Brown A R, Gunnarsson L, Kristiansson E, Tyler C R
Brixham Environmental Laboratory, AstraZeneca Safety, Health & Environment, Freshwater Quarry, Brixham, UK Biosciences, College of Life and Environmental Sciences, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter, Devon, UK.
Infectious Disease, Institute of Biomedicine, University of Gothenburg, Guldhedsgatan 10, 41346 Gothenburg, Sweden.
Philos Trans R Soc Lond B Biol Sci. 2014 Nov 19;369(1656). doi: 10.1098/rstb.2013.0576.
Fish represent the planet's most diverse group of vertebrates and they can be exposed to a wide range of pharmaceuticals. For practical reasons, extrapolation of pharmaceutical effects from 'model' species to other fish species is adopted in risk assessment. Here, we critically assess this approach. First, we show that between 65% and 86% of human drug targets are evolutionarily conserved in 12 diverse fish species. Focusing on nuclear steroid hormone receptors, we further show that the sequence of the ligand binding domain that plays a key role in drug potency is highly conserved, but there is variation between species. This variation for the oestrogen receptor, however, does not obviously account for observed differences in receptor activation. Taking the synthetic oestrogen ethinyloestradiol as a test case, and using life-table-response experiments, we demonstrate significant reductions in population growth in fathead minnow and medaka, but not zebrafish, for environmentally relevant exposures. This finding contrasts with zebrafish being ranked as more ecologically susceptible, according to two independent life-history analyses. We conclude that while most drug targets are conserved in fish, evolutionary divergence in drug-target activation, physiology, behaviour and ecological life history make it difficult to predict population-level effects. This justifies the conventional use of at least a 10× assessment factor in pharmaceutical risk assessment, to account for differences in species susceptibility.
鱼类是地球上脊椎动物中种类最多样化的群体，它们可能接触到各种各样的药物。出于实际原因，风险评估中采用了将药物效应从“模式”物种外推到其他鱼类物种的方法。在此，我们对这种方法进行了批判性评估。首先，我们发现人类药物靶点中有65%至86%在12种不同的鱼类物种中具有进化保守性。以核类固醇激素受体为重点，我们进一步表明，在药物效力中起关键作用的配体结合域序列高度保守，但物种之间存在差异。然而，雌激素受体的这种差异并不能明显解释观察到的受体激活差异。以合成雌激素乙炔雌二醇为例，通过生命表响应实验，我们证明，对于与环境相关的暴露水平，黑头呆鱼和青鳉的种群增长显著下降，但斑马鱼没有。根据两项独立的生活史分析，这一发现与斑马鱼被列为生态上更易受影响的物种形成了对比。我们得出结论，虽然大多数药物靶点在鱼类中是保守的，但药物靶点激活、生理、行为和生态生活史方面的进化差异使得难以预测种群水平的影响。这证明了在药物风险评估中常规使用至少10倍的评估因子是合理的，以考虑物种易感性的差异。
