Telomere length in children environmentally exposed to low-to-moderate levels of lead

Highlights

• This cross-sectional study analyzes the association between environmental lead exposure and telomere length in children.

• Blood lead concentrations were inversely associated with relative telomere length in 8-year-old children.

• Environmental lead exposure during childhood might contribute to telomere shortening, and in turn, future risk for disease.

Abstract

Shorter relative telomere length in peripheral blood is a risk marker for some types of cancers and cardiovascular diseases. Several environmental hazards appear to shorten telomeres, and this shortening may predispose individuals to disease. The aim of the present cross-sectional study was to assess the effect of environmental exposure to lead on relative telomere length (rTL) in children. A cohort of 99 8-year-old children was enrolled from 2007–2010. Blood lead concentrations (B-Pb) were measured by graphite furnace atomic absorption spectrometry, and blood rTL was measured by quantitative PCR.

The geometric mean of B-Pb was 3.28 μg/dl (range: 0.90–14.2), and the geometric mean of rTL was 1.08 (range: 0.49–2.09). B-Pb was significantly inversely associated with rTL in the children (r_S = − 0.25, p = 0.013; in further analyses both log-transformed-univariate regression analysis β = − 0.13, p = 0.026, and R²adj 4%; and β = − 0.12, p = 0.056 when adjusting for mothers' smoking during pregnancy, Apgar score, mother's and father's ages at delivery, sex and mother's education, R²adj 12%, p = 0.011). The effect of lead remained significant in children without prenatal tobacco exposure (N = 87, r_S = − 0.24, p = 0.024; in further analyses, β = − 0.13, p = 0.029, and R²adj 4%). rTL was not affected by sex, the concentrations of other elements in the blood (i.e., cadmium and selenium concentrations), or oxidative injury parameters (total antioxidant status, 8-hydroxydeoxyguanosine and thiobarbituric acid-reactive substances).

Lead exposure in childhood appears to be associated with shorter telomeres, which might contribute to diseases, such as cardiovascular disease. The inverse association between blood lead level and the telomeres in children emphasizes the importance of further reducing lead levels in the environment.

Introduction

Telomeres are repeated oligomer sequences (TTAGGG)_n that are at the ends of chromosomes. Together with the associated telomere proteins, which form the shelterin complex they form a type of a cap that prevents chromosome damage. The telomeres are shortened during each DNA replication cycle, and telomere shortening may be a marker of biological aging (for review: Stewart et al., 2012, Lu et al., 2013). Short telomere length in leukocytes in retrospective case control studies appeared to be a risk marker for cardiovascular diseases, such as arterial hypertension, arteriosclerosis, ischemic coronary disease and acute coronary syndromes (Fyhrquist et al., 2013, Willeit et al., 2010a), and for diabetes mellitus type 2 (Willeit et al., 2014), as well as susceptibility marker to cancer incidence and cancer mortality (Ma et al., 2011, Willeit et al., 2010b, McGrath et al., 2007). However, the opposite associations were observed in some cancers (Seow et al., 2014).

Environmental and occupational exposures appear to modify telomere length. Most studies have shown shorter telomeres in subjects that had been exposed to polycyclic aromatic hydrocarbons (Pavanello et al., 2010), N-nitrosamines (Li et al., 2011), pesticides (2,4-D, diazinon and aldrin; Andreotti et al., 2014), cadmium (Zota et al., 2015) and paints (for review: Zhang et al., 2013). Some toxic agents, such as arsenic (Li et al., 2012), benzene (Bassig et al., 2014), pesticides (alachlor; Andreotti et al., 2014) or persistent organic pollutants (Shin et al., 2010), have been associated with longer telomeres. In contrast, the data regarding particulate matter are contradictory and depend on whether the exposure is long- or short-term (Dioni et al., 2011, Wong et al., 2014a, Zhang et al., 2013). In addition, both prenatal exposure and later exposure to tobacco smoke were associated with shorter telomere length (Theall et al., 2013, Babizhayev and Yegorov, 2011, Valdes et al., 2005 Salihu et al., 2014). Therefore, telomere length is a promising biomarker of exposure and of susceptibility to disease (Silins and Hogberg, 2011).

Heavy metals, including lead, may interfere with nucleic acid physiology via either oxidative stress (Fenton-type reaction) (Fowler et al., 2011) or DNA changes at the epigenetic level (Broberg et al., 2014, Fragou et al., 2011, Kippler et al., 2013). Heavy metals have also been shown to affect the organization of chromatin and to lead to impairments in the nuclear membrane (Banfalvi et al., 2012), which is essential for telomere stability (Crabbe et al., 2012, Schober et al., 2009).

Environmental exposure to lead has decreased in recent decades in Europe (Strömberg et al., 2008, Hruba et al., 2012, Pawlas et al., 2013); however, adverse health effects, particularly neurotoxic effects, on developing children may still exist (Pawlas et al., 2012). Wu et al. (2012) showed that occupational exposure to high lead levels was associated with telomere length shortening in workers. However, less is known regarding the effects of environmental exposure to lead. One recent study did not observe any effects of lead exposure on leukocyte telomere length in an adult population with low blood lead levels (Zota et al., 2015). In the other there was no association between placental lead concentration and placental telomere length (Lin et al., 2013). Lead exposure during childhood may affect not only the health status during childhood but also the functioning and disease susceptibility of adults (Mazumdar et al., 2011, Theall et al., 2013) possibly through effects on telomere length.

The effects of accelerated telomere shortening during childhood on adult health are not fully understood; however, in the literature, short telomeres in blood are clearly associated with adult disease in retrospective case–control studies. The older mothers whose telomeres were shorter at delivery of their child appeared to have more frequently children with Down Syndrome (Ghosh et al., 2010). In case–control studies shorter telomeres were observed in children with autism (Li et al, 2014), as well as in those who experienced family violence (Drury et al, 2014), childhood trauma and developed posttraumatic stress disorder (O'Donovan et al, 2011). The literature is sparse and there is a need for follow-up to confirm the relationship between telomere length at childhood and diseases at adult age. There are few prospective studies in adults regarding the follow-up of participants with estimated telomere length at the baseline. Shorter baseline telomere length was associated with a higher risk of metabolic syndrome development in 2 and 6 years of follow-up in participants aged 18–65 (Revesz et al., 2014). Bakaysa et al. (2007) demonstrated in within pair analyses of 350 participants (175 pairs of twins) with a mean age of 78.8 that telomere length was a predictor of survival. Risk of death during the follow-up (mean 6.9 years) in twins with shorter telomeres was three times higher than in their co-twins with longer telomeres (Bakaysa et al., 2007). Shorter telomeres at baseline were associated with worse survival in idiopathic pulmonary fibrosis assessed as transplant-free survival time (Stuart et al., 2014), in patients with bladder cancer followed for up to 18 years (Russo et al., 2014) and in patients with colorectal cancer (Chen et al., 2014).

Telomere length most likely affects DNA methylation levels and gene expression in health and diseases (Buxton et al., 2014). Shorter telomeres and altered DNA methylation were shown in patients with Alzheimer's disease (Guan et al., 2013) and in patients with mild cognitive impairments (Moverare-Skrtic et al., 2012). Shorter telomere length has been used as a predictor of dementia and morbidity (Honig et al., 2012), diabetes type 2 (Zhao et al., 2013), cancer (Ma et al., 2011) and cardiovascular diseases (Muller and Rabelink, 2014). Therefore, nutritional, life-style or therapeutic intervention to slow telomere shortening would be promising for risk-associated populations.

In the present study, we examined telomere length in children with environmental exposure to lead near industrial emitters.