Yang, Zhao, Ren, Pang, Li (2020) Assessment of the endocrine-disrupting effects of diethyl phosphate, a nonspecific metabolite of organophosphorus pesticides, by in vivo and in silico approaches Environment international 135() 105383
Organophosphorus pesticides (OPs) remain one of the most commonly used pesticides, and their detection rates and residues in agricultural products, foods and environmental samples have been underestimated. Humans and environmental organisms are at high risk of exposure to OPs. Most OPs can be degraded and metabolized into dialkyl phosphates (DAPs) in organisms and the environment, and can be present in urine as biomarkers for exposure to OPs, of which diethyl phosphate (DEP) is a high-exposure metabolite. Epidemiological and cohort studies have found that DAPs are associated with endocrine hormone disorders, especially sex hormone disorders and thyroid hormone disorders, but there has been no direct causal evidence to support these findings. Our study explored the effects of chronic exposure to DEP on endocrine hormones and related metabolic indicators in adult male rats at actual doses that can be reached in the human body. The results showed that chronic exposure to DEP could cause thyroid-related hormone disorders in the serum of rats, causing symptoms of hyperthyroidism in rats, and could also lead to abnormal expression of thyroid hormone-related genes in the rat liver. However, DEP exposure did not seem to affect serum sex hormone levels, spermatogenesis or sperm quality in rats. The molecular interactions between DEP and thyroid hormone-related enzymes/proteins were investigated by molecular docking and molecular dynamics methods in silico. It was found that DEP could strongly interact with thyroid hormone biosynthesis, blood transport, receptor binding and metabolism-related enzymes/proteins, interfering with the production and signal regulation of thyroid hormones. In vivo and in silico experiments showed that DEP might be a potential thyroid hormone-disrupting chemical, and therefore, we need to be more cautious and rigorous regarding organophosphorus chemical exposure. Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.
有机磷农药（OPs）仍然是最常用的农药之一，其在农产品，食品和环境样品中的检出率和残留量被低估了。人类和环境生物极有可能接触OP。大多数OP可以在生物体和环境中降解并代谢为磷酸二烷基酯（DAPs），并且可以作为尿液中OP暴露的生物标记物存在于尿液中，其中磷酸二乙酯（DEP）是高暴露的代谢产物。流行病学和队列研究发现，DAP与内分泌激素失调有关，尤其是性激素失调和甲状腺激素失调，但尚无直接因果证据支持这些发现。我们的研究探索了长期暴露于DEP对成年雄性大鼠体内可达到的实际剂量内分泌激素和相关代谢指标的影响。结果表明，长期暴露于DEP可能导致大鼠血清中甲状腺相关激素紊乱，引起大鼠甲状腺功能亢进症状，还可能导致大鼠肝脏中甲状腺激素相关基因异常表达。但是，DEP暴露似乎并未影响大鼠血清性激素水平，精子发生或精子质量。通过计算机对接和分子动力学方法研究了DEP与甲状腺激素相关酶/蛋白质之间的分子相互作用。已经发现DEP可以与甲状腺激素的生物合成，血液运输，受体结合以及与代谢有关的酶/蛋白质强烈相互作用，从而干扰甲状腺激素的产生和信号调节。体内和计算机模拟实验表明，DEP可能是破坏甲状腺激素的潜在化学物质，因此，对于有机磷化学物质的暴露，我们需要更加谨慎和严格。版权所有©2019 The Authors。由Elsevier Ltd.发布。保留所有权利。