Abstract：
Numerous studies report active pharmaceutical compounds detected in both wastewater effluent and surface waters. Exposure to statin drugs in general, and atorvastatin in particular, is likely to be a concern. We hypothesized that chronic exposure to low concentrations of atorvastatin in water would result in an adverse effect on production of steroids regulating growth and development of the model amphibian Xenopus laevis. The FETAX assay was used to evaluate the effects of a range of doses of atorvastatin on developing embryos. A 60 day metamorphosis assay assessed the effects of aqueous atorvastatin exposure at environmentally concentrations on metamorphosing tadpoles. A 60 day chronic flow-through exposure evaluated the effects of chronic low concentrations of atorvastatin on adults. The purpose of the FETAX assay was to confirm that atorvastatin can reduce circulating cholesterol in X. laevis with a similar manner to that expected in humans. The results of the 60-day flow-through exposure on metamorphosing tadpoles showed significant evidence of altered cholesterol biosynthesis. The dose-dependent increase in cyp19a1 expression also indicated that the steroidogenesis pathway was affected. The RNAseq analysis confirmed that exposure to environmentally relevant concentrations of atorvastatin does cause significant alterations to global transcriptional profiles in a manner consistent with dysregulation of the cholesterol biosynthesis pathway, both through the downregulation of many genes involved in that pathway, but also in the impacts to other, related pathways. The qPCR data for both adult males and adult females indicated only slight changes in expression with the exception that hmgcr was significantly downregulated in males, and cyp3a4 expression was significantly downregulated in females. The data we present here indicated that chronic exposure to environmentally relevant concentrations of atorvastatin does have the potential to impact early life stage frogs, particularly by altering expression of genes involved in critical molecular pathways.
摘要：
许多研究报告了在废水和地表水中检测到的活性药物化合物。一般接触他汀类药物，尤其是阿托伐他汀，可能是一个令人担忧的问题。我们假设长期暴露于水中低浓度的阿托伐他汀会对调节两栖动物非洲爪狼模型生长和发育的类固醇的产生产生不利影响。使用FETAX测定来评估一系列剂量的阿托伐他汀对发育中的胚胎的影响。60天的变态试验评估了环境浓度的阿托伐他汀水溶液暴露对变态t的影响。60天的慢性流动暴露评估了慢性低浓度阿托伐他汀对成人的影响。FETAX测定的目的是确认阿托伐他汀可以降低X.laevis中的循环胆固醇,其方式与在人类中预期的方式相似。对变态t进行60天的流通暴露的结果表明，胆固醇生物合成发生了改变。cyp19a1表达的剂量依赖性增加也表明类固醇生成途径受到影响。RNAseq分析证实，暴露于环境相关浓度的阿托伐他汀确实会导致全局转录谱的显著改变，其方式与胆固醇生物合成途径的失调相一致。两者都是通过下调参与该途径的许多基因，而且对其他人的影响，相关途径。成年男性和成年女性的qPCR数据表明表达仅有轻微变化，除了hmgcr在男性中显著下调，cyp3a4在雌性中表达显著下调。我们在这里提供的数据表明，长期暴露于环境相关浓度的阿托伐他汀确实有可能影响早期生命阶段的青蛙。特别是通过改变参与关键分子途径的基因的表达。
