Downloaded from pmj.bmj.com on June 23, 2014 - Published by group.bmj.com
Republished review
Environmental and occupational exposure to chemicals and telomere length in human studies Xiao Zhang,1 Shao Lin,2 William E Funk,3 Lifang Hou1,4
1
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA 2 Department of Epidemiology & Biostatistics, School of Public Health, University at Albany, Rensselaer, New York, USA 3 Department of Anthropology, Northwestern University, Evanston, Illinois, USA 4 Department of Preventive Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA Correspondence to Dr Lifang Hou, Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Chicago, IL 60611, USA; [email protected] This is a reprint of a paper that first appeared in Occup Environ Med 2013, Volume 70, pages 743–749. Received 27 December 2012 Revised 16 May 2013 Accepted 27 May 2013 Published Online First 17 June 2013
ABSTRACT Telomeres are complexes of tandem repeats of DNA (50 -TTAGGG-30 ) 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 shortterm 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.
INTRODUCTION
To cite: Zhang X, Lin S, Funk WE, et al. Postgrad Med J 2013;89:722–728.
722
Human telomeres are complexes of tandem repeats of DNA (10–15 kb, 50 -TTAGGG-30 ) 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 telomerasebased 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
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.
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
Postgrad Med J 2013;89:722–728. doi:10.1136/postgradmedj-2012-101350rep
Downloaded from pmj.bmj.com on June 23, 2014 - Published by group.bmj.com
Republished review Figure 1 Hypothesized conceptual model for telomere length shortening and chemical exposure.
elucidate the mechanisms of disease development and identify populations at high risk for occupational and environmental diseases. 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.
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 Postgrad Med J 2013;89:722–728. doi:10.1136/postgradmedj-2012-101350rep
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 723
724 WBCs
WBCs
Arsenic37
WBCs
Lead15
PM7
WBCs
Occupational exposures to pesticides14
WBCs
WBCs WBCs
N-nitrosamines12 Occupational exposures to paints and pesticides13
Waste landfill sites17
WBCs
PAHs11
Buccal cells
WBCs
PAHs10
Occupational exposure in car mechanical workshops16
WBCs
WBCs
Benzene and toluene9
BC
8
Samples
161 highly exposed participants 41 low-exposed participants Median 0.37, range 0.18–0.67 in all subjects
48 coke-oven workers: 0.99 (0.31 to 3.00) 44 unexposed controls: 1.20 (0.43 to 2.12) p=0.038 145 coke-oven workers: 1.10±0.75 68 controls: 1.43±1.06 p=0.026 157 rubber workers: median 0.71, range 0.16–1.3 13 exposed MDS patients: 2.97±1.48 47 non-exposed MDS patients: 4.23±2.44 p=0.09 20 exposed MDS patients: MESF10 p=0.0013 60 battery workers with normal lead level: 1.91 ±0.46 84 battery workers with abnormal lead level: 1.66 ±0.63 p=0.01 120 exposed workers: 0 to 4.0 120 unexposed controls: 0 to 53.08 p=0.001 50 exposed pregnant women: mean 1.27 50 pregnant women: mean 3.11 p
Republished review
Environmental and occupational exposure to chemicals and telomere length in human studies Xiao Zhang,1 Shao Lin,2 William E Funk,3 Lifang Hou1,4
1
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA 2 Department of Epidemiology & Biostatistics, School of Public Health, University at Albany, Rensselaer, New York, USA 3 Department of Anthropology, Northwestern University, Evanston, Illinois, USA 4 Department of Preventive Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA Correspondence to Dr Lifang Hou, Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Chicago, IL 60611, USA; [email protected] This is a reprint of a paper that first appeared in Occup Environ Med 2013, Volume 70, pages 743–749. Received 27 December 2012 Revised 16 May 2013 Accepted 27 May 2013 Published Online First 17 June 2013
ABSTRACT Telomeres are complexes of tandem repeats of DNA (50 -TTAGGG-30 ) 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 shortterm 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.
INTRODUCTION
To cite: Zhang X, Lin S, Funk WE, et al. Postgrad Med J 2013;89:722–728.
722
Human telomeres are complexes of tandem repeats of DNA (10–15 kb, 50 -TTAGGG-30 ) 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 telomerasebased 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
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.
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
Postgrad Med J 2013;89:722–728. doi:10.1136/postgradmedj-2012-101350rep
Downloaded from pmj.bmj.com on June 23, 2014 - Published by group.bmj.com
Republished review Figure 1 Hypothesized conceptual model for telomere length shortening and chemical exposure.
elucidate the mechanisms of disease development and identify populations at high risk for occupational and environmental diseases. 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.
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 Postgrad Med J 2013;89:722–728. doi:10.1136/postgradmedj-2012-101350rep
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 723
724 WBCs
WBCs
Arsenic37
WBCs
Lead15
PM7
WBCs
Occupational exposures to pesticides14
WBCs
WBCs WBCs
N-nitrosamines12 Occupational exposures to paints and pesticides13
Waste landfill sites17
WBCs
PAHs11
Buccal cells
WBCs
PAHs10
Occupational exposure in car mechanical workshops16
WBCs
WBCs
Benzene and toluene9
BC
8
Samples
161 highly exposed participants 41 low-exposed participants Median 0.37, range 0.18–0.67 in all subjects
48 coke-oven workers: 0.99 (0.31 to 3.00) 44 unexposed controls: 1.20 (0.43 to 2.12) p=0.038 145 coke-oven workers: 1.10±0.75 68 controls: 1.43±1.06 p=0.026 157 rubber workers: median 0.71, range 0.16–1.3 13 exposed MDS patients: 2.97±1.48 47 non-exposed MDS patients: 4.23±2.44 p=0.09 20 exposed MDS patients: MESF10 p=0.0013 60 battery workers with normal lead level: 1.91 ±0.46 84 battery workers with abnormal lead level: 1.66 ±0.63 p=0.01 120 exposed workers: 0 to 4.0 120 unexposed controls: 0 to 53.08 p=0.001 50 exposed pregnant women: mean 1.27 50 pregnant women: mean 3.11 p
