Ecotoxicology and Wildlife Health Division, Wildlife and Landscape Science Directorate, Environment and Climate Change Canada, National Wildlife Research Centre, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1A 0H3, Canada.
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Haidian District, No. 18, Shuangqing Road, Beijing, 100085, PR China.
Chem Biol Interact. 2024 Aug 1;398:111095. doi: 10.1016/j.cbi.2024.111095. Epub 2024 Jun 4.
It is established that organophosphorus pesticide (OPP) toxicity results from modification of amino acids in active sites of target proteins. OPPs can also modify unrelated target proteins such as histones and such covalent histone modifications can alter DNA-binding properties and lead to aberrant gene expression. In the present study, we report on non-enzymatic covalent modifications of calf thymus histones adducted to selected OPPs and organophosphate flame retardants (OPFRs) in vitro using a bottom-up proteomics method approach. Histones were not found to form detectable adducts with the two tested OPFRs but were avidly modified by a few of the seven OPPs that were tested in vitro. Dimethyl phosphate (or diethyl phosphate) adducts were identified on Tyr, Lys and Ser residues. Most of the dialkyl phosphate adducts were identified on Tyr residues. Methyl and ethyl modified histones were also detected. Eleven amino residues in histones showed non-enzymatic covalent methylation by exposure of dichlorvos and malathion. Our bottom-up proteomics approach showing histone-OPP adduct formation warrants future studies on the underlying mechanism of chronic illness from exposure to OPPs.
研究证实，有机磷农药（OPP）毒性是由于靶蛋白活性部位氨基酸的修饰所致。OPP 还可以修饰不相关的靶蛋白，如组蛋白，这种共价组蛋白修饰可以改变 DNA 结合特性，并导致异常基因表达。在本研究中，我们使用一种从下到上的蛋白质组学方法，报告了选定的 OPP 和有机磷阻燃剂（OPFR）在体外对小牛胸腺组蛋白的非酶促共价修饰。研究未发现组蛋白与两种测试的 OPFR 形成可检测的加合物，但在体外测试的七种 OPP 中有几种能够强烈修饰组蛋白。在 Tyr、Lys 和 Ser 残基上鉴定出了二甲基磷酸（或二乙基磷酸）加合物。大多数二烷基磷酸加合物在 Tyr 残基上被鉴定出来。还检测到甲基和乙基修饰的组蛋白。暴露于敌敌畏和马拉硫磷会导致 11 个组蛋白氨基酸发生非酶促甲基化。我们的从下到上的蛋白质组学方法显示了组蛋白-OPP 加合物的形成，这为未来研究接触 OPP 引起的慢性疾病的潜在机制提供了依据。
