Gene Expression Profiles in Peripheral Lymphocytes by Arsenic Exposure and Skin Lesion Status in a Bangladeshi Population

Abstract

Millions of individuals worldwide are chronically exposed to arsenic through their drinking water. In this study, the effect of arsenic exposure and arsenical skin lesion status on genome-wide gene expression patterns was evaluated using RNA from peripheral blood lymphocytes of individuals selected from the Health Effects of Arsenic Longitudinal Study. Affymetrix HG-U133A GeneChip (Affymetrix, Santa Clara, CA) arrays were used to measure the expression of f22,000 transcripts. Our primary statistical analysis involved identifying differentially expressed genes between participants with and without arsenical skin lesions based on the significance analysis of microarrays statistic with an a priori defined 1% false discovery rate to minimize false positives. To better characterize differential expression, we also conducted Gene Ontology and pathway comparisons in addition to the gene-specific analyses. Fourhundred sixty-eight genes were differentially expressed between these two groups, from which 312 differentially expressed genes were identified by restricting the analysis to female never-smokers. We also explored possible differential gene expression by arsenic exposure levels among individuals without manifest arsenical skin lesions; however, no differentially expressed genes could be identified from this comparison. Our findings show that microarray-based gene expression analysis is a powerful method to characterize the molecular profile of arsenic exposure and arsenic-induced diseases. Genes identified from this analysis may provide insights into the underlying processes of arsenic-induced disease and represent potential targets for chemoprevention studies to reduce arsenicinduced skin cancer in this population.

Arsenic Induces Polyadenylation of Canonical Histone mRNA by Down-regulating Stem-Loop-binding Protein Gene Expression

“…Exposure to a carcinogenic metal, such as arsenic, has been associated with altered gene expression patterns both in vitro and in vivo, and it has been demonstrated that the arsenicinduced changes in gene expression may be epigenetically regulated (2)(3)(4)(5)(6)(7)(8)(9). Although arsenic is capable of inducing changes in gene expression by altering the levels of post-translational histone modifications in the promoters of genes, alterations in the expression of the histone genes themselves by arsenic has not been studied.…”

“…Instead of a poly(A) tail, canonical histones contain a conserved 26-nucleotide sequence that can form a stem-loop structure, consisting of a four-nucleotide loop and a six-base pair stem. These 26 highly conserved nucleotides are the binding site for the stem-loop-binding protein (SLBP) 4 (10). SLBP is critical for canonical histone pre-mRNA processing and histone mRNA translation (12) and is a major mediator of histone mRNA stability (13,14).…”

Effects of arsenic on porcine dendritic cells in vitro

“…The (geo)anthropogenic As levels in many of these countries (e.g. Bangladesh, India, Pakistan, Chili) have previously been shown to be associated with elevated incidences of immunotoxicity and (non)infectious diseases (Wu et al 2001;Argos et al 2006;Steinmaus et al 2013;Syed et al 2013).…”

“…Several immunotoxicology studies have shown that As exposure causes neutropenia and promotes recurrent infections. In addition, As exposure has been linked to many noninfectious diseases, including cancers and anemia (Argos et al 2006;Ghosh et al 2006;Andrew et al 2008;Banerjee et al 2009;Khan et al 2012). …”

Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: Identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility

“…We used oligonucleotide microarray to determine basal RNA expression profiles in arsenite-resistant and arsenite-sensitive human lymphoblast lines. Although a number of studies have compared gene expression levels in control and arsenite-treated human cells (Yih, et al, 2002, Rea, et al, 2003, Andrews et al, 2003Su, et al, 2006), and one study compared gene expression profiles in lymphocytes from arsenicexposed individuals with and without skin lesions (Argos et al, 2006), gene expression profiles comparing cells from normal, unexposed humans with different sensitivities to arsenite have not been reported.…”