Perturbation of Defense Pathways by Low-Dose Arsenic Exposure in Zebrafish Embryos

Abstract

BackgroundExposure to arsenic is a critical risk factor in the complex interplay among genetics, the environment, and human disease. Despite the potential for in utero exposure, the mechanism of arsenic action on vertebrate development and disease is unknown.ObjectivesThe objective of this study was to identify genes and gene networks perturbed by arsenic during development in order to enhance understanding of the molecular mechanisms of arsenic action.MethodsWe exposed zebrafish embryos at 0.25–1.25 hr postfertilization to 10 or 100 ppb arsenic for 24 or 48 hr. We then used total RNA to interrogate genome microarrays and to test levels of gene expression changes by quantitative real-time polymerase chain reaction (QPCR). Computational analysis was used to identify gene expression networks perturbed by arsenic during vertebrate development.ResultsWe identified a set of 99 genes that responded to low levels of arsenic. Nineteen of these genes were predicted to function in a common regulatory network that was significantly associated with immune response and cancer (p < 10−41). Arsenic-mediated expression changes were validated by QPCR.ConclusionsIn this study we demonstrated that arsenic significantly down-regulates expression levels of multiple genes potentially critical for regulating the establishment of an immune response. The data also provide molecular evidence consistent with phenotypic observations reported in other model systems. Additional mechanistic studies will help explain molecular events regulating early stages of the immune system and long-term consequences of arsenic-mediated perturbation of this system during development.

Immunomodulatory effect of arsenic on cytokine and HSP gene expression in Labeo rohita fingerlings

“…In several exposure studies different doses of arsenic for varying durations of time have been used by different research groups to see the wide spectrum of detrimental impacts of the toxicant eg. zebrafishes were exposed to 100 ppb [21] or 15 ppm Table 1 Primer sets used for semi-quantitative RT-PCR analysis of immune genes and HSP genes in Labeo rohita. [30] b-actin…”

“…It has been reported that arsenic exposure causes perturbation of defence systems in zebrafish [21,22], Clarius batrachus [23,24] and Sparus aurata [25]. However, reports are meager on commercially important species like the Indian major carps (IMCs) Catla catla, L. rohita, and Cirrhinus mrigala which are the main aquacultured species in the Indian subcontinent and contribute a major chunk (~87%) of the total aquaculture production [26].…”

Developmental toxicity screening in zebrafish

“…Jin et al (2011) showed that cypermethrin, which is a synthetic pyrethroid used as an insecticide both in agriculture and in consumer products, caused innate immune system disruption in zebrafish during the embryo stage (Table 11). Also, arsenic in low doses (10-100 ppb) has been shown to affect expression of genes associated with immune response (Mattingly et al, 2009). Scoring biomarkers of the innate immune system, several endocrine disruptors including 17b-estradiol, 17a-ethynyestradiol, permethrin, atrazine, and nonylphenol have been found to induce immunotoxicity (Jin et al, 2010).…”

A novel approach to analyze gene expression data demonstrates that the ΔF508 mutation in CFTR downregulates the antigen presentation pathway

“…Starting with the assumption that the ⌬F508 mutation causes consistent gene expression differences unobserved by the four studies, we reanalyzed the data using a methodology recently developed by our group (15,26,27,29). The exploratory gene array approach identifies biological patterns using the process shown in Fig.…”

“…First, it reviews published gene array studies designed to identify genes modified by the CF genotype. Second, it reanalyzes four publically available gene array data sets using a recently developed approach (15,26,27,29,37). We hypothesized that a uniform analysis might identify genes and pathways common to the studies chosen for analysis that might shed light on the CF disease process, and that these observations would have major prognostic and therapeutic implications.…”