Human therapeutic plasma levels of the selective serotonin reuptake inhibitor (SSRI) sertraline decrease serotonin reuptake transporter binding and shelter-seeking behavior in adult male fathead minnows.
Human therapeutic plasma levels of the selective serotonin reuptake inhibitor (SSRI) sertraline decrease serotonin reuptake transporter binding and shelter-seeking behavior in adult male fathead minnows.
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DOI：
10.1021/es204164b
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发表时间：
2012-02-21
影响因子：
11.4
通讯作者：
Brooks BW
中科院分区：
文献类型：
--
作者：
Valenti TW;Gould GG;Berninger JP;Connors KA;Keele NB;Prosser KN;Brooks BW
选择性5-羟色胺再摄取抑制剂（SSRIs）代表了一类药物，以前在水生生态系统中的报告。SSRIs被设计用于治疗人类的抑郁症和其他疾病，但被认为会对水生生物产生各种影响，从神经内分泌干扰到行为干扰。然而，与SSRI目标和生态重要的行为反应的鱼类的机械反应之间的关系的理解仍然是难以捉摸的。在此，连接不良后果途径（AOP）模型与内部剂量代表潜在的方法，为发展的理解药物风险的水生生物。我们选择舍曲林作为模型SSRI的28天的研究与成年男性黑头呆鱼。血清素再摄取转运蛋白（SERT）的结合活性（先前在哺乳动物和鱼类模型中证明对舍曲林暴露有反应）被选为与治疗活性相关的终点。使用数字跟踪软件监测寻求庇护的行为，以诊断行为异常。当考虑pH值对电离和log D的影响时，从外部暴露浓度准确地模拟了舍曲林超过人类治疗剂量的鱼血浆水平。我们观察到，当鱼血浆水平超过人类治疗阈值时，在治疗靶点（SERT）和寻求庇护行为的结合率在统计学上显著降低。这样的观察结果突出了耦合生理为基础的药代动力学建模和AOP方法的优势，并建议内部剂量测定应进行监测，以促进对SSRI暴露于水生脊椎动物的生态后果的理解。
Selective serotonin reuptake inhibitors (SSRIs) represent a class of pharmaceuticals previously reported in aquatic ecosystems. SSRIs are designed to treat depression and other disorders in humans, but are recognized to elicit a variety of effects on aquatic organisms, ranging from neuroendocrine disruption to behavioral perturbations. However, an understanding of the relationships among mechanistic responses associated with SSRI targets and ecologically important behavioral responses of fish remains elusive. Herein, linking Adverse Outcomes Pathways (AOP) models with internal dosimetry represent potential approaches for developing an understanding of pharmaceutical risks to aquatic life. We selected sertraline as a model SSRI for a 28-d study with adult male fathead minnows. Binding activity of the serotonin reuptake transporter (SERT), previously demonstrated in mammals and fish models to respond to sertraline exposure, was selected as an endpoint associated with therapeutic activity. Shelter-seeking behavior was monitored using digital tracking software to diagnose behavioral abnormalities. Fish plasma levels of sertraline exceeding human therapeutic doses were accurately modeled from external exposure concentrations when pH influences on ionization and log D were considered. We observed statistically significant decreases in binding at the therapeutic target (SERT) and shelter-seeking behavior when fish plasma levels exceeded human therapeutic thresholds. Such observations highlights the strengths of coupling physiologically based pharmacokinetic modeling and AOP approaches and suggest that internal dosimetry should be monitored to advance an understanding of the ecological consequences of SSRI exposure to aquatic vertebrates.
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影响因子：
2.7
作者：
Egan, Rupert J.;Bergner, Carisa L.;Hart, Peter C.;Cachat, Jonathan M.;Canavello, Peter R.;Elegante, Marco F.;Elkhayat, Salem I.;Bartels, Brett K.;Tien, Anna K.;Tien, David H.;Mohnot, Sopan;Beeson, Esther;Glasgow, Eric;Amri, Hakima;Zukowska, Zofia;Kalueff, Allan V.
通讯作者：
Kalueff, Allan V.
影响因子：
4.5
作者：
Fitzsimmons, PN;Fernandez, JD;Nichols, JW
通讯作者：
Nichols, JW
影响因子：
4.1
作者：
Chu, Shaogang;Metcalfe, Chris D.
通讯作者：
Metcalfe, Chris D.
影响因子：
11.4
作者：
Gunnarsson, Lina;Jauhiainen, Alexandra;Larsson, D. G. Joakim
通讯作者：
Larsson, D. G. Joakim
DOI：
10.3109/10799898809049009
发表时间：
1988-01-01
期刊：
JOURNAL OF RECEPTOR RESEARCH
影响因子：
--
作者：
DIETL, M;PALACIOS, JM
通讯作者：
PALACIOS, JM