Propranolol is a heavily prescribed, nonspecific beta-adrenoceptor (bAR) antagonist frequently found in wastewater effluents, prompting concern over its potential to adversely affect exposed organisms. In the present study, the transcriptional responses of 4, 5, and 6 days postfertilization (dpf) ±1 h fathead minnow, exposed for 6, 24, or 48 h to 0.66 or 3.3 mg/L (nominal) propranolol were characterized using RNA sequencing. The number of differentially expressed genes (DEGs) was used as an estimate of sensitivity. A trend toward increased sensitivity with age was observed; fish >7 dpf at the end of exposure were particularly sensitive to propranolol. The DEGs largely overlapped among treatment groups, suggesting a highly consistent response that was independent of age. Cluster analysis was performed using normalized count data for unexposed and propranolol-exposed fish. Control fish clustered tightly by age, with fish ≥7 dpf clustering away from younger fish, reflecting developmental differences. When clustering was conducted using exposed fish, in cases where propranolol induced a minimal or no transcriptional response, the results mirrored those of the control fish and did not appreciably cluster by treatment. In treatment groups that displayed a more robust transcriptional response, the effects of propranolol were evident; however, fish <7 dpf clustered away from older fish, despite having similar numbers of DEGs. Increased sensitivity at 7 dpf coincided with developmental milestones with the potential to alter propranolol pharmacokinetics or pharmacodynamics, such as the onset of exogenous feeding and gill functionality as well as increased systemic expression of bAR. These results may have broader implications because toxicity testing often utilizes fish <4 dpf, prior to the onset of these potentially important developmental milestones, which may result in an underestimation of risk for some chemicals. Environ Toxicol Chem 2024;43:807–820. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

中文翻译：

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年龄和暴露时间对生命早期黑头鲦鱼 (Pimephales promelas) 对水性普萘洛尔暴露敏感性的影响

普萘洛尔是一种处方较多的非特异性 β-肾上腺素能受体 (bAR) 拮抗剂，常见于废水中，引起人们对其对暴露生物体产生不利影响的可能性的担忧。在本研究中，使用 RNA 表征受精后 4、5 和 6 天 (dpf) ±1 小时黑头鲦鱼暴露于 0.66 或 3.3 mg/L（标称）普萘洛尔 6、24 或 48 小时的转录反应测序。差异表达基因（DEG）的数量被用作敏感性的估计。观察到随着年龄的增长敏感性增加的趋势；暴露结束时> 7 dpf 的鱼对普萘洛尔特别敏感。治疗组之间的 DEG 很大程度上重叠，表明与年龄无关的高度一致的反应。使用未暴露和普萘洛尔暴露的鱼的归一化计数数据进行聚类分析。控制鱼按年龄紧密聚集，≥7 dpf 的鱼远离较年轻的鱼聚集，反映发育差异。当使用暴露的鱼进行聚类时，在普萘洛尔诱导最小转录反应或不诱导转录反应的情况下，结果与对照鱼的结果相似，并且通过处理没有明显聚类。在表现出更强的转录反应的治疗组中，普萘洛尔的作用是明显的。然而，尽管 DEG 数量相似，但 <7 dpf 的鱼远离较老的鱼。 7 dpf 时敏感性的增加与具有改变普萘洛尔药代动力学或药效学潜力的发育里程碑相一致，例如外源摄食和鳃功能的开始以及 bAR 的全身表达增加。这些结果可能具有更广泛的影响，因为毒性测试通常在这些潜在的重要发育里程碑出现之前使用 <4 dpf 的鱼，这可能会导致低估某些化学品的风险。环境毒理学2024；43：807–820。 2023 年出版。本文是美国政府的作品，在美国属于公共领域。