Abstract：
Azole fungicides are widely used chemicals in agriculture and medicine. Their antifungal activity involves inhibition of steroid biosynthesis via inhibition of several cytochrome p450 enzymes. Evidence is accumulating in fish species to suggest azole fungicides perturb multiple hormone signaling pathways. The objective of this review was to comprehensively review data for azole-mediated impacts on the teleost endocrine system. We emphasize aspects of azole-induced endocrine disruption in several fish species, with special focus on the hypothalamic-pituitary-gonadal (HPG), hypothalamus-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenal (HPA) axis. Histopathological, physiological, and molecular data suggest azole fungicides at environmentally relevant concentrations and above are endocrine disruptors in fish. Endocrine disruption has been well documented for some azoles (e.g., difenconazole, fadrozole, ketoconazole, tebuconazole, triadimefon), but there are little data for others (e.g., cyproconazole, expoxiconazole, imidazole, metoconazole, nocodazole) in fish, revealing a knowledge gap in our understanding of azole toxicity. Based upon literature, computational analyses of transcriptome responses revealed progesterone-mediated oocyte maturation, insulin signaling pathway, adrenergic signaling, and metabolism of angiotensinogen may be processes disrupted by azoles. However, hormonal regulation of the sympathetic nervous system and the cardiovascular system in response to azole exposure has yet to be investigated in fish. Recommendations for studies moving forward include focus on non-steroid endocrine pathways, mechanisms of neuroendocrine disruption, and transgenerational effects of azoles on fish. This critical review identifies knowledge gaps and future directions for environmental studies focused on the effects of azoles in aquatic species.
摘要：
唑类杀菌剂是农业和医药中广泛使用的化学品。它们的抗真菌活性涉及通过抑制几种细胞色素p450酶来抑制类固醇生物合成。在鱼类中积累的证据表明，唑类杀菌剂会干扰多种激素信号通路。这篇综述的目的是全面审查唑类介导的对硬骨鱼内分泌系统影响的数据。我们强调了几种鱼类中唑类药物引起的内分泌干扰的各个方面，特别关注下丘脑-垂体-性腺（HPG），下丘脑-垂体-甲状腺（HPT）和下丘脑-垂体-肾上腺（HPA）轴。组织病理学,生理,分子数据表明，与环境相关的浓度及以上的唑类杀菌剂是鱼类的内分泌干扰物。某些唑类药物的内分泌干扰已得到充分证明(例如，苯醚康唑,法德罗唑,酮康唑,戊唑醇,triadimefon),但其他人的数据很少(例如，环丙唑,expoxconazole,咪唑,美康唑,诺考达唑）在鱼类中，揭示了我们对唑类药物毒性理解的知识差距。根据文献,转录组反应的计算分析揭示了孕酮介导的卵母细胞成熟，胰岛素信号通路,肾上腺素能信号，血管紧张素原的代谢可能是被唑类药物破坏的过程。然而,尚未在鱼类中研究交感神经系统和心血管系统对唑类药物暴露的激素调节。对未来研究的建议包括关注非类固醇内分泌途径，神经内分泌紊乱的机制，以及唑类药物对鱼类的跨代效应。这篇重要的评论确定了知识空白和环境研究的未来方向，重点是唑类药物对水生物种的影响。
