Interactions of natural and synthetic compounds with steroidogenic enzymes and sex hormone receptor signalling

天然和合成化合物与类固醇生成酶和性激素受体信号传导的相互作用

• 批准号: RGPIN-2018-05271
• 负责人: Sanderson, Thomas
• 金额: $ 2.62万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=664242
• 关键词: Interactions; natural; synthetic; compounds; steroidogenic

BACKGROUND: Society is increasing concerned that chemicals in their environment may disrupt endocrine processes, potentially resulting in reproductive problems, certain cancers and other toxicities related to sexual differentiation, growth and development in humans and wildlife. My NSERC programme aims to identify 'emerging' pesticides, medications and natural compounds that interfere with steroid synthesis. Aromatase (CYP19) and steroid 5-alpha-reductase (SRD5A) are of particular interest as they are key to producing the most potent estrogens and androgens, 17β-estradiol and dihydrotestosterone, and are involved in various endocrine pathologies. In humans, aromatase is expressed in numerous tissues under the control of at least 10 alternate promoters; this unlike non-primates where aromatase is expressed in gonads and brain only. Thus, the promoter-specific disruption of aromatase by environmental chemicals can have widely differing effects in humans that would be missed in laboratory animals. In wildlife, steroidogenesis is difficult to study because experimental animals are rarely available. However, we are developing innovative cell-based systems designed to mimic in vitro, a physiological environment, that is relevant for humans and wildlife in vivo. THEMES: My NSERC programme has 3 main themes: (1) identify the structural requirements of natural or synthetic chemicals that enable them to interfere with the function of steroidogenic enzymes; (2) elucidate cellular mechanisms involved in inhibition/induction of steroidogenesis and determine effects on estrogen and androgen receptor-mediated signalling in cell-based bioassays; (3) develop physiologically relevant cell-based models to study chemical endocrine disruption in humans and wildlife, focusing on 2-D and 3-D co-culture systems. SIGNIFICANCE: My NSERC programme is expected to have several impacts. Theme 1 will focus on emerging contaminants to which humans and wildlife are increasingly exposed and will identify those of concern as endocrine disrupters and in need of further study. A mechanism-based structure-activity analysis will help identify novel endocrine disrupters to be prioritized for testing based on molecular structure. Theme 2 will help us better understand how chemicals alter cell signalling pathways to disrupt the gene expression of steroidogenic enzymes. The interaction of emerging pesticides and natural compounds with the tissue-specific regulation of aromatase in humans will provide fundamental knowledge on sex-differences in how our endocrine system reacts to chemical exposures in our environment. Theme 3 will provide physiologically and toxicologically relevant test systems for the mechanistic study of (novel) endocrine disrupting chemicals and which will refine, reduce or may replace the need for animal experiments.

背景：社会越来越关注环境中的化学物质可能扰乱内分泌过程，可能导致生殖问题、某些癌症和其他与人类和野生动物的性别分化、生长和发育有关的毒性。我的NSERC项目旨在识别干扰类固醇合成的“新兴”杀虫剂、药物和天然化合物。芳香化酶（CYP19）和类固醇5- α还原酶（SRD5A）是产生最有效的雌激素和雄激素，17β-雌二醇和二氢睾酮的关键，并参与各种内分泌病理。在人类中，芳香化酶在至少10个交替启动子的控制下在许多组织中表达；这与非灵长类动物不同，芳香酶只在性腺和大脑中表达。因此，环境化学物质对芳香化酶的启动子特异性破坏可以对人类产生广泛不同的影响，而这些影响在实验室动物中可能会被忽略。在野生动物中，类固醇的发生很难研究，因为实验动物很少。然而，我们正在开发创新的基于细胞的系统，旨在模拟体外的生理环境，这与人类和野生动物在体内有关。主题：我的NSERC项目有三个主要主题：(1)确定天然或合成化学物质的结构要求，使它们能够干扰类固醇酶的功能；(2)阐明参与抑制/诱导甾体生成的细胞机制，并在基于细胞的生物测定中确定对雌激素和雄激素受体介导的信号传导的影响；(3)建立基于生理相关细胞的模型，研究人类和野生动物的化学内分泌干扰，重点关注二维和三维共培养系统。意义：我的NSERC项目预计会产生几个影响。主题1将侧重于人类和野生动物越来越多地接触到的新出现的污染物，并将确定值得关注的内分泌干扰物和需要进一步研究的污染物。基于机制的结构-活性分析将有助于识别基于分子结构优先进行测试的新型内分泌干扰物。主题2将帮助我们更好地理解化学物质如何改变细胞信号通路，从而破坏类固醇生成酶的基因表达。新出现的农药和天然化合物与人体芳香化酶的组织特异性调节的相互作用将为我们的内分泌系统如何对环境中的化学物质暴露作出反应的性别差异提供基础知识。主题3将为（新型）内分泌干扰化学品的机理研究提供生理学和毒理学相关的测试系统，并将改进、减少或可能取代对动物实验的需求。