Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals
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.
Section snippets
Study participants
Participants for this work were drawn from two longitudinal studies in Bangladeshi with similar source populations: the Bangladesh Vitamin E and Selenium Trial (BEST) (Argos et al., 2013) and the Health Effects of Arsenic Longitudinal Study (HEALS) (Ahsan et al., 2006).
BEST is a randomized chemoprevention trial evaluating the long-term effects of vitamin E or selenium supplementation on non-melanoma skin cancer (NMSC) risk and oxidative stress. BEST participants (n=7000) are adult residents in
Results
Participant characteristics are shown in Table 1. Urinary arsenic concentrations ranged from 1.3 to 4004 µg/g (median=158.02 µg/g) in BEST and from 8 to 8556 µg/g in HEALS. Relative telomere length ranged from 0.22 to 1.78 (median=0.62) among the 167 participants from HEALS (data not shown). Arsenic concentrations in drinking water among HEALS participants ranged from 0.1 to 864.0 µg/L (median=50.0 µg/L), the majority of which were far higher than the Maximum Contaminant Levels (MCLs) water
Discussion
In this population-based study, we assessed the associaton of arsenic exposure with mononuclear cell expression of telomere-related genes and telomere length measured in whole blood. We observed associations between urinary arsenic and expression of several genes with known roles in telomere biology, including TERF2, WRN, DKC1, TERF2IP and OBFC1. We also observed an interaction between urinary arsenic and arsenic metabolism efficiency in relation to expression of WRN. In addition, we observed
Funding
This work was supported by NIH Grants R01ES020506 (B.L. Pierce), P42ES010349 (J.H. Graziano, H. Ahsan), R01CA102484 (H. Ahsan), and R01CA107431 (H. Ahsan).
Acknowledgements
We would like to thank all HEALS and BEST study participants and staff.
References (72)
Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study
Lancet
(2010)Telomeric damage in early stage of chronic lymphocytic leukemia correlates with shelterin dysregulation
Blood
(2011)Genetic toxicology of a paradoxical human carcinogen, arsenic: a review
Mutat. Res.
(2001)A DNA polymerase-{alpha}{middle dot}primase cofactor with homology to replication protein A-32 regulates DNA replication in mammalian cells
J. Biol. Chem.
(2009)Association between telomere length in blood and mortality in people aged 60 years or older
Lancet
(2003)Arsenic in drinking water and lung cancer: a systematic review
Environ. Res.
(2008)Arsenic induces telomerase expression and maintains telomere length in human cord blood cells
Toxicology
(2009)A prospective study of telomere length and the risk of skin cancer
J. Investig. Dermatol.
(2009)Arsenic toxicity and potential mechanisms of action
Toxicol. Lett.
(2002)Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites
Toxicol. Appl. Pharmacol.
(2001)