Skip to main content
SpringerLink
Log in

Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells

  • PCBs: Exposures, Effects, Remediation and Regulation with special reference to PCBs in Schools
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

PCBs are persistent organic pollutants that are carcinogenic and immunotoxic and have developmental toxicity. This suggests that they may interfere with normal cell maturation. Cancer and stem/progenitor cells have telomerase activity to maintain and protect the chromosome ends, but lose this activity during differentiation. We hypothesized that PCBs interfere with telomerase activity and the telomere complex, thereby disturbing cell differentiation and stem/progenitor cell function. HL-60 cells are cancer cells that can differentiated into granulocytes and monocytes. We exposed HL-60 cells to PCB126 (dioxin-like) and PCB153 (nondioxin-like) 6 days before and during 3 days of differentiation. The differentiated cells showed G0/G1 phase arrest and very low telomerase activity. hTERT and hTR, two telomerase-related genes, were downregulated. The telomere shelterins TRF1, TRF2, and POT1 were upregulated in granulocytes, and TRF2 was upregulated and POT1 downregulated in monocytes. Both PCBs further reduced telomerase activity in differentiated cells, but had only small effects on the differentiation and telomere-related genes. Treatment of undifferentiated HL-60 cells for 30 days with PCB126 produced a downregulation of telomerase activity and a decrease of hTERT, hTR, TRF1, and POT1 gene expression. With PCB153, the effects were less pronounced and some shelterin genes were increased after 30 days of exposure. With each PCB, no differentiation of cells was observed and cells continued to proliferate despite reduced telomerase activity, resulting in shortened telomeres after 30 days of exposure. These results indicate cell-type and PCB congener-specific effects on telomere/telomerase-related genes. Although PCBs do not seem to strongly affect differentiation, they may influence stem or progenitor cells through telomere attrition with potential long-term consequences for health.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • ATSDR (2000) Toxicological profile for polychlorinated biphenyls. Atlanta, GA

  • Bailey SM, Murnane JP (2006) Telomeres, chromosome instability and cancer. Nucleic Acids Res 34:2408–2417

    Article  CAS  Google Scholar 

  • Bartova E, Kozubek S, Kozubek M, Jirsova P, Lukasova E, Skalnikova M, Buchnickova K (2000) The influence of the cell cycle, differentiation and irradiation on the nuclear location of the abl, bcr and c-myc genes in human leukemic cells. Leuk Res 24:233–241

    Article  CAS  Google Scholar 

  • Birnie GD (1988) The HL60 cell line: a model system for studying human myeloid cell differentiation. Br J Cancer 9:41–5

    CAS  Google Scholar 

  • Bock KW (1994) Aryl hydrocarbon or dioxin receptor: biologic and toxic responses. Rev Physiol Biochem Pharmacol 125:1–42

    CAS  Google Scholar 

  • Cawthon RM (2002) Telomere measurement by quantitative PCR. Nucleic Acids Res 30:e47

    Article  Google Scholar 

  • Cerni C (2000) Telomeres, telomerase, and myc. An update. Mutat Res 462:31–47

    Article  CAS  Google Scholar 

  • Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, Greider CW, DePinho RA (1999) p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97:527–538

    Article  CAS  Google Scholar 

  • Colgin LM, Baran K, Baumann P, Cech TR, Reddel RR (2003) Human POT1 facilitates telomere elongation by telomerase. Curr Biol CB 13:942–946

    Article  CAS  Google Scholar 

  • Deville L, Hillion J, Segal-Bendirdjian E (2009) Telomerase regulation in hematological cancers: a matter of stemness? Biochim Biophys Acta 1792:229–239

    Article  CAS  Google Scholar 

  • Eisenberg DT (2011) An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. Am J Hum Biol Off J Hum Biol Counc 23:149–167

    Article  Google Scholar 

  • Fuoco R, Colombini MP, Ceccarini A, Abete C (1996) Polychlorobiphenyls in Antarctica. Microchem J 54:384–390

    Article  Google Scholar 

  • Gourronc FA, Robertson mM, Herrig AK, Lansdorp PM, Goldman FD, Klingelhutz AJ (2010) Proliferative defects in dyskeratosis congenita skin keratinocytes are corrected by expression of the telomerase reverse transcriptase, TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 or the telomerase RNA component, TERC. Exp Dermatol 19:279–288

    Article  CAS  Google Scholar 

  • Greenberg RA, Chin L, Femino A, Lee KH, Gottlieb GJ, Singer RH, Greider CW, DePinho RA (1999) Short dysfunctional telomeres impair tumorigenesis in the INK4a (delta2/3) cancer-prone mouse. Cell 97:515–525

    Article  CAS  Google Scholar 

  • Grimalt JO, van Drooge BL, Ribes A, Vilanova RM, Fernandez P, Appleby P (2004) Persistent organochlorine compounds in soils and sediments of European high altitude mountain lakes. Chemosphere 54:1549–1561

    Article  CAS  Google Scholar 

  • Jacobus JA, Flor S, Klingelhutz A, Robertson LW, Ludewig G (2008) 2-(4′-Chlorophenyl)-1,4-benzoquinone increases the frequency of micronuclei and shortens telomeres. Environ Toxicol Pharmacol 25:267–272

    Article  CAS  Google Scholar 

  • Jasek E, Mirecka J, Litwin JA (2008) Effect of differentiating agents (all-trans retinoic acid and phorbol 12-myristate 13-acetate) on drug sensitivity of HL60 and NB4 cells in vitro. Folia Histochem Cytobiol / Pol Acad Sci Pol Histochem Cytochemical Soc 46:323–330

    CAS  Google Scholar 

  • Kim NW, Wu F (1997) Advances in quantification and characterization of telomerase activity by the telomeric repeat amplification protocol (TRAP). Nucleic Acids Res 25:2595–2597

    Article  CAS  Google Scholar 

  • Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015

    Article  CAS  Google Scholar 

  • Kopec AK, Burgoon LD, Ibrahim-Aibo D, Mets BD, Tashiro C, Potter D, Sharratt B, Harkema JR, Zacharewski TR (2010) PCB153-elicited hepatic responses in the immature, ovariectomized C57BL/6 mice: comparative toxicogenomic effects of dioxin and non-dioxin-like ligands. Toxicol Appl Pharmacol 243:359–371

    Article  CAS  Google Scholar 

  • Koyanagi Y, Kobayashi D, Yajima T, Asanuma K, Kimura T, Sato T, Kida T, Yagihashi A, Kameshima H, Watanabe N (2000) Telomerase activity is down regulated via decreases in hTERT mRNA but not TEP1 mRNA or hTERC during the differentiation of leukemic cells. Anticancer Res 20:773–778

    CAS  Google Scholar 

  • Kuppusamy SP (2012) Telomerase and telomere dysregulation in polychlorinated biphenyl (PCB) exposed human skin keratinocytes. Dissertation. The University of Iowa, Iowa City

  • Lauby-Secretan B, Loomis D, Grosse Y, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha N, Baan R, Mattock H, Straif K, International Agency for Research on Cancer Monograph Working Group IARC, Lyon, France (2013) Carcinogenicity of polychlorinated biphenyls and polybrominated biphenyls. Lancet Oncol 14:287–288

    Article  CAS  Google Scholar 

  • Liu D, O’Connor MS, Qin J, Songyang Z (2004a) Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem 279:51338–51342

    Article  CAS  Google Scholar 

  • Liu L, Berletch JB, Green JG, Pate MS, Andrews LG, Tollefsbol TO (2004b) Telomerase inhibition by retinoids precedes cytodifferentiation of leukemia cells and may contribute to terminal differentiation. Mol Cancer Ther 3:1003–1009

    CAS  Google Scholar 

  • Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA, Weinberg RA (1997) hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90:785–795

    Article  CAS  Google Scholar 

  • Ohyashiki JH, Sashida G, Tauchi T, Ohyashiki K (2002) Telomeres and telomerase in hematologic neoplasia. Oncogene 21:680–687

    Article  CAS  Google Scholar 

  • Olovnikov AM (1971) Principle of marginotomy in template synthesis of polynucleotides. Dokl Akad Nauk SSSR 201:1496–1499

    CAS  Google Scholar 

  • Ramakrishnan S, Eppenberger U, Mueller H, Shinkai Y, Narayanan R (1998) Expression profile of the putative catalytic subunit of the telomerase gene. Cancer Res 58:622–625

    CAS  Google Scholar 

  • Rignall B, Grote K, Gavrilov A, Weimer M, Kopp-Schneider A, Krause E, Appel KE, Buchmann A, Robertson LW, Lehmler HJ, Kania-Korwel I, Chahoud I, Schwarz M (2013) Biological and tumor-promoting effects of dioxin-like and non-dioxin-like polychlorinated biphenyls in mouse liver after single or combined treatment. Toxicol Sci Off J Soc Toxicol 133:29–41

    Article  CAS  Google Scholar 

  • Robertson LW, Ludewig G (2011) Polychlorinated biphenyl (PCB) carcinogenicity with special emphasis on airborne PCBs. Gefahrst Reinhalt Luft 71:25–32

    CAS  Google Scholar 

  • Sakai H, Iwata H, Kim EY, Tsydenova O, Miyazaki N, Petrov EA, Batoev VB, Tanabe S (2006) Constitutive androstane receptor (CAR) as a potential sensing biomarker of persistent organic pollutants (POPs) in aquatic mammal: molecular characterization, expression level, and ligand profiling in Baikal seal (Pusa sibirica). Toxicol Sci Off J Soc Toxicol 94:57–70

    Article  CAS  Google Scholar 

  • Scheele J, Teufel M, Niessen KH (1992) Chlorinated hydrocarbons in the bone marrow of children: studies on their association with leukaemia. Eur J Pediatr 151:802–805

    Article  CAS  Google Scholar 

  • Senthilkumar PK, Klingelhutz AJ, Jacobus JA, Lehmler H, Robertson LW, Ludewig G (2011) Airborne polychlorinated biphenyls (PCBs) reduce telomerase activity and shorten telomere length in immortal human skin keratinocytes (HaCat). Toxicol Lett 204:64–70

    Article  CAS  Google Scholar 

  • Senthilkumar PK, Robertson LW, Ludewig G (2012) PCB153 reduces telomerase activity and telomere length in immortalized human skin keratinocytes (HaCaT) but not in human foreskin keratinocytes (NFK). Toxicol Appl Pharmacol 259:115–123

    Article  CAS  Google Scholar 

  • Shay JW, Bacchetti S (1997) A survey of telomerase activity in human cancer. Eur J Cancer 33:787–791

    Article  CAS  Google Scholar 

  • Stewart SA, Hahn WC, O’Connor BF, Banner EN, Lundberg AS, Modha P, Mizuno H, Brooks MW, Fleming M, Zimonjic DB, Popescu NC, Weinberg RA (2002) Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc Natl Acad Sci U S A 99:12606–12611

    Article  CAS  Google Scholar 

  • Ueda A, Hamadeh HK, Webb HK, Yamamoto Y, Sueyoshi T, Afshari CA, Lehmann JM, Negishi M (2002) Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol Pharmacol 61:1–6

    Article  CAS  Google Scholar 

  • van Steensel B, de Lange T (1997) Control of telomere length by the human telomeric protein TRF1. Nature 385:740–743

    Article  Google Scholar 

  • van Steensel B, Smogorzewska A, de Lange T (1998) TRF2 protects human telomeres from end-to-end fusions. Cell 92:401–413

    Article  Google Scholar 

  • Vindelov LL (1977) Flow microfluorometric analysis of nuclear DNA in cells from solid tumors and cell suspensions. A new method for rapid isolation and straining of nuclei. Virchows Archiv B Cell Pathol 24:227–242

    CAS  Google Scholar 

  • Ward MH, Colt JS, Metayer C, Gunier RB, Lubin J, Crouse V, Nishioka MG, Reynolds P, Buffler PA (2009) Residential exposure to polychlorinated biphenyls and organochlorine pesticides and risk of childhood leukemia. Environ Health Perspect 117:1007–1013

    Article  CAS  Google Scholar 

  • Watson JD (1972) Origin of concatemeric T7 DNA. Nat New Biol 239:197–201

    Article  CAS  Google Scholar 

  • Wege H, Chui MS, Le HT, Tran JM, Zern MA (2003) SYBR Green real-time telomeric repeat amplification protocol for the rapid quantification of telomerase activity. Nucleic Acids Res 31:E3–3

    Article  CAS  Google Scholar 

  • WHO (1993) Polychlorinated biphenyls and terphenyls. Environmental health criteria. World Health Organization, Geneva, p 682

  • Wu X, Amos CI, Zhu Y, Zhao H, Grossman BH, Shay JW, Luo S, Hong WK, Spitz MR (2003) Telomere dysfunction: a potential cancer predisposition factor. J Natl Cancer Inst 95:1211–1218

    Article  CAS  Google Scholar 

  • Wu Y, Xu Y, Shen Y, Wang C, Guo G, Hu T (2012) Tetramethylpyrazine potentiates arsenic trioxide activity against HL-60 cell lines. Braz J Med Biol Res Rev Bras Pesquisas Med Biol / Soc Bras Biofisica 45:187–196

    CAS  Google Scholar 

  • Yamada K, Yajima T, Yagihashi A, Kobayashi D, Koyanagi Y, Asanuma K, Yamada M, Moriai R, Kameshima H, Watanabe N (2000) Role of human telomerase reverse transcriptase and telomeric-repeat binding factor proteins 1 and 2 in human hematopoietic cells. Jpn J Cancer Res Gann 91:1278–1284

    Article  CAS  Google Scholar 

  • Ye J, Renault VM, Jamet K, Gilson E (2014) Transcriptional outcome of telomere signalling. Nat Rev Genet 15:491–503

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Hans Joachim Lehmler, The University of Iowa, for providing the PCB126 and PCB153, and the staff of the Flow Cytometry Core Facility of the University of Iowa for their help in cell cycle analysis. This work was supported by the National Institute of Environmental Health Sciences Superfund Research Program, grant number P42 ES013661. X. Xin was supported by the Training Core of this grant.

Conflict of interest

The authors declare that they have no competing interests.

Author information

Author notes

  1. P. K. Senthilkumar

    Present address: Risk Evaluation Branch, Center for Disease Control and Prevention, Cincinnati, OH, 45226, USA

Authors and Affiliations

  1. Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, 52242, USA

    Xing Xin, P. K. Senthilkumar, Jerald L. Schnoor & Gabriele Ludewig

  2. Department of Civil and Environmental Engineering, The University of Iowa, Iowa City, IA, 52242, USA

    Jerald L. Schnoor

  3. Department of Occupational and Environmental Health, The University of Iowa, 100 Oakdale Campus, IREH, Iowa City, IA, 52242-5000, USA

    Jerald L. Schnoor & Gabriele Ludewig

Authors
  1. Xing Xin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. K. Senthilkumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jerald L. Schnoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gabriele Ludewig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gabriele Ludewig.

Additional information

Responsible editor: Philippe Garrigues

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 24 kb)

ESM 2

(DOCX 28 kb)

ESM 3

(DOCX 16 kb)

ESM 4

(DOCX 16 kb)

ESM 5

(DOCX 18 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xin, X., Senthilkumar, P.K., Schnoor, J.L. et al. Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells. Environ Sci Pollut Res 23, 2173–2185 (2016). https://doi.org/10.1007/s11356-015-5187-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-015-5187-y

Keywords

Search

Navigation