Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA.
Environ Health Perspect. 2011 Oct;119(10):1356-63. doi: 10.1289/ehp.1103441. Epub 2011 Jun 17.
Chronic arsenic exposure is a worldwide health problem. How arsenic exposure promotes a variety of diseases is poorly understood, and specific relationships between experimental and human exposures are not established. We propose phenotypic anchoring as a means to unify experimental observations and disease outcomes.
We examined the use of phenotypic anchors to translate experimental data to human pathology and investigated research needs for which phenotypic anchors need to be developed.
During a workshop, we discussed experimental systems investigating arsenic dose/exposure and phenotypic expression relationships and human disease responses to chronic arsenic exposure and identified knowledge gaps. In a literature review, we identified areas where data exist to support phenotypic anchoring of experimental results to pathologies from specific human exposures.
Disease outcome is likely dependent on cell-type-specific responses and interaction with individual genetics, other toxicants, and infectious agents. Potential phenotypic anchors include target tissue dosimetry, gene expression and epigenetic profiles, and tissue biomarkers.
Translation to human populations requires more extensive profiling of human samples along with high-quality dosimetry. Anchoring results by gene expression and epigenetic profiling has great promise for data unification. Genetic predisposition of individuals affects disease outcome. Interactions with infectious agents, particularly viruses, may explain some species-specific differences between human pathologies and experimental animal pathologies. Invertebrate systems amenable to genetic manipulation offer potential for elaborating impacts of specific biochemical pathways. Anchoring experimental results to specific human exposures will accelerate understanding of mechanisms of arsenic-induced human disease.
慢性砷暴露是一个全球性的健康问题。砷暴露如何促进各种疾病尚不清楚，也没有建立实验暴露与人类暴露之间的具体关系。我们提出表型锚定作为将实验观察结果与疾病结果统一起来的一种方法。
我们研究了使用表型锚定将实验数据转化为人体病理学，并探讨了需要开发表型锚定的研究需求。
在一次研讨会上，我们讨论了研究砷剂量/暴露和表型表达关系的实验系统，以及人类对慢性砷暴露的疾病反应，并确定了知识差距。在文献综述中，我们确定了存在数据的领域，这些数据可以支持将实验结果与特定人类暴露引起的病理学进行表型锚定。
疾病结果可能取决于细胞类型特异性反应以及与个体遗传、其他毒物和感染因子的相互作用。潜在的表型锚包括靶组织剂量测定、基因表达和表观遗传谱以及组织生物标志物。
向人类群体的转化需要对人类样本进行更广泛的分析，并进行高质量的剂量测定。通过基因表达和表观遗传谱进行结果锚定具有数据统一的巨大潜力。个体的遗传易感性影响疾病结果。与感染因子（特别是病毒）的相互作用可能解释了人类病理学和实验动物病理学之间一些物种特异性差异。易于遗传操作的无脊椎动物系统为详细阐述特定生化途径的影响提供了潜力。将实验结果与特定的人类暴露相锚定将加速对砷诱导的人类疾病机制的理解。
