Arsenic Toxicology: Translating between Experimental Models and Human Pathology

Abstract

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.

The Effect of Chronic Arsenic Exposure in Zebrafish

“…The effects of long-term arsenic exposure, induced pathogenicity, and carcinogenicity have been investigated in multiple rodent models. 15 However, many experiments conducted with the rodent models have been jeopardized by several confounding factors. For instance, the metabolism of arsenic in rats is inconsistent with the human metabolism for the following reasons: (1) arsenic remains in the blood circulation of rats longer than that of humans; (2) arsenic is accumulated in erythrocytes of rats; (3) arsenic is methylated more extensively and excreted in the urine at a much slower rate in rats.…”

“…15 Currently, most studies using rodent models adopt a short-term exposure to mimic acute arsenic poisoning. However, the development of certain human disorders often requires years of arsenic exposure.…”

Mechanisms of action for arsenic in cardiovascular toxicity and implications for risk assessment

“…In a recent review article, States et al (2011) argued for a concept linking experimental observations to human pathology called "phenotypic anchoring" (2011). The fundamental concept of "phenotypic anchoring" is that specific alterations in gene expression due to specific environmental toxins is related to phenotypic alterations such as histopathologic or functional changes .…”

The Role of the Epigenome in Translating Neighborhood Disadvantage Into Health Disparities

“…Exposure to PAHs and PM 2.5 have modest effects on the global methylation of the promoter sequences of genes involved in cancer, cardiovascular, and respiratory diseases [38]. Exposure to air pollution is also associated with hypermethylation of candidate genes that play a role in the pathogenesis of asthma (e.g., the transcription factor interferon gamma) [39,40].…”