Journal of Preventive Medicine and Public Health

  • 제55권3호
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  • Pages.280-288
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  • 2022
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  • 1975-8375(pISSN)
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  • 2233-4521(eISSN)
대한예방의학회 (The Korean Society for Preventive Medicine)
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The Role of CYP2B6*6 Gene Polymorphisms in 3,5,6-Trichloro-2-pyridinol Levels as a Biomarker of Chlorpyrifos Toxicity Among Indonesian Farmers

  • Liem, Jen Fuk (Doctoral Program, Faculty of Medicine Universitas Indonesia) ;
  • Suryandari, Dwi A. (Department of Biology, Faculty of Medicine Universitas Indonesia) ;
  • Malik, Safarina G. (Eijkman Institute for Molecular Biology, National Research and Innovation Agency) ;
  • Mansyur, Muchtaruddin (Community Medicine Department, Faculty of Medicine Universitas Indonesia) ;
  • Soemarko, Dewi S. (Community Medicine Department, Faculty of Medicine Universitas Indonesia) ;
  • Kekalih, Aria (Community Medicine Department, Faculty of Medicine Universitas Indonesia) ;
  • Subekti, Imam (Department of Internal Medicine, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo General Hospital) ;
  • Suyatna, Franciscus D. (Department of Pharmacology and Therapeutics, Faculty of Medicine Universitas Indonesia) ;
  • Pangaribuan, Bertha (Prodia Occupational Health Institute International)
  • 투고 : 2021.12.10
  • 심사 : 2022.03.24
  • 발행 : 2022.05.31
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초록

Objectives: One of the most widely used pesticides today is chlorpyrifos (CPF). Cytochrome P450 (CYP)2B6, the most prominent catalyst in CPF bioactivation, is highly polymorphic. The objective of our study was to evaluate the role of CYP2B6*6, which contains both 516G>T and 785A>G polymorphisms, in CPF toxicity, as represented by the concentration of 3,5,6-trichloro-2-pyridinol (TCPy), among vegetable farmers in Central Java, Indonesia, where CPF has been commonly used. Methods: A cross-sectional study was conducted among 132 vegetable farmers. Individual socio-demographic and occupational characteristics, as determinants of TCPy levels, were obtained using a structured interviewer-administered questionnaire and subsequently used to estimate the cumulative exposure level (CEL). TCPy levels were detected with liquid chromatography-mass spectrometry. CYP2B6*6 gene polymorphisms were analyzed using a TaqMan® SNP Genotyping Assay and Sanger sequencing. Linear regression analysis was performed to analyze the association between TCPy, as a biomarker of CPF exposure, and its determinants. Results: The prevalence of CYP2B6*6 polymorphisms was 31% for *1/*1, 51% for *1/*6, and 18% for *6/*6. TCPy concentrations were higher among participants with CYP2B6*1/*1 than among those with *1/*6 or *6/*6 genotypes. CYP2B6*6 gene polymorphisms, smoking, CEL, body mass index, and spraying time were retained in the final linear regression model as determinants of TCPy. Conclusions: The results suggest that CYP2B6*6 gene polymorphisms may play an important role in influencing susceptibility to CPF exposure. CYP2B6*6 gene polymorphisms together with CEL, smoking habits, body mass index, and spraying time were the determinants of urinary TCPy concentrations, as a biomarker of CPF toxicity.

키워드

과제정보

The authors received financial support for the research and publication of this article from Universitas Indonesia through PUTI Grant (No. NKB-4085/UN2.RST/HKP.05.00/2020) and Prodia Group.

참고문헌

  1. Casida JE, Bryant RJ. The ABCs of pesticide toxicology: amounts, biology, and chemistry. Toxicol Res (Camb) 2017;6(6):755-763. https://doi.org/10.1039/C7TX00198C
  2. Khan K, Ismail AA, Abdel Rasoul G, Bonner MR, Lasarev MR, Hendy O, et al. Longitudinal assessment of chlorpyrifos exposure and self-reported neurological symptoms in adolescent pesticide applicators. BMJ Open 2014;4(3):e004177. https://doi.org/10.1136/bmjopen-2013-004177
  3. Ventura C, Nieto MR, Bourguignon N, Lux-Lantos V, Rodriguez H, Cao G, et al. Pesticide chlorpyrifos acts as an endocrine disruptor in adult rats causing changes in mammary gland and hormonal balance. J Steroid Biochem Mol Biol 2016;156:1-9. https://doi.org/10.1016/j.jsbmb.2015.10.010
  4. Shrestha S, Parks CG, Goldner WS, Kamel F, Umbach DM, Ward MH, et al. Pesticide use and incident hypothyroidism in pesticide applicators in the agricultural health study. Environ Health Perspect 2018;126(9):97008. https://doi.org/10.1289/EHP3194
  5. Damalas CA, Koutroubas SD. Farmers' exposure to pesticides: toxicity types and ways of prevention. Toxics 2016;4(1):1. https://doi.org/10.3390/toxics4010001
  6. Kim KH, Kabir E, Jahan SA. Exposure to pesticides and the associated human health effects. Sci Total Environ 2017;575:525-535. https://doi.org/10.1016/j.scitotenv.2016.09.009
  7. Johansson I, Ingelman-Sundberg M. Genetic polymorphism and toxicology--with emphasis on cytochrome P450. Toxicol Sci 2011;120(1):1-13. https://doi.org/10.1093/toxsci/kfq374
  8. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138(1):103-141. https://doi.org/10.1016/j.pharmthera.2012.12.007
  9. Testai E, Buratti FM, Consiglio ED. Chlorpyrifos. In: Krieger R, editor. Hayes' handbook of pesticide toxicology. 3rd ed. London: Academic Press; 2010, p. 1505-1526.
  10. Rendic SP, Guengerich FP. Human family 1-4 cytochrome P450 enzymes involved in the metabolic activation of xenobiotic and physiological chemicals: an update. Arch Toxicol 2021;95(2):395-472. https://doi.org/10.1007/s00204-020-02971-4
  11. Farahat FM, Ellison CA, Bonner MR, McGarrigle BP, Crane AL, Fenske RA, et al. Biomarkers of chlorpyrifos exposure and effect in Egyptian cotton field workers. Environ Health Perspect 2011;119(6):801-806. https://doi.org/10.1289/ehp.1002873
  12. Callahan CL, Hamad LA, Olson JR, Ismail AA, Abdel-Rasoul G, Hendy O, et al. Longitudinal assessment of occupational determinants of chlorpyrifos exposure in adolescent pesticide workers in Egypt. Int J Hyg Environ Health 2017;220(8):1356-1362. https://doi.org/10.1016/j.ijheh.2017.09.006
  13. Zanger UM, Klein K. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Front Genet 2013;4:24. https://doi.org/10.3389/fgene.2013.00024
  14. Crane AL, Klein K, Zanger UM, Olson JR. Effect of CYP2B6*6 and CYP2C19*2 genotype on chlorpyrifos metabolism. Toxicology 2012;293(1-3):115-122. https://doi.org/10.1016/j.tox.2012.01.006
  15. LeBeau AL, Johnson GT, McCluskey JD, Harbison RD. Evaluation of urinary pesticide biomarkers among a sample of the population in the United States. J Clinic Toxicol 2012;S5:003.
  16. Dosemeci M, Alavanja MC, Rowland AS, Mage D, Zahm SH, Rothman N, et al. A quantitative approach for estimating exposure to pesticides in the Agricultural Health Study. Ann Occup Hyg 2002;46(2):245-260. https://doi.org/10.1093/annhyg/mef011
  17. Liem JF, Mansyur M, Soemarko DS, Kekalih A, Subekti I, Suyatna FD, et al. Cumulative exposure characteristics of vegetable farmers exposed to chlorpyrifos in Central Java - Indonesia; a cross-sectional study. BMC Public Health 2021;21(1):1066. https://doi.org/10.1186/s12889-021-11161-5
  18. Zakeri S, Amiri N, Pirahmadi S, Dinparast Djadid N. Genetic variability of CYP2B6 polymorphisms in southeast Iranian population: implications for malaria and HIV/AIDS treatment. Arch Iran Med 2014;17(10):685-691.
  19. Smith JN, Wang J, Lin Y, Timchalk C. Pharmacokinetics of the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCPy) in rat saliva. Toxicol Sci 2010;113(2):315-325. https://doi.org/10.1093/toxsci/kfp283
  20. Centers for Disease Control and Prevention. Urinary pyrethroids, herbicides, and OP metabolites in urine NHANES 2007-2008. Method No: 6103.03 [cited 2021 Dec 1]. Available from: https://wwwn.cdc.gov/nchs/data/nhanes/2007-2008/labmethods/uphopm_e_met.pdf.
  21. Martinez-Moral MP, Kannan K. How stable is oxidative stress level? An observational study of intra- and inter-individual variability in urinary oxidative stress biomarkers of DNA, proteins, and lipids in healthy individuals. Environ Int 2019;123:382-389. https://doi.org/10.1016/j.envint.2018.12.009
  22. Zhu H, Kannan K. Inter-day and inter-individual variability in urinary concentrations of melamine and cyanuric acid. Environ Int 2019;123:375-381. https://doi.org/10.1016/j.envint.2018.12.018
  23. Hedrich WD, Hassan HE, Wang H. Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B 2016;6(5):413-425. https://doi.org/10.1016/j.apsb.2016.07.016
  24. Helsby NA, Yong M, van Kan M, de Zoysa JR, Burns KE. The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes. Br J Clin Pharmacol 2019;85(9):1925-1934. https://doi.org/10.1111/bcp.14031
  25. Ellison CA, Abou El-Ella SS, Tawfik M, Lein PJ, Olson JR. Allele and genotype frequencies of CYP2B6 and CYP2C19 polymorphisms in Egyptian agricultural workers. J Toxicol Environ Health A 2012;75(4):232-241. https://doi.org/10.1080/15287394.2012.641201
  26. Yuce-Artun N, Kose G, Suzen HS. Allele and genotype frequencies of CYP2B6 in a Turkish population. Mol Biol Rep 2014;41(6):3891-3896. https://doi.org/10.1007/s11033-014-3256-9
  27. Guan S, Huang M, Chan E, Chen X, Duan W, Zhou SF. Genetic polymorphisms of cytochrome P450 2B6 gene in Han Chinese. Eur J Pharm Sci 2006;29(1):14-21. https://doi.org/10.1016/j.ejps.2006.04.004
  28. Noren E, Lindh C, Rylander L, Glynn A, Axelsson J, Littorin M, et al. Concentrations and temporal trends in pesticide biomarkers in urine of Swedish adolescents, 2000-2017. J Expo Sci Environ Epidemiol 2020;30(4):756-767. https://doi.org/10.1038/s41370-020-0212-8
  29. Meeker JD, Barr DB, Ryan L, Herrick RF, Bennett DH, Bravo R, et al. Temporal variability of urinary levels of nonpersistent insecticides in adult men. J Expo Anal Environ Epidemiol 2005;15(3):271-281. https://doi.org/10.1038/sj.jea.7500402
  30. Wang L, Liu Z, Zhang J, Wu Y, Sun H. Chlorpyrifos exposure in farmers and urban adults: metabolic characteristic, exposure estimation, and potential effect of oxidative damage. Environ Res 2016;149:164-170. https://doi.org/10.1016/j.envres.2016.05.011
  31. Garabrant DH, Aylward LL, Berent S, Chen Q, Timchalk C, Burns CJ, et al. Cholinesterase inhibition in chlorpyrifos workers: characterization of biomarkers of exposure and response in relation to urinary TCPy. J Expo Sci Environ Epidemiol 2009;19(7):634-642. https://doi.org/10.1038/jes.2008.51
  32. Leemans M, Couderq S, Demeneix B, Fini JB. Pesticides with potential thyroid hormone-disrupting effects: a review of recent data. Front Endocrinol (Lausanne) 2019;10:743. https://doi.org/10.3389/fendo.2019.00743
  33. Foxenberg RJ, Ellison CA, Knaak JB, Ma C, Olson JR. Cytochrome P450-specific human PBPK/PD models for the organophosphorus pesticides: chlorpyrifos and parathion. Toxicology 2011;285(1-2):57-66. https://doi.org/10.1016/j.tox.2011.04.002
  34. Hofmann MH, Blievernicht JK, Klein K, Saussele T, Schaeffeler E, Schwab M, et al. Aberrant splicing caused by single nucleotide polymorphism c.516G>T [Q172H], a marker of CYP2B6*6, is responsible for decreased expression and activity of CYP2B6 in liver. J Pharmacol Exp Ther 2008;325(1):284-292. https://doi.org/10.1124/jpet.107.133306
  35. Teodoro M, Briguglio G, Fenga C, Costa C. Genetic polymorphisms as determinants of pesticide toxicity: recent advances. Toxicol Rep 2019;6:564-570. https://doi.org/10.1016/j.toxrep.2019.06.004
  36. Llop S, Murcia M, Iniguez C, Roca M, Gonzalez L, Yusa V, et al. Distributions and determinants of urinary biomarkers of organophosphate pesticide exposure in a prospective Spanish birth cohort study. Environ Health 2017;16(1):46. https://doi.org/10.1186/s12940-017-0255-z
  37. Li AJ, Chen Z, Lin TC, Buck Louis GM, Kannan K. Association of urinary metabolites of organophosphate and pyrethroid insecticides, and phenoxy herbicides with endometriosis. Environ Int 2020;136:105456. https://doi.org/10.1016/j.envint.2019.105456
  38. Lee S, Poet TS, Smith JN, Busby-Hjerpe AL, Timchalk C. Effect of in vivo nicotine exposure on chlorpyrifos pharmacokinetics and pharmacodynamics in rats. Chem Biol Interact 2010;184(3):449-457. https://doi.org/10.1016/j.cbi.2010.01.024
  39. Eaton DL, Daroff RB, Autrup H, Bridges J, Buffler P, Costa LG, et al. Review of the toxicology of chlorpyrifos with an emphasis on human exposure and neurodevelopment. Crit Rev Toxicol 2008;38 Suppl 2:1-125.
  40. National Pesticide Information Center. Pesticide vapor pressure topic fact sheet; 2016 [cited 2021 Dec 1]. Available from: http://npic.orst.edu/factsheets/vaporpressure.html.