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Environmental and occupational exposure to chemicals and telomere length in human studies
  1. Xiao Zhang1,
  2. Shao Lin2,
  3. William E Funk3,
  4. Lifang Hou1,4
  1. 1Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
  2. 2Department of Epidemiology & Biostatistics, School of Public Health, University at Albany, Rensselaer, New York, USA
  3. 3Department of Anthropology, Northwestern University, Evanston, Illinois, USA
  4. 4Department of Preventive Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
  1. Correspondence to Dr Lifang Hou, Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Chicago, IL 60611, USA; l-hou{at}northwestern.edu

Abstract

Telomeres are complexes of tandem repeats of DNA (5′-TTAGGG-3′) and protein that cap eukaryotic chromosomes and play a critical role in chromosome stability. Telomeres shorten with aging and this process can be accelerated by increased oxidative stress and episodes of inflammation. Evidence is rapidly growing that telomere length (TL) may be affected by environmental chemicals that have frequently been associated with chronic diseases. In this article, we review the published data on TL in relation to environmental and occupational exposure to several chemicals based on our own and others’ studies. The environmental and occupational exposures associated with shorter TL include traffic-related air pollution (ie, particulate matter (PM), black carbon (BC), and benzene and toluene), polycyclic aromatic hydrocarbons (PAHs), N-nitrosamines, pesticides, lead, exposure in car mechanical workshops, and hazardous waste exposure. Arsenic, persistent organic pollutants (POPs) and short-term exposure to PM are associated with longer TL. We discuss the possible reasons for the differences in results, including time- and dose-related issues, study design, and possible mechanisms involved in telomere regulation. We also discuss the future directions and challenges for TL-related environmental and occupational health research, such as investigation of TL in subpopulations of blood leukocytes, and the study of genetic and epigenetic factors that may regulate telomere integrity using longitudinal designs.

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What this paper adds

  • Increasing evidence has linked environmental and occupational pollutants with telomere length (TL), but the results are inconsistent, with some showing TL shortening and others TL lengthening.

  • Several possible mechanisms, including inflammation, oxidative stress, telomerase activation and other mechanisms maintaining telomere integrity, may be responsible for the TL changes associated with environmental and occupational exposure to chemicals.

  • Future human studies of TL in relation to environmental and occupational pollutants and associated diseases face several challenges, including investigation of TL in specific cells, genetic and epigenetic factors that may regulate telomere integrity, and prospective changes in TL.

  • The study of TL in easily obtainable surrogate tissues may well identify novel and easy-to-measure biomarkers of past exposure as well predict future disease, thus contributing to the development of preventive strategies and policies for environmental and occupational diseases.

Introduction

Human telomeres are complexes of tandem repeats of DNA (10–15 kb, 5′-TTAGGG-3′) and associated capping proteins that protect chromosome stability from nucleolytic degradation, chromosome end-to-end fusion and breakage–fusion–bridge cycles.1 Telomeres shorten with age, which process can be accelerated by exposure to environmental and occupational factors that causes oxidative stress and chronic inflammation.2 However, telomere integrity is largely maintained by a telomerase-based mechanism, in which telomerase plays a key role by adding hexameric (TTAGGG) repeats to the telomeric ends of the chromosomes, thus compensating for the continued erosion of telomeres.1 Telomerase activity is high in stem cells, germ cells and malignant tissues, quantifiable in some somatic cells, including blood leukocytes, but undetectable in most normal somatic cells.3 In somatic cells, it has been hypothesised that alternative non-telomerase-based mechanisms may be triggered to maintain telomere length (TL) integrity when TL become critically short due to environmental and occupational exposures.3 Therefore, telomeric DNA is dynamic, and TL is considered the result of a balance between telomere shortening and lengthening (maintaining) processes.3

Epidemiological studies have consistently linked exposure to environmental chemicals with increased risks for various chronic diseases.4 Both genetic mutations altering the DNA sequence5 and epigenetic factors not involving DNA sequence changes4 have been demonstrated to be involved in diseases related to environmental chemicals. Studies have also shown TL is associated with environmental and occupational diseases, such as cancers and cardiovascular diseases (CVD).3 ,6 Oxidative stress and inflammation, the two major pathways for such diseases, are also risk factors for TL shortening.3 Therefore, TL may serve as an indicator of exposure to environmental and occupational chemicals, and TL shortening may be an additional factor linking such chemicals with their related diseases (figure 1). Investigation of TL in relation to environmental and occupational chemicals may help elucidate the mechanisms of disease development and identify populations at high risk for occupational and environmental diseases.

Figure 1

Hypothesized conceptual model for telomere length shortening and chemical exposure.

Some evidence concerning exposure to environmental and occupational chemicals and TL has begun to accumulate. As listed in table 1, 14 human studies so far have examined TL in relation to environmental and occupational chemical exposures, with the majority of studies reporting shorter TL as a result of exposure. In this review, we summarise previous observations on TL and environmental and occupational chemical exposures according to shorter or longer TL, and provide possible explanations and suggest future directions in TL research.

Table 1

Studies evaluating the association of telomere length with environmental and occupational chemicals

TL and exposure to environmental and occupational chemicals

Shorter TL and environmental and occupational chemical exposures

Of 14 studies, 11 have reported that shorter TL is associated with environmental and occupational exposures, including traffic-related air pollution (ie, particulate matter (PM),7 black carbon (BC),8 and benzene and toluene9), occupational exposure (ie, polycyclic aromatic hydrocarbons (PAHs),10 ,11 N-nitrosamines,12 pesticides,13 ,14 lead,15 exposure in car mechanical workshops)16 and hazardous waste.17 Taken together, these studies suggest that exposure to environmental and occupational chemicals may accelerate telomere shortening, which may be a possible biological mechanism for chronic diseases. Below we present a summary of these findings in more detail.

Traffic-related air pollution

Air pollution has been associated with increased cardiovascular and respiratory morbidity and mortality.7 In our own Beijing Truck Driver Air Pollution Study, we investigated the relationship of personal and ambient PM exposure with blood TL in 60 truck drivers (highly exposed group) and 60 indoor workers (low exposed group). In this study, in order to test both the short- and long-term effects of PM on TL, we used ambient PM10 data on the days of examination, as well as measurements recorded on the days leading up to the examinations. Averages measurements collected 1 day, 1–2 days, 1–5 days, 1–7 days, 1–10 days and 1–14 days before the examinations were evaluated. In addition, personal PM2.5 and elemental carbon (EC) were recorded during work hours on the examination days. Overall, the levels of personal PM2.5 and EC during work hours on the examination days, as well as of ambient PM10 on or 1–2 days prior to the examination days, were associated with increased TL. We observed no statistically significant associations of TL with ambient PM10 levels averaged over 1–5 days or 1–10 days before the examinations. However, we found a significant inverse association of TL with average PM10 levels 1–14 days prior to the examinations.7

Traffic emissions are comprised of a mixture of by-products of the combustion process, such as BC, benzene and toluene, and exposure to traffic emissions has been shown to generate oxidative stress.18 In a study of residents in the Massachusetts area in the Normative Aging Study (a prospective study of aging), TL was negatively associated with 1-year exposure to BC, a surrogate for traffic pollution among non-smokers.8 In another study, traffic workers were exposed to a high level of benzene and toluene, two additional components of traffic exposure. In this study, Hoxha et al measured TL in blood DNA from traffic officers and 57 office workers as referents, who had been employed in their current job for at least 1 year. It was observed that TL was shorter in traffic officers than in office workers, and that TL decreased with increasing level of personal exposure to benzene and toluene in all subjects combined.9

These studies reported that shorter TL is associated with long-term exposure to air pollution. This observation is biologically plausible, as chronic inflammation is associated with rapidly increased numbers of leukocytes, which requires a higher rate of cell replication. Telomeric DNA is dynamic, and TL typically shortens with each cell division.3 Oxidative stress could also influence the extent of telomere loss during each replication due to the high guanine content of the telomere squence.19 Therefore, chronic inflammation and oxidative stress are considered major mechanisms that influence TL, which can also be mediated by long-term PM exposure and exposure to other combustion products such as benzene.8

Polycyclic aromatic hydrocarbons

PAHs are established lung carcinogens that cause chromosome instability, with exposures being widespread due to smoking and environmental pollutants.20 Two human studies have reported that shorter TL was associated with PAHs exposure in Chinese coke-oven workers11 and Italian coke-oven workers.10 It was speculated that benzo[a]pyrene (BP), a tracer of PAHs mixtures that forms stable anti-BP diolepoxide (anti-BPDE)–DNA adducts, is a known carcinogen that could modify DNA and cause genetic mutations.21 Pavanello et al10 further observed that TL decreased in association with increasing levels of anti-BPDE–DNA adducts, indicating their direct role in the TL shortening process. In the same population, global DNA hypomethylation and p53 promoter hypomethylation were observed in subjects exposed to PAHs,10 ,22 indicating that epigenetic changes may contribute to PAHs-related TL shortening. Finally, high exposure to PAHs through metabolic activation has been shown to produce oxidative stress, which also causes damage to telomeres.10

N-nitrosamines

Workers in the rubber industry are exposed to complex mixtures of toxic substances, including N-nitrosamines, which can also induce oxidative stress and result in the formation of DNA adducts.23 It has been reported that rubber workers have an increased risk of cancer and coronary and respiratory diseases.23 In a recent study among workers in the rubber industry in Sweden, Li et al12 observed an association between shorter TL and exposure to N-nitrosamines, in line with a rat study demonstrating an association of shorter TL with exposure to N-butyl-N-(4-hydroxybutyl) nitrosamine.24 However, as workers in the rubber industry are exposed to a complex environment, there may be other unmeasured exposures in rubber fumes that might positively correlate with N-nitrosamines and cause telomere shortening.

Lead

Lead is one of the most prevalent toxic environmental metals and has been associated with CVD and cancer.25 Lead is used in some major industries, while lead compounds are widely used in industrial processes, and lead exposure is a chronic occupational hazard. Lead has substantial oxidative properties, and long-term exposure can inhibit telomerase activity by influencing shelterin protein Rap1p, resulting in physiological stress and TL shortening.26 Recently, Wu et al15 for the first time observed an association between shorter TL and occupational exposure to lead in Chinese battery manufacturing plant workers, indicating that TL may be one of the targets damaged by lead toxicity. More studies, for example on whether TL shortening makes cells hypersensitive to lead-induced genotoxicity and on the dose–response relationship between lead exposure and TL changes, are needed in the future.15

Pesticides

Pesticides are widely used and pervasive in our environment. Several pesticides have repeatedly been associated with cancers and CVD.27 Potential mechanisms underlying these associations include the generation of oxidative stress and immunotoxicity, which are also involved in telomere shortening.27 In patients with myelodysplastic syndromes (MDS), two studies found that shorter TL was associated with previous exposure to paints and pesticides13 and to organic solvents and pesticides.14 The authors hypothesised that prolonged occupational exposure to these chemicals might play a role in increasing the risk of developing MDS via acceleration of the rate of telomere shortening.28 This hypothesis was supported by the observed shorter TL in MDS patients who had received cytoreductive treatment, suggesting that pesticides could accelerate telomere erosion as a consequence of proliferative stress.29

Automobile mechanical workshops

Workers in automobile mechanical workshops are exposed to complex chemical mixtures, including petrochemicals, a group of substances with potential genotoxic effects, and petrol vapours, which are classified as carcinogenic to humans.30 In a study comprising 120 automobile mechanical workers and 120 unexposed controls, Eshkoor et al observed shorter TL in buccal cell DNA from mechanical workers compared with controls. The association between TL and age was significant in workers and combined individuals, but not in controls, indicating that occupational exposure in automobile mechanical workshops may be a risk factor for aging-related TL shortening.16

The glutathione S-transferase (GST) genes, including GSTT1, GSTM1 and GSTP1, play an important role in detoxifying xenobiotics.31 In the same study population, GSTT1 and GSTM1 polymorphisms showed significant differences in DNA damage markers in buccal cells between workers and controls.31 Previous studies have demonstrated that GSTM1 enzymes protect cells against oxidative stress, and lack of GSTM1 enzymes increases oxidative DNA damage in smokers.32 Taken together, GST may influence DNA damage and participate in TL shortening in automobile mechanical workers. However, using buccal cells for TL measurement has limitations, such as the high rates of cell division and turnover relative to other blood cells, such as lymphocytes,33 a heterogeneous population containing karyorrhectic, karyolytic and pyknotic cells, and a highly oxygenated microenvironment that may affect telomere shortening.34 Therefore, the interpretation of the results in this study should be treated with caution.

Hazardous waste

The hazardous waste sites in the Campania region of Italy, referred to as the ‘Triangle of Death’, are distributed over a wide, densely populated area, and plagued by illegal dumping of toxic industrial chemicals and low-level radioactive waste.35 The European collaborative study EUROHAZCON has reported an increased risk of congenital anomalies around hazardous waste landfill sites.36 Pregnant women and children living in polluted areas are at high risk, and chemical exposures during fetal growth are of particular concern.36 In pregnant women living in the ‘Triangle of Death’ region, De Felice et al17 found an association of shorter TL and lower human telomerase reverse transcriptase (hTERT) mRNA levels with hazardous waste exposure. In human studies, TL attrition due to inflammation and oxidative stress is counteracted by telomerase activity, and the reduction in telomerase activity may have contributed to the generation of telomeric abnormalities. The persistent oxidative stress in exposed women may accelerate telomere attrition and loss of telomerase activity, which may result in telomere integrity disruption and the resulting activation of premature cellular senescence.17

Longer TL and exposure to environmental chemicals

Although most studies observed shorter TL in relation to environmental and occupational chemical exposures, four studies have reported longer TL in highly exposed compared to low exposed individuals. These exposures include arsenic,37 persistent organic pollutants (POPs)38 and short-term exposure to PM.7 ,39 We describe these studies in greater detail below.

Arsenic

Arsenic is a potent carcinogen and can increase risk for CVD.40 Arsenic in drinking water is a major public health problem worldwide,40 and in in vitro studies arsenic increased telomerase activity and elongated TL at low doses, but decreased telomerase activity and shortened TL at higher doses.40 The effect of arsenic at higher doses may be caused by cytotoxicity, but arsenic concentrations in humans may not reach these threshold levels.41 In a study of a population in Inner Mongolia, Mo et al42 found a positive association between arsenic in drinking water and the mRNA of two DNA repair genes (OGG1 and ERCC), indicating a linkage between oxidative stress and arsenic exposure in humans. In the same population, Mo et al43 also found increased hTERT expression with low-dose arsenic, which is in line with a recent finding of an association between low-dose arsenic exposure and increased expression of hTERT and longer TL in a population of Argentinian women.37 However, no correlation between TL and hTERT was observed.37 As a possible explanation for this null result, Li et al hypothesised that the selected biomarkers might be time-dependent, and that the chronic effects of arsenic exposure might differ from the acute effects on arsenic-mediated hTERT expression. Some other processes could also be involved in the arsenic-related telomere lengthening, which is supported by the correlation between TL and other telomere-related genes, such as HUS1 and MUS8.37

Persistent organic pollutants

POPs are a group of synthetic chemicals sharing a number of common properties, such as long-term persistence, diffusion in the environment, and bioaccumulation in the food chain.44 Recent epidemiological studies have reported associations of low-dose POPs with cancer and CVD.44 The only study reporting data on pesticides and TL found that low-dose exposures to POPs, including organochlorine pesticides, polychlorinated biphenyls (PCBs) and polybrominated diphenylethers (PBDEs), were associated with longer TL in an apparently healthy Korean population.38 However, in the same study, it was also reported that exposures to higher levels of POPs resulted in longer TL.38 These dose-dependent associations are consistent with in vitro studies on arsenic, a common constituent of pesticides, showing increased telomerase activity and elongated TL at a low doses, but decreased telomerase activity and shortened TL at a higher doses.37 Additional studies are needed to confirm such dose-dependent associations and the underlying mechanisms.

Particulate matter

Although the toxic effect of several metals in PM are well recognised, the molecular mechanisms underlying the association between PM and chronic diseases remain poorly understood. Experimental and epidemiological studies suggest that PM mass and metal components may induce biological changes, including oxidative stress and chronic inflammation—the two key determinants of TL.3 In a study of male healthy steel workers with well-characterised exposure to metal-rich particles near Brescia in Italy, Dioni et al39 reported a rapid and significant increase in blood TL following 3 days of exposure. It was hypothesised that acute inflammation, a central process in mediating health effects resulting from short-term PM exposure, might be a possible mechanism leading to TL increase in inflammatory cells.39 Consistent with this, in our Beijing Truck Driver Air Pollution Study, we observed increased TL associated with personal PM2.5 and EC during work hours on the examination days in all subjects.7 We also found that PM10 on the examination day was associated with longer TL. However, the PM10-related increase in TL appeared to decrease with longer exposure to PM10 up to 10 days. When TL was examined with PM10 levels that were averaged over the 14 days before the day of the examination, we found a negative association.7 This observation, along with findings of associations of longer TL with 3-day PM exposures,39 and shorter TL with long-term BC8 and benzene exposures,9 indicates that short-term PM exposures might result in an acute increase in TL that could help sustain the inflammatory mechanisms associated with acute PM health effects, while longer exposures might cause telomere shortening with an increased long-term risk of cardiovascular and respiratory disease.6 As such, TL may serve as an important biological marker of PM-related chronic diseases. However, we cannot exclude other unmeasured characteristics, such as lifestyle factors or other environmental exposures,3 that may also affect TL.

Future directions in TL environmental exposure using surrogate tissues

Although evidence linking environmental and occupational exposure to TL has begun to accumulate, various issues remain to be addressed.

Limited studies have investigated the relationship between chemical exposures and TL in human populations. For instance, lead15 and arsenic37 have been examined in only one human study with a limited number of study subjects. Several additional in vitro studies have shown that chemical exposures induce aging and telomere shortening, but this has not been examined in humans.3 In addition, other factors that have been shown to affect TL, such as older age, cigarette smoking, gender, ethnicity, overweight/obesity, the mitotic activity of mononuclear cells, psychological stress, diet, low physical activity and other unknown factors, may be confounders of exposure to environmental and occupational chemicals.3 ,45 More large-scale investigations examining these factors, as well as the possible biological effects of these factors on TL, such as earlier immune senescence and elevated inflammatory processes, are needed in the future to better understand the role of environmental and occupational diseases in TL.

Some subpopulations of blood leukocytes may have shorter or longer telomeres than the others. For example, it has been shown that TL is different in memory versus naive and CD41 versus CD81 T cells.46 In inflammatory cells, clonal expansion of leukocytes, in particular T and B lymphocytes, occurs rapidly in subpopulations with longer telomeres, which could result in an increase in average TL.47 Previous studies have shown that systemic inflammatory responses to PM exposure are associated with the presence of less mature leukocytes.48 Therefore, migration of less mature cells, which may have longer telomeres due to lower cell division, could also have contributed to increased average TL. In addition, it was demonstrated that telomerase is activated in mononuclear cells that undergo mitosis, which may further impact TL measurement.47 ,49 Future studies should measure TL after the separation of specific leukocyte subpopulations based on their functions and maturity; such cell subsets may make a specific contribution to telomere environmental research.

Genetic variation in telomere-related genes is important in telomere biology.50 For example, the T allele of the −1381 promoter SNP in hTERT was associated with longer TL and increased telomerase activity than in individuals with the CC genotype.51 Mirabello et al52 recently observed an association of TL with single nucleotide polymorphisms (SNPs) in several telomere-related genes, such as MEN1, MRE1A, RECQL5 and TNKS. These findings indicate that telomere-related genes play important roles in maintaining telomere integrity, and account for the differences in TL between individuals and across populations.53 ,54 ,55

Rapidly growing evidence has linked environmental and occupational chemicals with epigenetic alterations, including changes in DNA methylation, histone modifications and microRNAs.4 These epigenetic mechanisms have also been demonstrated to play a role in telomere maintenance and integrity.56 For example, cells that lack SUV39H1 and SUV39H2 histone methyltransferases show decreased levels of H3K9 trimethylation at telomeres, which is concomitant with aberrant telomere elongation.57 Mammalian cells that are genetically deficient in DNA methyltransferases (DNMTs) have dramatically elongated telomeres compared with wild-type controls, which coincides with decreased DNA methylation at subtelomeric domains. It was also observed that DNMT-deficient cells have increased telomeric recombination that may lead to TL changes. Thus, epigenetic factors may play important roles in telomere integrity maintenance,58 and future studies of epigenetic effects on environmental and occupational exposure-related TL changes need to be taken into account.

Finally, because TL maintenance is a dynamic process, longitudinal studies to examine the effect of prenatal exposure on TL at birth and TL attrition rate with increasing age in response to environmental exposures will provide information on the dynamics of TL throughout life and aging. As far as we know, there is only one pilot study on TL and prenatal chemical exposure, showing shorter TL measured by quantitative fluorescence in situ hybridisation (FISH) in individuals with prenatal exposure to glycol ether.59 However, since only six in utero-exposed individuals with dysmorphic features, mental retardation and persistent cytogenetic damage were included, larger studies are needed to confirm this finding. Furthermore, as regards single time-point measurements of TL, such results may not provide any information on the cumulative burden of exposures over time. As such, TL may act only as a biomarker of aging at certain stages of life, and thus longitudinal studies are needed to better address this question.60 Such studies will allow us to examine whether, and to what extent, telomere dynamics is associated with environment chemicals as well as the aetiological role of TL shortening in chronic diseases. Lastly, we also note the possibility of publication bias, such as positive results bias and outcome reporting bias, which may be present in the studies summarised in this review.

In summary, TL was observed to both increase and decrease with environmental and occupational chemical exposures in the studies outlined in this review. This is potentially related to inflammatory and oxidative processes underlying the effects of environmental chemicals on human health. Either excessively shorter or longer TL may contribute to environmental and occupational disease development if the delicate TL balance is broken.

Acknowledgments

This work was supported by funding from the NIEHS (R21 ES020010 and R21 ES020984–01).

References

Footnotes

  • Contributors LH designed the review with help from XZ, SL and WEF. XZ collected, abstracted and checked the data. XZ and LH wrote the first draft of the manuscript. All of the authors contributed to interpretation and final revision of the paper.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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