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

CBET 1335711David Cwiertny爱荷华州大学特伦波隆(TBA)是一种在动物养殖中广泛使用的高价值合成代谢促进剂，但其代谢产物是水生生物中强有力的内分泌干扰化合物。最近，TBA代谢物的快速光转化被发现在环境条件下在地表水中是可逆的，长期以来一直被认为可以减轻其环境风险。这种史无前例的行为导致TBA代谢物以依赖于温度和pH的速度进行独特的昼夜循环和大量再生，这意味着这些新出现的污染物在地表水中存在无法识别的持久性。值得注意的是，结构相似的化合物，包括一些人类药物，似乎也发生了可逆光水化作用，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，其行为与几乎所有当前预测命运的模型和调控生态系统风险评估范例相混淆。在这些发现的推动下，该项目对二烯酮和三烯酮类固醇的光转化进行了全面的机理研究。PIs假设，如果不评估光产物的形成和长期稳定性，就无法准确评估这些类固醇的发生、命运、运输和生态风险。这项研究主要关注TBA代谢物，因为它们的广泛使用和破坏内分泌的能力，本研究将(I)表征TBA代谢物光转化产物；(Ii)确定促进形成能够回复到母体结构或相关类固醇类似物的亚稳态产物的环境因素；(Iii)探索可逆光水合作用是否适用于其他二烯酮和三烯酮类固醇和药物；以及(Iv)定量评估结构相似的类固醇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最有效的治疗药物或非法作为业绩增强剂。这类化合物包括醋酸曲诺酮，一种被用作美国生产的绝大多数肉牛的生长促进剂的合成类固醇，以及Dienogest，一种用作口服避孕药的黄体酮，其效力是左旋诺孕酮的10倍(即B计划)。虽然这些化合物在阳光下很容易降解，但这种光反应的产物是不稳定的，最终会分解或还原为产生它们的生物活性类固醇。因此，该项目将把二烯酮和三烯酮类固醇确立为一类新的环境污染物，其转化不一定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构成的风险的基本范式。总而言之，该项目的成果将有助于改进对二烯酮和三烯酮类固醇在自然系统中的发生、去向、迁移和建模的评估，并为优化工程处理系统提供见解，这些系统旨在通过隔离或转化这种新出现的污染物类别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.