Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals

Highlights

• Urinary arsenic was associated with expression of multiple telomere-related genes.

• High arsenic exposure was associated with longer telomeres.

• Arsenic's association with WRN expression was modified by arsenic metabolism status.

• Arsenic's carcinogenic mechanism may involve telomere dysfunction.

Abstract

Background

Inorganic arsenic is a carcinogen whose mode of action may involve telomere dysfunction. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres and altered expression of telomere-related genes in peripheral blood. In this study, we evaluated the association of urinary arsenic concentration with expression of telomere-related genes and telomere length in Bangladeshi individuals with a wide range of arsenic exposure through naturally contaminated drinking water.

Methods

We used linear regression models to estimate associations between urinary arsenic and array-based expression measures for 69 telomere related genes using mononuclear cell RNA samples from 1799 individuals. Association between arsenic exposure and a qPCR-based telomere length measure was assessed among 167 individuals.

Results

Urinary arsenic was possitively associated with expression of WRN, and negatively associated with TERF2, DKC1, TERF2IP and OBFC1 (all P<0.00035, Bonferroni-corrected threshold). We detected interaction between urinary arsenic and arsenic metabolism efficiency in relation to expression of WRN (P for interaction =0.00008). In addition, we observed that very high arsenic exposure was associated with longer telomeres compared to very low exposure (P=0.02).

Discussion

Our findings suggest that arsenic's carcinogenic mode of action may involve alteration of telomere maintenance and/or telomere damage. This study extends our knowledge regarding the effect of arsenic on telomere length and expression of telomere-related genes.

Introduction

The telomere is a tandem repeat sequence (TTAGGG)_n at the end of human chromosomes that binds a protein complex to protect chromosome ends from DNA damage and chromosome fusion events. In differentiated cells, telomere sequences shorten with each cell division due to the “end replication problem” (Olovnikov, 1973), eventually triggering senscence. In stem cells, telomere length is maintained by telomerase, but length grandually decreases over the life-course (Finkel et al., 2007, McEachern et al., 2000). Telomerase activity is low or absent in most differentiated cells, resulting in a finite capacity for replication. Short telomere length in peripheral blood leukocytes is often considered a general biomarker of aging (Butler et al., 2004), but both shorter and longer telomeres have been associated with risk of a number of chronic diseases (Cawthon et al., 2003, Fitzpatrick et al., 2007, Sanders et al., 2012) and cancers (Han et al., 2009, Nan et al., 2011a, Shen et al., 2011, Stewart and Weinberg, 2000, Zimmermann and Martens, 2008).

As a potential biomarker of cancer risk, telomere length may be influenced by cancer-causing agents, such as arsenic. Exposure to inorganic arsenic through contaminated drinking water affects >100 million people worldwide (Ravenscroft et al., 2009), and chronic exposure to high levels (e.g., >300 μg/L in drinking water) shows clear association with increased risk for cancers of the lung (Celik et al., 2008), bladder (Mink et al., 2008), liver (Liu and Waalkes, 2008), skin (Yu et al., 2006), and kidney (Chen et al., 1992, Yuan et al., 2010). The mechanisms by which arsenic contributes to carcinogenesis are not entirely understood. Arsenic is not believed to directly damage DNA (Basu et al., 2001), and a variety of potential modes of action for arsenic toxicity have been proposed (Bhattacharjee et al., 2013, Hughes, 2002, Hughes et al., 2011, Kitchin, 2001, Schoen et al., 2004). These include oxidative stress, reduced DNA repair capacity, and increased cell turnover due to cytotoxicity, all of which could potentially damage telomeres.

Experimental studies suggest that arsenic has dose-dependent effects on telomere length and telomerase. Studies of cell lines (Zhang et al., 2003), animal models (Liu et al., 2003), and human cells (Ferrario et al., 2009) indicate that arsenic reduces telomere length at high concentrations (>1 μM), decreasing cell survival, but may increase telomerase activity and maintain telomere length at lower concentrations (<1 μM), increasing survival. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres in peripheral blood leukocytes (Chatterjee et al., 2014, Li et al., 2012) and increased expression of telomerase (Mo et al., 2009b), although few studies have addressed these research questions in human populations. In the present study, we estimated the association between arsenic exposure and expression of 69 telomere-related genes in mononuclear cells among 1799 Bangladeshi individuals. We also estimated the association between arsenic exposure and telomere length in peripheral blood in separate sample of 167 Bangladeshi individuals.