Air pollution and telomere length: a systematic review of 12,058 subjects

Introduction

Air pollution is a ubiquitous public health issue. Indoor and outdoor air pollution are the 3^rd and 9^th risk factors for worldwide mortality and morbidity (1). It is estimated that 4.3 million urban people will die prematurely due to outdoor air pollution in 2050, which accounts for 65% of the total death all over the world (2). Although air pollutants has long been understood to affect the respiratory system, the adverse effects on the cardiovascular system cause mortality impacts that exceed those from lung diseases and cancers (3,4). The impact of both short and long term exposure to air pollution on the cardiovascular system has been confirmed by epidemiological studies (4). Long term exposure to air pollutants contributes to the risk of both ischemic and non-ischemic cardiovascular disease (CVD) (5). Acute effects of elevated ambient particulate matter (PM) levels are more likely to occur on people who are elderly or already have CVD, even if this has not been recognized (4). The length of the chromosomal telomere is a biological clock, reflecting the biological aging process of cells. CVD is known clearly as age-related disease and researchers have been working on identifying a biomarker to reflect aging, as people with same chronological age may have different health status (6). Studies have demonstrated that individuals with shorter leukocyte telomere length (LTL) have an increased risk of myocardial infarction (7,8), coronary heart disease (9), heart failure (10), hypertension (11) and stroke (8). One study using Mendelian randomization approach proved causal effect of shorter genetically determined telomere length (TL) on CVD and cancer (12). TL can be a cardiovascular biomarker for biological aging. Until now, inflammatory reactions and oxidative stress are understood as critical mechanisms linking air pollution with related morbidity and mortality (13). These processes also accelerate telomere shortening (6). However, the reported relationships between air pollution and telomeres are inconsistent. Therefore, the aims of this study were to summarize the effects of air pollution on TL through a systematic review of literature, and to identify possible issues, including the factors hampering the quantification of the pooled estimates.

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline when performing our systematic review and meta-analysis (14). Electronic databases including PubMed, Embase, Scopus, Web of Science as well as Ovid (with all resources) were searched for articles that had examined the association between air pollution and TL. There was no restriction to language and study type. “Telomere”, “air pollution”, “air pollutant”, “particulate matter” and related free text terms were used for the search. Search hedges created are listed in the online supplementary material (Supplementary file). The first search was performed on 18 January 2016, and the last search was performed on 16 August 2017.

We followed the US Environmental Protection Agency criteria for ambient air pollutants, such as PM, nitrogen oxides (NO_x), carbon monoxide (CO), sulfur dioxide (SO₂), and ozone (O₃). There was no restriction to language and no time limit on publication date. We excluded studies of tobacco smoke, animal, cell-line, and genetic studies. Published conference abstracts, reviews, editorials and duplicates were also excluded. The most extensive article was chosen when more than one publication included the same content. When information was insufficient to make a judgment on the eligibility of a study, efforts were made to contact its corresponding author to obtain further information.

Two reviewers (Bing Zhao and Kazuaki Negishi), independently searched for studies and reviewed full-text through screening title and abstract using inclusion and exclusion criteria. A standard protocol was used to extract data from appropriate articles. The information collected included location, publication year, study design, samples size, tissue source, age, sex, participant characteristics, air pollutants and levels, monitoring methods, mean and standard deviation of TL, the outcome of association, and the characteristics of control group.

The Newcastle-Ottawa Quality Assessment Scale for cohort studies (15) was used as a unified standard to assess the quality of included studies. This tool contains eight items with three main components: selection, comparability, and outcome. The number of stars the study obtained represents the assessment results. A maximum of nine stars can be given for each study.

Results

The systematic search identified 2,151 titles (Figure 1). After removing 425 duplicates, 1,726 records were screened. After title and abstract review, a further 1,665 records were excluded. After full text screening of the 61 remaining articles, 25 articles that examined the relationship between air pollution and TL were finally included in this systematic review.

Figure 1 PRISMA flow chart. This flow chart illustrates the selection process for identified articles.

Table 1 summarizes the characteristics from the 25 articles (n=12,058 subjects) included in qualitative analysis (16-40). The sample sizes ranged from 14 (24) to 6,796 (40). All were observational studies: 14 cross-sectional (16-18,22-24,26,27,32-35,38,40), 6 cohort (20,29,30,36,37,39) and 5 case-control studies (19,21,25,28,31). All applied Cawthon’s protocol based on polymerase chain reaction (PCR) analysis method to measure TL: 19 studies (n=10,568 subjects) assessed LTL (16,18-20,22-27,30-33,36-40), 2 studies with placenta TL (17,28), 2 for buccal cell telomere (21,34) and 2 from sperm (29) and saliva (35) respectively (Figure 2). Among two versions of Cawthon’s protocols, 6 studies (16,17,27,33,35,38) followed Cawthon’s newer version published in 2009 (41), while remaining articles applied the original Cawthon’s method (42). Geographically, 11 studies were conducted in Europe (17,19,20,23,25,26,31-33,35,36), with 10 in Asia (16,18,21,22,27-29,34,38,39) and 4 in North America (24,30,37,40). Multiple ethnicities were included: 7,023 Americans, 3,254 Europeans and 1,781 Asians. The comparative groups were those who exposed to filtered air or clean air; and those not exposed to air pollution.

Table 1 Summary of included studies
Full table

Figure 2 Sources of telomere length assessment. (A) Based on the number of articles. 76% of studies evaluated leukocyte TL, while buccal cell, placenta, sperm and saliva are the other resources. (B) Based on the number of participants. Among these studies, leukocyte was used for 87.6% of population, placenta for 3.7%, sperm for 3.7%, saliva for 2.8% and buccal cell for 2.2%. TL, telomere length.

The concentration of airborne PM was investigated in 8 articles (20,22,33-37,39). Seven (22,33-37,39) of these examined the association between PM <2.5 µm in aerodynamic diameter (PM_2.5) and TL, and PM <10 µm in aerodynamic diameter (PM₁₀) were reported in 5 articles (20,22,35,36,39). Dioni et al. (20) and Wong et al. (37) used PM data from multiple sites in factories to calculate the personal exposures. One study included both personal and ambient air pollutants. Small-sized gravimetric samplers were carried by study subjects to measure personal PM_2.5 exposure and ambient PM₁₀ data were obtained from the local environmental agency (22). Personal exposure monitors (PEMs) were used in a pilot study (34). Pieters et al. (33), Walton et al. (35) and Ward-Caviness et al. (36) estimated PM level from fixed monitoring sites. Xia et al. (39) measured real-time ambient PM level using an Environmental Dust Monitor, and data for other gaseous pollutants were obtained from governmental monitoring stations.

Urinary metabolite for polycyclic aromatic hydrocarbons (PAHs) of workers were measured as a marker of personal exposure in 4 studies (18,26,29,31), while Lee et al. (24) calculated individual exposure to PAHs via monitoring site and outdoor residential samples. Occupational air pollutants studied included benzene (16,23), toluene (23,26) and welding fumes (25). A study focused on traffic pollutants used the distance from major road and traffic density to estimate the exposure data. Exposure to lead and cadmium was assessed through blood (32,38,40) and placental measurements (28). McCracken et al. (30) estimated the annual ambient black carbon (BC) exposure on elderly veterans based on a spatiotemporal model. One study examined long term effect of indoor air pollution from household fuel combustion on LTL via related questions to assess the pollution level (27).

Of 19 articles examined the association between LTL and air pollution, 15 found shorter LTL with air pollution (18,19,23-27,30-33,36-38,40), 2 longer (16,20) and 1 mixed result (22) (Table 2). The one remaining study showed non-significant association between LTL and short-term exposure to PM or other gaseous pollutants in type 2 diabetes patients (39). TL from saliva was found to be longer after pollution in children (35). The remaining five studies of placenta (17,28), buccal cells (21,34) or sperm (29) reported shorter TL with air pollution (Figure 3).

Table 2 Main findings of included studies
Full table

Figure 3 Outcome of telomere length. (A) Based on the number of articles. 20 of 25 studies found association between shorter telomere with air pollution, with 3 longer and 1 mixed result. Remaining one study did not demonstrate significant association between LTL and short-term exposure to PM or other gaseous pollutants in type 2 diabetes patients. (B) Based on the number of participants. 94.8% of population in these studies demonstrated the association between air pollution with shorter telomere length. LTL, leukocyte telomere length; PM, particulate matter.

Traffic pollutants appear to be associated with shorter LTL (23,24) and placental TL (17). The length of telomeres was reduced with the increase in traffic exposure in these three cross-sectional studies. One used airborne benzene and toluene to indicate the degree of pollution, one study selected ambient PAHs for vehicle exhaust, and the other used the distance to main road and residential surrounding greenness to estimate exposure. However, inconsistent result was demonstrated in a study where workers were used products containing benzene (16). Similarly, Hou et al. (22) found that truck drivers had increasing TL with personal exposure to PM_2.5, elemental carbon and ambient PM₁₀ on the inspection day, while their TL became shorter after 14 days. Interestingly, children from London exposed to traffic pollution had longer TL in salivary cells (35).

Coke oven workers showed shorter TL in both China (18) and Poland (31), where people are widely exposed to PAHs. People who worked in rubber (26), battery (38), boiler (37), welding (25) and car repair (21) environments all showed shorter TL. However, a group of male steel worker had longer TL after three consecutive working days (20).

In contrast to short-term exposure, the dynamic change of TL tends to be different when focusing on annual exposure to air pollutants. Pieters et al. (33) demonstrated that annual 5 µg/m³ PM_2.5 enhancement was related to 16.8% decreasing in TL of elderly people. Similarly, the TL of elderly men was decreased by 7.6% with increasing in the interquartile range of annual BC (0.25 µg/m³) (30), and this association was stronger among men more than 75 years old. This inverse association between annual BC and TL in male was replicated by another study (36). Pawlas et al. (32) found that children with higher blood lead levels had shorter telomeres. In another study lead was not associated with placenta TL, while placental cadmium concentration was correlated with shorter placental TL (28). Similarly, participants in a US national survey also displayed associations between cadmium and shorter TL while the result was not significant for lead (40). Another study showed that pregnant women who lived near waste landfill sites highly exposed to atmospheric pollution from garbage burning had shorter TL (19). The rubbish in this region has mismanaged involving illegal industrial waste as well as household waste. Women exposed to biomass smoke from cooking which contain PM_2.5 and BC had TL measured from buccal cells. More heavily exposed women had 43% shorter TL compared with the low exposure group (34). This was corresponding to another finding between exposure to cooking solid fuel and shorter LTL (27). A study of people with type 2 diabetes did not find significant relationship between TL and short term ambient PM or other gaseous pollutants (39).

Ten studies (19,29,30,32,34-37,39,40) were awarded more than seven stars and remaining 15 studies (16-18,20-28,31,33,38) were graded stars with the number from four to six (Table 3).

Table 3 Quality assessment of included study
Full table

Discussion

This is the first systematic review of studies assessing the association between air pollution and TL. The dominant findings (80% of articles and 94.8% of subjects) were that that air pollution was associated with shorter TL. While results of studies of leukocyte TL and salivary TL had diverse outcomes, telomeres from buccal cells, placental tissue and sperm all became shorter after exposure. Although all reports used Cawthon’s protocol for TL measurements and most evaluated chromosomes from leukocytes, discordant reporting formats did not allow a quantitative meta-analysis.

The telomere is a region of tandem repetitive DNA and protein complexes that cap the ends of chromosome, playing a critical role in maintaining chromosome stability (43). Due to the requirement of 5’ to 3’ replication and RNA primer, DNA polymerase cannot fully duplicate the end of the chromosome in somatic cells, which leads the telomere shortened after each cycle of the DNA replication (44). TL is approximately 30–100 bp shorter during each cell division process and can act as a senescent marker (45). The components of human telomeres are thousands of TTAGGG nucleotide repeats and protein (46). This special sequence TTAGGG makes telomeres have high content of guanine and are sensitive to oxidative stress (47). The damage caused by oxidative stress can be accumulated and lead to telomere erosion during the lifetime of cell. The shortening of telomere gradually progresses after each DNA replication cycle and accelerate the cell aging. The most important oxidative stress substance is reactive oxygen species (ROS). ROS easily reacts with nucleic acids, protein and lipids. If the cells do not have enough ability to detoxify these ROS, telomere erosion will happen. Interestingly, Telomere shortening is not an irreversible process. For example, a study of lifestyle intervention demonstrated lengthening of telomeres in the intervention group that persisted 5 years post intervention (48).

In studies included in this review, shorter leucocyte TL was common in people with polluted working or living conditions. Long-term accumulation of air pollution seems to lead to attrition of TL. A cross-sectional study of workers in a battery plant found that body lead burden, measured from 24 h urine, had stronger inverse association with leucocyte TL than blood lead levels (38). Lead can deposit in bone which act as an effective body barrier to decrease the lead in bioavailable blood. There was only one study that did not find an association between short-term PM exposure and leucocyte TL (39). The subjects included in this study were all patients with type 2 diabetes and their telomere dynamics in response to acute stressors such as air pollution may not be generalizable to the wider population.

Every article, identified through our systematic review, used Cawthon’s protocol. This technique was first proposed in 2002 and requires tiny amount of DNA to perform PCR for TL assessment (42). Smaller amounts of DNA requirement make this method easily applied to epidemiological studies that usually have large sample size (49). In 2009, Cawthon revised the original version of the method to avoid the methodological shortcoming and named it monochrome multiplex quantitative PCR (41). Due to this development of the method over time, 6 of 20 studies in this systematic review followed Cawthon’s 2009 version method (16,17,27,33,35,38), while remaining articles still measured TL through Cawthon’s initial method. It seems these two versions of protocol are similar for identified articles in this systematic review and the results are rarely affected by the version they used.

Five types of human tissues were used for TL measurements. A total of 10,568 people in these studies were examined using leukocyte TL, 450 with placenta TL, 444 with sperm TL, 333 with salivary TL and 263 with buccal cell TL. Although TLs in different tissue resources are inconsistent, the attrition rates of TL are similar for adult somatic tissue (50). Leucocytes are widely used for TL measurement because they are easy to extract from blood samples. However, buccal or salivary cells are easier to obtain, the technique is not as invasive, or expensive. The use of placental tissue is limited to research focusing on pregnant women and their offspring. Sperm TL is targeted to investigate male reproductive health.

Air pollutants have various forms including PM, liquids and gases (51,52). The composition and duration of the exposure to air pollutants influences the potential mechanism of action in affecting TL. Many different sources of PM have been shown to induce oxidative stress (53-55), including ambient PM_0.25, PM_2.5, BC, particle-bound metals and PAHs. Two studies (33,37) found the inverse relationship between PM_2.5 and LTL: one reported with each increase of 1 mg/m³ per hour for cumulative PM_2.5 exposure in the past month, TL decreased 0.04 units relatively, while the other found associations with annual average PM_2.5 concentrations.

Metals can contribute to telomere disorders in multiple ways. Cadmium can accelerate the production of ROS and disturb the antioxidative response (56). It also prevents the function of DNA mismatch repair systems (57). Other metals provoke the release of inflammatory cytokines (58). One study found longer TL in steel workers exposed to metal-rich PM for 3 working days compared with their TL on the first day before working (20).

Five papers reported the relationship between PAHs exposure and TL of which 3 indicated shorter LTL and 1 with shorter sperm TL. PAHs are a group of organic compounds comprised of multiple benzene rings which can be produced by incomplete combustion (59). Among the studies focused on LTL, Lee et al. (24) chose the level of ambient PAHs with 4, 5 or 6 benzene rings as exposure estimate, while the other two measured urinary metabolite 1-hydroxypyrene (1-OHPyr) to reflect PAHs level. Although 1-OHPyr is regarded as a reliable biomarker (59), it is difficult to determine the specific species of PAHs exposure in these articles and we can’t make a quantitative analysis.

Two reports demonstrated longer TL in acute phases after exposure to pollutants. Workers exposed to benzene for 5 separate days during a 2-week period (16), and truck drivers with short-term ambient PM pollution (22) both had longer TL compared with control groups. Little is known about the underlying mechanisms of longer TL in those exposed. Because of the discrepancy to other reports and of uncertainty, further researches are warranted to determine true effect size of air pollution on TL.

Recently, another study has been published after we finished this systematic review (60). It examined the TL from cord blood of newborns and also found shorter TL was associated with prenatal exposure to PAH. The comparison was between two groups of neonates born before and after the closure of the coal burning power plant, which indicated the benefits of reducing air pollution on children’s health.

We followed the PRISMA guideline when performing this systematic review, but prospective register with the PROSPERO database of systematic reviews was not successful during data extraction stage. Despite different sources of TL and various air pollutants were obtained through comprehensive search in multiple databases, the heterogeneity among these studies did not allow us to do meta-analysis to make a quantitative inference. All studies were observational and thus have an inherent risk of selection bias.

Conclusions

Most of the studies support the association between air pollution exposure and shortened TL. Uniform reporting format would be required to enable combined estimates of the magnitude of the effect size of the impacts of air pollution on TL.

Search criteria

PubMed

(telomer*) AND ((((particulate AND matter*)) OR (air AND pollution*)) OR (air AND pollutant*))

Results: 62 articles

Scopus

(((ALL (particulate) AND ALL (matter*))) OR ((ALL (air) AND ALL (pollution*))) OR ((ALL (air) AND ALL (pollutant*)))) AND (ALL (telomer*))

Results: 1,426 articles

Embase

1 telomer*

2 ('air'/exp OR air AND pollution*) OR ('air'/exp OR air AND pollutant*) OR (particulate AND matter*)

3 #1 AND #2

Results: 81 articles

Web of Science

1 # 1

TOPIC: (particulate) AND TOPIC: (matter*)

Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC Timespan=All years

2 # 2

TOPIC: (air) AND TOPIC: (pollution*)

Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC Timespan=All years

3 # 3

TOPIC: (air) AND TOPIC: (pollutant*)

Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC Timespan=All years

4 # 4

#3 OR #2 OR #1

Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC Timespan=All years

5 # 5

TOPIC: (telomere*)

Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC Timespan=All years

6 # 6

#5 AND #4

Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI, CCR-EXPANDED, IC Timespan=All years

Results: 45 articles

Ovid

1 (pollutant* and air).af.

2 (pollution* and air).af.

3 (matter* and particulate).af.

4 1 or 2 or 3

5 telomer*.af.

6 4 and 5

Results: 537 articles

Last search: 16 August 2017

Acknowledgements

The authors thank Ms Elizabeth Seymour, for her support in systematic review. K Negishi is supported by a fellowship award from the Heart Foundation, which had no role in the preparation of this manuscript.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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