Department of Environmental Toxicology, University of California, Davis, CA, United States; Nicholas School of the Environment, Duke University, Durham, NC, United States.
Nicholas School of the Environment, Duke University, Durham, NC, United States.
Reprod Toxicol. 2019 Oct;89:83-92. doi: 10.1016/j.reprotox.2019.07.007. Epub 2019 Jul 14.
Mitochondrial toxicity has been proposed as a potential cause of developmental defects in humans. We evaluated 51 organophosphate and carbamate pesticides using the U.S. EPA ToxCast and Tox21 databases. Only a small number of them bind directly to cholinesterases in the parent form. The hydrophobicity of organophosphate pesticides is correlated significantly to TSPO binding affinity, mitochondrial membrane potential reduction in HepG2 cells, and developmental toxicity in Caenorhabditis elegans and Danio rerio (p < 0.05). Structural analysis suggests that in some cases the Krebs cycle is a potential target of organophosphate and carbamate exposure at early life stages. The results support the hypothesis that mitochondrial effects of some organophosphate pesticides-particularly those that require enzymatic activation to the oxon form-may augment the documented effects of disruption of acetylcholine signaling. This study provides a proof of concept for applying new approach methodologies to interrogate mechanisms of action for cumulative risk assessment.
线粒体毒性被认为是人类发育缺陷的潜在原因。我们使用美国环保署 ToxCast 和 Tox21 数据库评估了 51 种有机磷和氨基甲酸酯类农药。其中只有少数以母体形式直接与胆碱酯酶结合。有机磷农药的疏水性与 TSPO 结合亲和力、HepG2 细胞中线粒体膜电位降低以及秀丽隐杆线虫和斑马鱼的发育毒性显著相关（p < 0.05）。结构分析表明，在某些情况下，三羧酸循环可能是生命早期有机磷和氨基甲酸酯暴露的潜在靶点。研究结果支持这样一种假设，即某些有机磷农药的线粒体效应——特别是那些需要酶激活为氧肟酸形式的农药——可能会增强已记录的乙酰胆碱信号中断的影响。本研究为应用新方法方法学来探究累积风险评估的作用机制提供了一个概念验证。
