Traffic-Related Air Pollution Contributes to Development of Facial Lentigines: Further Epidemiological Evidence from Caucasians and Asians

  • Author Footnotes
    9 These authors contributed equally to this work.
    Anke Hüls
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    IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany
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    Andrea Vierkötter
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    IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany
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  • Author Footnotes
    9 These authors contributed equally to this work.
    Wenshan Gao
    Footnotes
    9 These authors contributed equally to this work.
    Affiliations
    Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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  • Ursula Krämer
    Affiliations
    IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany
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  • Yajun Yang
    Affiliations
    State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China

    Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
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  • Anan Ding
    Affiliations
    Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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  • Sabine Stolz
    Affiliations
    IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany
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  • Mary Matsui
    Affiliations
    The Estee Lauder Companies, Melville, New York, USA
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  • Haidong Kan
    Affiliations
    Key Lab of Public Health Safety, Fudan University, Shanghai, China
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  • Author Footnotes
    ∗ for questions regarding the Chinese Taizhou cohort and [email protected] for questions regarding the analysis of data derived from the Taizhou cohort
    Sijia Wang
    Footnotes
    ∗ for questions regarding the Chinese Taizhou cohort and [email protected] for questions regarding the analysis of data derived from the Taizhou cohort
    Affiliations
    Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
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  • Author Footnotes
    9 These authors contributed equally to this work.
    Li Jin
    Correspondence
    Additional corresponding authors
    Footnotes
    9 These authors contributed equally to this work.
    Affiliations
    State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China

    Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
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  • Author Footnotes
    9 These authors contributed equally to this work.
    Jean Krutmann
    Correspondence
    Primary corresponding author
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    IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany
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    9 These authors contributed equally to this work.
    Tamara Schikowski
    Footnotes
    9 These authors contributed equally to this work.
    Affiliations
    IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany

    Swiss Tropical and Public Health Institute, Basel, Switzerland

    University of Basel, Basel, Switzerland
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  • Author Footnotes
    9 These authors contributed equally to this work.
    ∗ for questions regarding the Chinese Taizhou cohort and [email protected] for questions regarding the analysis of data derived from the Taizhou cohort
Open ArchivePublished:February 08, 2016DOI:https://doi.org/10.1016/j.jid.2015.12.045

      Abbreviations:

      PM (particulate matter), PM10 (particulate matter of <10 μm in diameter), SALIA (Study on the Influence of Air Pollution on Lung Function, Inflammation and Aging)
      To the Editor
      Skin integrity is compromised by air pollution (
      • Krutmann J.
      • Liu W.
      • Li L.
      • Pan X.
      • Crawford M.
      • Sore G.
      • et al.
      Pollution and skin: from epidemiological and mechanistic studies to clinical implications.
      ). Chronic exposure to traffic-related particulate matter (PM) was previously linked to development of facial lentigines in 400 Caucasian women from the Study on the Influence of Air Pollution on Lung Function, Inflammation and Aging (SALIA) cohort study. In addition to PM, traffic-related air pollution is characterized by increased concentrations of nitrogen dioxide (NO2). NO2 exposure is known to be associated with low lung function and lung cancer (
      • Adam M.
      • Schikowski T.
      • Carsin A.E.
      • Cai Y.
      • Jacquemin B.
      • Sanchez M.
      • et al.
      Adult lung function and long-term air pollution exposure. ESCAPE: a multicentre cohort study and meta-analysis.
      ,
      • Hamra G.
      • Laden F.
      • Cohen A.
      • Raaschou-Nielsen O.
      • Brauer M.
      • Loomis D.
      Lung cancer and exposure to nitrogen dioxide and traffic: a systematic review and meta-analysis.
      ). The effects of NO2 on human skin have never been investigated. Because environmentally induced lung and skin aging appear to be closely related (
      • Vierkötter A.
      • Schikowski T.
      • Sugiri D.
      • Matsui M.S.
      • Krämer U.
      • Krutmann J.
      MMP-1 and -3 promoter variants are indicative of a common susceptibility for skin and lung aging: results from a cohort of elderly women (SALIA).
      ), we assessed the link between chronic exposure to NO2 and lentigo development. Data from an extended SALIA population and an independent study of Han Chinese from the Chinese Taizhou cohort were analyzed.
      Both cohort studies are described in detail elsewhere (
      • Schikowski T.
      • Ranft U.
      • Sugiri D.
      • Vierkötter A.
      • Brüning T.
      • Harth V.
      • et al.
      Decline in air pollution and change in prevalence in respiratory symptoms and chronic obstructive pulmonary disease in elderly women.
      ,
      • Vossoughi M.
      • Schikowski T.
      • Vierkötter A.
      • Sugiri D.
      • Hoffmann B.
      • Teichert T.
      • et al.
      Air pollution and subclinical airway inflammation in the SALIA cohort study.
      ,
      • Wang X.
      • Lu M.
      • Qian J.
      • Yang Y.
      • Li S.
      • Lu D.
      • et al.
      Rationales, design and recruitment of the Taizhou Longitudinal Study.
      ). In this study, lentigines were visually evaluated by trained personnel according to photo reference scales (
      • Tschachler E.
      • Morizot F.
      Ethnic differences in skin aging.
      ) and on the basis of the validated skin aging score SCINEXA (
      • Vierkötter A.
      • Ranft U.
      • Krämer U.
      • Sugiri D.
      • Reimann V.
      • Krutmann J.
      The SCINEXA: a novel, validated score to simultaneously assess and differentiate between intrinsic and extrinsic skin ageing.
      ,
      • Vierkötter A.
      • Schikowski T.
      • Ranft U.
      • Sugiri D.
      • Matsui M.
      • Krämer U.
      • et al.
      Airborne particle exposure and extrinsic skin aging.
      ) in a highly standardized manner as described by
      • Li M.
      • Vierkötter A.
      • Schikowski T.
      • Hüls A.
      • Ding A.
      • Matsui M.S.
      • et al.
      Epidemiological evidence that indoor air pollution from cooking with solid fuels accelerates skin aging in Chinese women.
      . Lentigines were valued as follows: 0 indicated no spots, 5 indicated 1–10 spots, 30 indicated 11–50 spots, and 75 indicated more than 50 spots. In SALIA, air pollution exposure was estimated with land-use regression models according to the European Study of Cohorts for Air Pollution Effects (ESCAPE) study (
      • Beelen R.
      • Hoek G.
      • Vienneau D.
      • Eeftens M.
      • Dimakopoulou K.
      • Pedeli X.
      • et al.
      Development of NO2 and NOx land use regression models for estimating air pollution exposure in 36 study areas in Europe—The ESCAPE project.
      ,
      • Eeftens M.
      • Beelen R.
      • de Hoogh K.
      • Bellander T.
      • Cesaroni G.
      • Cirach M.
      • et al.
      Development of Land Use Regression models for PM(2.5), PM(2.5) absorbance, PM(10) and PM(coarse) in 20 European study areas; results of the ESCAPE project.
      ). In the Taizhou cohort, data from monitoring stations provided by the Taizhou Environmental Bureau were used. Linear regression models adjusted for potential confounders were used to analyze the association between NO2 exposure and the relative amount of lentigines (Figure 1). Adjusted regression coefficients were transformed to geometric mean ratios with 95% confidence intervals. Statistical computing was performed with R version 3.1.2 (Foundation for Statistical Development, Vienna, Austria).
      Figure 1
      Figure 1Association between an increase of 10 μg/m3 in NO2 exposure and the relative amount of lentigines in women from the German SALIA cohort and in women older than 50 years from the Chinese Taizhou cohort. All models were adjusted for age, BMI (kg/m2), smoking history, passive smoking, socioeconomic status and daily average sun exposure during adult life. In the analysis of the SALIA population we adjusted additionally for skin type (skin type I or II vs. skin type III or IV according to Fitzpatrick), sunbed use (yes or no), time of sun bathing and the use of sun protection. In the analysis of the Taizhou cohort we adjusted additionally indoor air pollution exposure (coal or biomass heating). *P < 0.05; **P < 0.01; ***P < 0.001.
      Table 1 shows a brief description of the study characteristics and Supplementary Tables S1 and S2 (online) show a description of number of lentigines in both cohorts. Mean levels of NO2 exposure were 28.8 μg/m3 in the SALIA study area and 24.1 μg/m3 in the Taizhou study area.
      Table 1Study characteristics of the German SALIA cohort and the Chinese Taizhou cohort
      CharacteristicSALIATaizhou
      N8061072
      Female, n (%)806 (100.0)743 (69.3)
      Age (in y), AM (min–max)73.5 (66.7–79.8)59.0 (27.9–89.7)
      <10 y of education, n (%)143 (17.7)883 (82.4)
      BMI, AM (95% CI)27.3 (27.0–27.6)24.0 (23.8–24.2)
      Ever smoked, n (%)162 (20.1)231 (21.5)
      Pack years, AM (95% CI)3.9 (3.0–4.7)6.0 (5.1–6.8)
      Passive smoking, n (%)486 (60.3)437 (40.8)
      Average daily sun exposure during lifetime (in h), AM (95% CI)2.6 (2.5–2.7)3.5 (3.4–3.6)
      Average yearly time of sun bathing (in h), AM (95% CI)8.4 (7.0–9.8)NA
      Skin type I or II, n (%)
      1 Skin type from type I to IV according to Fitzpatrick was assessed only in the SALIA study population.
      455 (56.5)NA
      Sunbed use, n (%)145 (18.0)NA
      Use of cosmetic with sun protection factor, n (%)491 (60.9)45 (4.2)
      Coal/biomass heating, n (%)75 (9.3)480 (44.8)
      NO2 level (μg/m3;),
      2 SALIA cohort: air pollution exposure was estimated with land-use regression models according to the procedure developed in the European Study of Cohorts for Air Pollution Effects (ESCAPE) study; Taizhou cohort: air pollution exposure was obtained from state monitoring stations.
      mean (SD)
      28.80 (7.84)24.06 (6.16)
      Abbreviations: AM, arithmetic mean; BMI, body mass index; CI, confidence interval; max, maximum; min, minimum; NA, not applicable; SD, standard deviation.
      1 Skin type from type I to IV according to Fitzpatrick was assessed only in the SALIA study population.
      2 SALIA cohort: air pollution exposure was estimated with land-use regression models according to the procedure developed in the European Study of Cohorts for Air Pollution Effects (ESCAPE) study; Taizhou cohort: air pollution exposure was obtained from state monitoring stations.
      Exposure to NO2 was significantly associated with more lentigines on the cheeks in both cohorts (Figure 1, see Supplementary Table S3 online). In SALIA, an increase of 10 μg/m3 in NO2 was associated with 25% more lentigines on the cheeks (P = 0.003). The strongest association between NO2 and lentigines was on the cheeks of women older than 50 years (Figure 1, see Supplementary Table S3). This association was identical to the one observed in elderly German women from the SALIA study. Accordingly, in Chinese women older than 50 years, an increase of 10 μg/m3 in NO2 was associated with 24% more lentigines on the cheeks (P < 0.001).
      Of note, no association was observed with lentigines on the dorsal hands and forearms, further strengthening the concept that the pathogenesis of lentigines might differ depending on anatomical site. In a first sensitivity analysis we studied the association between NO2 and PM of <10 μm in diameter (PM10) on lentigines in two separate models (see Supplementary Figure S1 online). This analysis showed that NO2 had a slightly stronger effect on lentigines than did PM10. In a second sensitivity analysis we analyzed two-pollutant models that included NO2 and PM10 (see Supplementary Figure S2 online). The effects of NO2 and PM10 were reduced and not significant anymore. This shows that the effects of NO2 and PM10 cannot be disentangled because of high correlation between these measures. These analyses were performed in SALIA only, where individual exposure measures were available.
      To the best of our knowledge this is the largest epidemiological study showing a link between traffic-related air pollution and the formation of lentigines. Furthermore, we showed the association not only in Caucasians but also in Asians, a population in which lentigo formation is considered to be a hallmark of skin aging.
      We previously reported the association between traffic-related soot exposure and increased lentigo formation (
      • Vierkötter A.
      • Schikowski T.
      • Ranft U.
      • Sugiri D.
      • Matsui M.
      • Krämer U.
      • et al.
      Airborne particle exposure and extrinsic skin aging.
      ). Soot, which frequently results from diesel exhaust, is a mixture of carbon particles covered by organic compounds including polycyclic aromatic hydrocarbons. Polycyclic aromatic hydrocarbon-induced activation of aryl hydrocarbon receptor signaling in epidermal cells might provide a mechanistic explanation for these epidemiological observations (
      • Krutmann J.
      • Liu W.
      • Li L.
      • Pan X.
      • Crawford M.
      • Sore G.
      • et al.
      Pollution and skin: from epidemiological and mechanistic studies to clinical implications.
      ). Indeed, stimulation of primary human epidermal keratinocytes with ambient soot was recently shown to cause an activation of the aryl hydrocarbon receptor and subsequent gene transcription (
      • Nakamura M.
      • Morita A.
      • Seité S.
      • Haarmann-Stemmann T.
      • Grether-Beck S.
      • Krutmann J.
      Environment-induced lentigines (EILs): formation of solar lentigines beyond ultraviolet radiation.
      ). Whether similar mechanisms are also involved in gaseous pollutant-induced lentigo formation is currently not known. In fact, no studies have been conducted to assess the effects of NO2 on epidermal cells. There is evidence, however, for proinflammatory effects of NO2 on human bronchial epithelial cells (
      • Ayyagari V.N.
      • Januszkiewicz A.
      • Nath J.
      Effects of nitrogen dioxide on the expression of intercellular adhesion molecule-1, neutrophil adhesion, and cytotoxicity: studies in human bronchial epithelial cells.
      ).
      Several studies found an effect of NO2 on the lung (
      • Adam M.
      • Schikowski T.
      • Carsin A.E.
      • Cai Y.
      • Jacquemin B.
      • Sanchez M.
      • et al.
      Adult lung function and long-term air pollution exposure. ESCAPE: a multicentre cohort study and meta-analysis.
      ). In these studies NO2 mostly served as a marker for a mixture of pollutants formed in the high temperature combustion of fossil fuels, including fine and ultrafine particles. Further mechanistic studies are needed to clarify whether NO2 is one of the causal substances inducing the effect.
      Strengths of this study are the use of two large ethnically different cohorts (Caucasians and Asians), centrally defined harmonized variables about living conditions and sun exposure, and the use of the SCINEXA to evaluate skin aging in both study populations. There are also some limitations. Air pollution data were obtained from state monitoring stations in the Taizhou cohort; therefore, individual assignment of exposure was fairly coarse leading to small spatial variation. Furthermore, in the SALIA study there might be higher nonsystematic errors in the individual exposure data. Nevertheless, the similar effect estimates in both studies indicate a true underlying effect.
      In conclusion, our results corroborate and extend our previous notion that exposure to traffic-related air pollutants influences the formation of lentigines. They indicate that this conclusion is relevant for Caucasians and Asians and that air pollution-associated gases contribute to this effect.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      The SALIA follow-up study 2008/2009 was funded by the German Statutory Accident Insurance (DGUV), and the skin aging investigation in this follow-up study was funded by Sonderforschungsbereich 728 and Bundesministerium für Umwelt, Naturschutz, Bau und Reaktorsicherheit Teilprojekt C1. The Taizhou study was partly supported by grants from National Natural Science Foundation of China (grant no. 31322030) and Ministry of Science and Technology (grant no. 2011BAI09B00) and also by a Max Planck-CAS Paul Gerson Unna Independent Research Group Leadership Award (to SW), a National Thousand Young Talents Award (to SW), and a Chinese Academy of Sciences Visiting Professor Fellowship (President’s International Fellowship Initiative, to JK) and was part of an International Leibniz Research Project between IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany and Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai, China/Fudan University. Furthermore, the 2 studies were financially supported by research grants from The Estee Lauder Companies. We also thank all study participants.

      Supplementary Material

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      Linked Article

      • Age-Dependent Decrease of Mitochondrial Complex II Activity in Human Skin Fibroblasts
        Journal of Investigative DermatologyVol. 136Issue 5
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          The mitochondrial theory of aging remains one of the most widely accepted aging theories and implicates mitochondrial electron transport chain dysfunction with subsequent increasing free radical generation. Recently, complex II of the electron transport chain appears to be more important than previously thought in this process, suggested predominantly by nonhuman studies. We investigated the relationship between complex II and aging using human skin as a model tissue. The rate of complex II activity per unit of mitochondria was determined in fibroblasts and keratinocytes cultured from skin covering a wide age range.
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