Kumar Konidala Kranthi, Bommu Umadevi, Pabbaraju Neeraja
Department of Zoology, Sri Venkateswara University, Tirupati, 517502 AP, India.
Environ Sci Pollut Res Int. 2022 Sep;29(43):65806-65825. doi: 10.1007/s11356-022-20443-3. Epub 2022 Apr 30.
A myriad of tobacco-associated chemicals may have possibilities to developmental/reproductive axis and endocrine-disruption impacts. Mostly they breach the biotransformation of cholesterol in mitochondria by interfering with steroidogenic pathway genes, prompting to adverse effects in steroid biosynthesis; however, studies are scanty. The quantitative structure-activity relationship (QSAR) modeling and comparative docking strategies were used to understand structural features of dataset compounds that influence developmental/reproductive toxicity and estrogen and androgen receptor-binding abilities, and to predict binding levels of toxicants with steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (CYP11A1) active sites. Developed QSAR models presented good robustness and predictive ability that were determined from the applicability domain and, clustering and classification of chemicals by performing self-organizing maps. Accordingly, the exorbitant amount of polycyclic aromatic hydrocarbons (PAHs) and a limited number of other chemicals including N-nitrosamines and nicotine was represented as potential developmental/reproductive toxicants as well as estrogen and androgen receptor binders. From the docking analysis, hydrogen bonding, nonpolar, atomic π-stacking, and π-cation interactions were found between PAHs (bay and fjord structural pockets) and functional hotspot residues of StAR and CYP11A1, which strengthened the subtle structural changes at domains. These govern barrier effects to cholesterol binding and/or locking cholesterol to complicate its ejection from the Ω1 loop of StAR, and further mitigates steroid biosynthesis through cholesterol by CYP11A1; therefore, they are presumably considered as block-cluster mechanisms. These outcomes are significant to be hopeful to estimate developmental/reproductive toxicity and endocrine-disruption activities of other environmental pollutants, and could be useful for further assessment to discover binding mechanisms of PAHs with other steroidogenesis pathway genes.
大量与烟草相关的化学物质可能会对发育/生殖轴和内分泌干扰产生影响。它们大多通过干扰类固醇生成途径基因破坏线粒体中胆固醇的生物转化，从而对类固醇生物合成产生不利影响；然而，相关研究较少。使用定量构效关系（QSAR）建模和比较对接策略来了解影响发育/生殖毒性以及雌激素和雄激素受体结合能力的数据集化合物的结构特征，并预测毒物与类固醇生成急性调节蛋白（StAR）和胆固醇侧链裂解酶（CYP11A1）活性位点的结合水平。所开发的QSAR模型具有良好的稳健性和预测能力，这是通过适用性域以及通过执行自组织映射对化学物质进行聚类和分类来确定的。因此，大量的多环芳烃（PAHs）以及包括N - 亚硝胺和尼古丁在内的其他有限数量的化学物质被认为是潜在的发育/生殖毒物以及雌激素和雄激素受体结合剂。通过对接分析发现，PAHs（海湾和峡湾结构口袋）与StAR和CYP11A1的功能性热点残基之间存在氢键、非极性、原子π堆积和π - 阳离子相互作用，这加强了结构域的细微结构变化。这些作用对胆固醇结合产生屏障效应和/或将胆固醇锁定，使其从StAR的Ω1环排出变得复杂，并进一步通过CYP11A1减轻胆固醇介导的类固醇生物合成；因此，它们可能被视为阻断 - 聚集机制。这些结果对于估计其他环境污染物的发育/生殖毒性和内分泌干扰活性具有重要意义，并且可能有助于进一步评估以发现PAHs与其他类固醇生成途径基因的结合机制。
