Academic journal article Environmental Health Perspectives

Arsenic Toxicology: Translating between Experimental Models and Human Pathology

Academic journal article Environmental Health Perspectives

Arsenic Toxicology: Translating between Experimental Models and Human Pathology

Article excerpt

BACKGROUND: 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.

OBJECTIVES: 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.

METHODS: 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.

DISCUSSION: 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.

CONCLUSIONS: 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.

KEY WORDS: arsenic, biomarkers, dosimetry, epigenetics, gene expression, phenotypic anchoring. Environ Health Perspect 119:1356-1363 (2011). http://dx.doi.org/10.1289/ehp.110344l [Online 17 June 2011]

Arsenic exposure via drinking water affects > 140 million people worldwide and causes cancer and bronchopulmonary, cardiovascular, and metabolic diseases and neuropathies. Various experimental models have been developed to understand how arsenic exposure causes these diverse disease outcomes. Translation of laboratory arsenic toxicology studies to human health is important but is complicated by inexact dose conversion between in vitro, murine, and human exposures and species-specific metabolic differences. Here, we discuss issues in dose conversion and potential means to translate findings in selected experimental model systems to an understanding of human arsenic toxicology. Phenotypic anchoring of results from model systems by tissue dosimetry, gene expression and epigenetic mark profiling, and tissue biomarker identification should promote development of a coherent picture of mechanisms of arsenic-induced human disease. We discuss research needs critical to progress in translation of experimental findings. We also highlight a human-specific disease end point and discuss advantages of invertebrate systems to address specific questions in a simpler background with fewer confounding factors.

Dose and Exposure Conversion

Data collected in human studies often include exposures but not doses. Urine and toenail arsenic are often used as indicators of body burden but are subject to wide individual variation with similar exposures. Dose conversion between human and murine exposures is a complicated issue, Calculating dose requires careful determination of amounts consumed and is rarely reported. Often, consumption estimates are based on data from published studies. However, water consumption can vary greatly in mice and is markedly different in different strains (Bachmanov et al. …

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