Transcriptome kinetics of arsenic-induced adaptive response in zebrafish liver

Abstract

-Arsenic is a prominent environmental toxicant and carcinogen; however, its molecular mechanism of toxicity and carcinogenicity remains poorly understood. In this study, we performed microarray-based expression profiling on liver of zebrafish exposed to 15 parts/million (ppm) arsenic [As(V)] for 8 -96 h to identify global transcriptional changes and biological networks involved in arsenic-induced adaptive responses in vivo. We found that there was an increase of transcriptional activity associated with metabolism, especially for biosyntheses, membrane transporter activities, cytoplasm, and endoplasmic reticulum in the 96 h of arsenic treatment, while transcriptional programs for proteins in catabolism, energy derivation, and stress response remained active throughout the arsenic treatment. Many differentially expressed genes encoding proteins involved in heat shock proteins, DNA damage/repair, antioxidant activity, hypoxia induction, iron homeostasis, arsenic metabolism, and ubiquitin-dependent protein degradation were identified, suggesting strongly that DNA and protein damage as a result of arsenic metabolism and oxidative stress caused major cellular injury. These findings were comparable with those reported in mammalian systems, suggesting that the zebrafish liver coupled with the available microarray technology present an excellent in vivo toxicogenomic model for investigating arsenic toxicity. We proposed an in vivo, acute arsenic-induced adaptive response model of the zebrafish liver illustrating the relevance of many transcriptional activities that provide both global and specific information of a coordinated adaptive response to arsenic in the liver. microarray expression profiling; arsenic toxicity; oxidative stress; fish toxicogenomics ARSENIC IS AN IMPORTANT and ubiquitous environmental toxicant, and the risk of arsenic poisoning in humans is a public health issue worldwide (1,23,27,46,54). In addition, arsenic is classified as a human carcinogen based on several epidemiological studies showing an association of arsenic exposure with cancers in lung, bladder, kidney, and liver (33, 54). Aside from cancers, arsenic ingestion is also associated with other human diseases such as blackfoot disease, atherosclerosis, hypertension, diabetes mellitus, skin lesions, and liver injury (19,20,37,54,62). Despite these findings and the fact that arsenic is the most extensively studied of the metals and metalloids in drinking water, the molecular mechanisms of arsenic toxicity and carcinogenicity are poorly understood (34,46). This is partly due to the difficulty of inducing cancer with arsenic in animal models and the complex effects induced by arsenic through a variety of mechanisms that influence numerous signal transduction pathways, as these effects vary depending on cell type, dosage, and form of arsenic used (7, 60). Thus many different modes of action have been proposed, and these include both genotoxic and nongenotoxic effects (33,34,46). Some of the genotoxic effects include induction of chromosomal abnor...

Intracellular Arsenic Speciation and Quantification in Human Urothelial and Hepatic Cells

“…Protein degradation is predominantly mediated by the proteasomes but can also take place in lysosomes, especially during turnover of membrane proteins (Clague & Urbé, 2010). An increased turnover of arsenic-bound proteins is in agreement with the evidence of the catabolism of arsenic-induced improperly folded or damaged proteins via the ubiquitindependent protein degradation pathway in zebrafish liver (Lam et al, 2006). Several studies report that protein ubiquitination not only targets protein degradation using the proteasome pathway but also the lysosomal pathway (Marques et al, 2004;Barriere et al;, Shenoy et al, 2008Arancibia-Cárcamo et al, 2009).…”

Environmental OMICS: Current Status and Future Directions

“…It is found ubiquitously in our environment including drinking water, foods, soil, and airborne particles, and there is a generally well-accepted doseresponse relationship between arsenic ingestion and cancer incidence [34,35]. Microarray-based expression profiling of the livers of zebrafish exposed to arsenic revealed global transcriptional changes and suggested that DNA and protein damages due to arsenic metabolism and the arsenic-induced oxidative stress are the major causes of cellular injuries observed in the liver [36]. Many genes encoding proteins in-volved in DNA damage/repair, antioxidant activity, hypoxia induction, iron homeostasis, arsenic metabolism, heat shock proteins, and ubiquitin-dependent protein degradation were found to be differentially expressed [36].…”

“…Microarray-based expression profiling of the livers of zebrafish exposed to arsenic revealed global transcriptional changes and suggested that DNA and protein damages due to arsenic metabolism and the arsenic-induced oxidative stress are the major causes of cellular injuries observed in the liver [36]. Many genes encoding proteins in-volved in DNA damage/repair, antioxidant activity, hypoxia induction, iron homeostasis, arsenic metabolism, heat shock proteins, and ubiquitin-dependent protein degradation were found to be differentially expressed [36]. cDNA microarray and enzyme-linked immunosorbent assays were also used to identify genes involved in arsenic-associated atherosclerosis [37].…”

MARCADORES MITOCONDRIALES DE ESTRÉS OXIDATIVO Y LIPOTOXICIDAD EN DORADA (Sparus aurata)

“…In any case, the hepatic production of GRP75 seems to be especially sensitive to stress, and a recent study evidenced low transcript levels of GRP75 in the liver of gilthead sea bream in comparison to data found in the common dentex (Dentex dentex L.) (Bermejo-Nogales et al, 2007), a stressful fish closely related to gilthead sea bream. Likewise, in vivo toxicogenomic studies indicated that the expression of GRP75 is 2-3 times increased in the liver of zebrafish exposed to arsenic for 8-96 h (Lam et al, 2006). Taken together all these findings, the inducible expression of fish GRP75 could be considered an adaptive response to restore cellular homeostasis in a distorted and oxidative milieu.…”

“…The key role of Hsp70 and Hsp90 families on development has been evidenced during zebrafish embryogenesis (Krone et al, 2003), and even it is known that most hepatic Hsp including GRP75 are up-regulated in zebrafish toxicogenomic models (Lam et al, 2006). Extensive studies have also revealed that the production of Hsp is induced by common aquaculture stressors (e.g.…”