Reversible photohydration in diene and triene steroids: A mechanism for unexpected persistence of unique, biologically active steroidal contaminants?

CBET 1335711 David Cwiertny爱荷华大学醋酸群勃龙（TBA）是一种高价值的合成代谢生长促进剂，广泛用于动物农业，但其代谢产物是水生生物中有效的内分泌干扰化合物。 最近，TBA代谢物的快速光转化，长期以来被认为是减轻其环境风险，被发现是可逆的表面沃茨在环境条件下。 这种前所未有的行为导致独特的昼夜循环和TBA代谢物的大量再生，其速率取决于温度和pH值，这意味着这些新出现的污染物在地表沃茨中存在未被认识到的持久性。 值得注意的是，可逆的光水合作用也出现在结构类似的化合物中，包括一些人类药物，这表明二烯酮和三烯酮类固醇可能代表了一类新的环境污染物，其行为混淆了几乎所有当前的预测命运模型和监管生态系统风险评估范式。 受这些发现的启发，本项目代表了二烯酮和三烯酮类固醇光转化的全面机制研究。PI假设，如果不评价光产物形成和长期稳定性，就无法准确评估这些类固醇的发生、归宿、运输和生态风险。 由于TBA代谢物的广泛使用和内分泌干扰的能力，本研究主要集中在TBA代谢物上，将（i）表征TBA代谢物光转化产物;（ii）确定促进能够恢复到母体结构或相关甾体类似物的亚稳态产物形成的环境因素;（iii）探索可逆的光水合是否可推广到其他二烯酮和三烯酮甾体和药物;和（iv）定量评估结构相似的甾体转化产物的生物活性的保守性。作为一类，二烯酮和三烯酮类固醇是作为性能增强剂的药物或抗炎药在治疗上使用的最有效的类固醇。包括在这类化合物中的是醋酸群勃龙，一种用作美国生产的绝大多数肉牛的生长促进剂的合成代谢类固醇，和地诺孕素，一种用作口服避孕药的孕酮，其效力是左炔诺孕酮的10倍（即，计划B）。 虽然这些化合物在阳光下容易降解，但这种光反应的产物是不稳定的，最终会分解或转化为产生它们的生物活性类固醇。因此，该项目将建立二烯酮和三烯酮类固醇作为一类新的环境污染物，其转化不一定会减少对生态系统健康的威胁，从而挑战我们作为一个社区评估和控制污染物带来的风险的基本范式。 总的来说，该项目的成果将有助于改善自然系统中二烯酮和三烯酮类固醇的发生，命运，运输和建模的评估，并为工程处理系统的优化提供见解，该系统旨在通过隔离或转化这种新兴的污染物来保护脆弱的水生生态系统。

CBET 1335711David CwiertnyUniversity of IowaTrenbolone acetate (TBA) is a high-value anabolic growth promoter used extensively in animal agriculture, yet its metabolites are potent endocrine disrupting compounds in aquatic organisms. Recently, the rapid phototransformation of TBA metabolites, long thought to mitigate their environmental risk, was found to be reversible in surface waters at ambient conditions. This unprecedented behavior results in unique diurnal cycling and substantial regeneration of TBA metabolites at rates that are temperature and pH dependent, implying unrecognized persistence for these emerging contaminants in surface waters. Notably, reversible photohydration also appears to occur for structurally analogous compounds, including some human pharmaceuticals, suggesting that dienone and trienone steroids may represent a new class of environmental contaminants whose behavior confounds nearly all current predictive fate models and regulatory ecosystem risk assessment paradigms. Motivated by these findings, this project represents a comprehensive mechanistic investigation of dienone and trienone steroid phototransformation. The PIs hypothesize that the occurrence, fate, transport and ecological risks of these steroids cannot be accurately assessed without evaluating photoproduct formation and long-term stability. Focusing efforts primarily on TBA metabolites due to their widespread use and capability for endocrine disruption, this study will (i) characterize TBA metabolite phototransformation products; (ii) determine environmental factors promoting the formation of metastable products capable of reversion to parent structures or related steroidal analogs; (iii) explore whether reversible photohydration is generalizable to other dienone and trienone steroids and pharmaceuticals; and (iv) assess quantitatively conservation of bioactivity for structurally similar steroidal transformation products. As a class, dienone and trienone steroids are among the most potent used therapeutically as pharmaceuticals or illicitly as performance enhancing agents. Included in this compound class are trenbolone acetate, an anabolic steroid used as a growth promoter for the overwhelming majority of beef cattle produced in the United States, and dienogest, a progestin used as an oral contraceptive that is 10 times as potent as levonorgestrel (i.e., Plan B). While these compounds readily degrade in sunlight, the products of this photoreaction are unstable and ultimately decompose or revert into the bioactive steroid from which they were generated. Thus, this project will establish dienone and trienone steroids as a new class of environmental contaminants whose transformations do not necessarily reduce threats to ecosystem health, thereby challenging fundamental paradigms by which we as a community assess and control the risk posed by contaminants. Collectively, outcomes of this project will facilitate the improved assessment of the occurrence, fate, transport, and modeling of dienone and trienone steroids in natural systems, and provide insights for optimization of engineered treatment systems designed to protect vulnerable aquatic ecosystems by sequestering or transforming this emerging contaminant class.