced total SOD and SOD2 activities by 17% and 19%, respectively, at the same concentration. In contrast, none of the three organophosphate pesticides induced the opening of the mitochondrial permeability transition pore. These results suggest that the reduction in CAT and SOD2 activities, critical antioxidant enzymes, leads to the accumulation of reactive oxygen species within mitochondria, ultimately resulting in mitochondrial damage. This mechanism likely underlies the observed cardiotoxicity induced by these organophosphate pesticides.