School of Biosciences, University of Birmingham , Edgbaston, Birmingham B15 2TT, United Kingdom.
Environ Sci Technol. 2011 Apr 15;45(8):3759-67. doi: 10.1021/es103814d. Epub 2011 Mar 16.
The ability of targeted and nontargeted metabolomics to discover chronic ecotoxicological effects is largely unexplored. Fenitrothion, an organophosphate pesticide, is categorized as a "red list" pollutant, being particularly hazardous to aquatic life. It acts primarily as a cholinesterase inhibitor, but evidence suggests it can also act as an androgen receptor antagonist. Whole-organism fenitrothion-induced toxicity is well-established, but information regarding target and off-target molecular toxicities is limited. Here we study the molecular responses of male roach ( Rutilus rutilus ) exposed to fenitrothion, including environmentally realistic concentrations, for 28 days. Acetylcholine was assessed in brain; steroid metabolism was measured in testes and plasma; and NMR and mass spectrometry-based metabolomics were conducted on testes and liver to discover off-target toxicity. O-demethylation was confirmed as a major route of pesticide degradation. Fenitrothion significantly depleted acetylcholine, confirming its primary mode of action, and 11-ketotestosterone in plasma and cortisone in testes, showing disruption of steroid metabolism. Metabolomics revealed significant perturbations to the hepatic phosphagen system and previously undocumented effects on phenylalanine metabolism in liver and testes. On the basis of several unexpected molecular responses that were opposite to the anticipated acute toxicity, we propose that chronic pesticide exposure induces an adapting phenotype in roach, which may have considerable implications for interpreting molecular biomarker responses in field-sampled fish.
靶向和非靶向代谢组学发现慢性生态毒理学效应的能力在很大程度上尚未得到探索。 毒死蜱是一种有机磷农药,被归类为“红色清单”污染物,对水生生物特别危险。 它主要作为胆碱酯酶抑制剂起作用,但有证据表明它也可以作为雄激素受体拮抗剂。 全生物体毒死蜱诱导的毒性已经得到充分证实,但关于靶标和非靶标分子毒性的信息有限。 在这里,我们研究了雄性鳊鱼( Rutilus rutilus )暴露于毒死蜱后的分子反应,包括在 28 天内暴露于环境现实浓度。 在大脑中评估了乙酰胆碱; 在睾丸和血浆中测量了类固醇代谢; 在睾丸和肝脏上进行了基于 NMR 和质谱的代谢组学研究,以发现非靶标毒性。 O-脱甲基化被确认为农药降解的主要途径。 毒死蜱显著耗尽了乙酰胆碱,证实了其主要作用模式,以及血浆中的 11-酮睾酮和睾丸中的皮质酮,表明类固醇代谢受到干扰。 代谢组学揭示了肝脏磷酸原系统的显著扰动,以及以前在肝脏和睾丸中未记录到的苯丙氨酸代谢的影响。 基于几种与预期急性毒性相反的意外分子反应,我们提出慢性农药暴露会诱导鳊鱼产生适应表型,这可能对解释现场采样鱼类的分子生物标志物反应具有重要意义。