The Role of CYP2B6*6 Gene Polymorphisms in 3,5,6-Trichloro-2-pyridinol Levels As a Biomarker of Chlorpyrifos Toxicity Among Indonesian Farmers

Overview

Journal J Prev Med Public Health

Specialty Public Health

Date 2022 Jun 9

PMID 35678002

Authors

Jen Fuk Liem

Dwi A Suryandari

Safarina G Malik

Muchtaruddin Mansyur

Dewi S Soemarko

Aria Kekalih

Imam Subekti

Franciscus D Suyatna

Bertha Pangaribuan

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

The determinants of thyroid function among vegetable farmers with primary exposure to chlorpyrifos: A cross-sectional study in Central Java, Indonesia.

Liem J, Subekti I, Mansyur M, Soemarko D, Kekalih A, Suyatna F Heliyon. 2023; 9(6):e16435.

PMID: 37251483 PMC: 10220374. DOI: 10.1016/j.heliyon.2023.e16435.

References

Eaton D, Daroff R, Autrup H, Bridges J, Buffler P, Costa L . Review of the toxicology of chlorpyrifos with an emphasis on human exposure and neurodevelopment. Crit Rev Toxicol. 2008; 38 Suppl 2:1-125. DOI: 10.1080/10408440802272158. View

Leemans M, Couderq S, Demeneix B, Fini J . Pesticides With Potential Thyroid Hormone-Disrupting Effects: A Review of Recent Data. Front Endocrinol (Lausanne). 2020; 10:743. PMC: 6915086. DOI: 10.3389/fendo.2019.00743. View

Damalas C, Koutroubas S . Farmers' Exposure to Pesticides: Toxicity Types and Ways of Prevention. Toxics. 2017; 4(1). PMC: 5606636. DOI: 10.3390/toxics4010001. View

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. DOI: 10.1016/j.envres.2016.05.011. View

Zakeri S, Amiri N, Pirahmadi S, Djadid N . Genetic variability of CYP2B6 polymorphisms in southeast Iranian population: implications for malaria and HIV/AIDS treatment. Arch Iran Med. 2014; 17(10):685-91. DOI: 0141710/AIM.009. View

Meeker J, Barr D, Ryan L, Herrick R, Bennett D, Bravo R . Temporal variability of urinary levels of nonpersistent insecticides in adult men. J Expo Anal Environ Epidemiol. 2004; 15(3):271-81. DOI: 10.1038/sj.jea.7500402. View

Lee S, Poet T, Smith J, Busby-Hjerpe A, Timchalk C . Effect of in vivo nicotine exposure on chlorpyrifos pharmacokinetics and pharmacodynamics in rats. Chem Biol Interact. 2010; 184(3):449-57. DOI: 10.1016/j.cbi.2010.01.024. View

Ventura C, Ramos Nieto M, Bourguignon N, Lux-Lantos V, Rodriguez H, Cao G . Pesticide chlorpyrifos acts as an endocrine disruptor in adult rats causing changes in mammary gland and hormonal balance. J Steroid Biochem Mol Biol. 2015; 156:1-9. DOI: 10.1016/j.jsbmb.2015.10.010. View

Hedrich W, Hassan H, Wang H . Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016; 6(5):413-425. PMC: 5045548. DOI: 10.1016/j.apsb.2016.07.016. View

10.

Zanger U, Klein K . Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Front Genet. 2013; 4:24. PMC: 3588594. DOI: 10.3389/fgene.2013.00024. View

11.

Zhu H, Kannan K . Inter-day and inter-individual variability in urinary concentrations of melamine and cyanuric acid. Environ Int. 2018; 123:375-381. PMC: 6402796. DOI: 10.1016/j.envint.2018.12.018. View

12.

Kim K, Kabir E, Jahan S . Exposure to pesticides and the associated human health effects. Sci Total Environ. 2016; 575:525-535. DOI: 10.1016/j.scitotenv.2016.09.009. View

13.

Foxenberg R, Ellison C, Knaak J, Ma C, Olson J . Cytochrome P450-specific human PBPK/PD models for the organophosphorus pesticides: chlorpyrifos and parathion. Toxicology. 2011; 285(1-2):57-66. PMC: 7275873. DOI: 10.1016/j.tox.2011.04.002. View

14.

Llop S, Murcia M, Iniguez C, Roca M, Gonzalez L, Yusa V . Distributions and determinants of urinary biomarkers of organophosphate pesticide exposure in a prospective Spanish birth cohort study. Environ Health. 2017; 16(1):46. PMC: 5436449. DOI: 10.1186/s12940-017-0255-z. View

15.

Teodoro M, Briguglio G, Fenga C, Costa C . Genetic polymorphisms as determinants of pesticide toxicity: Recent advances. Toxicol Rep. 2019; 6:564-570. PMC: 6595235. DOI: 10.1016/j.toxrep.2019.06.004. View

16.

Noren E, Lindh C, Rylander L, Glynn A, Axelsson J, Littorin M . Concentrations and temporal trends in pesticide biomarkers in urine of Swedish adolescents, 2000-2017. J Expo Sci Environ Epidemiol. 2020; 30(4):756-767. PMC: 8075908. DOI: 10.1038/s41370-020-0212-8. View

17.

Guan S, Huang M, Chan E, Chen X, Duan W, Zhou S . Genetic polymorphisms of cytochrome P450 2B6 gene in Han Chinese. Eur J Pharm Sci. 2006; 29(1):14-21. DOI: 10.1016/j.ejps.2006.04.004. View

18.

Crane A, Klein K, Zanger U, Olson J . Effect of CYP2B6*6 and CYP2C19*2 genotype on chlorpyrifos metabolism. Toxicology. 2012; 293(1-3):115-122. PMC: 3935332. DOI: 10.1016/j.tox.2012.01.006. View

19.

Zanger U, Schwab M . Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013; 138(1):103-41. DOI: 10.1016/j.pharmthera.2012.12.007. View

20.

Garabrant D, Aylward L, Berent S, Chen Q, Timchalk C, Burns C . Cholinesterase inhibition in chlorpyrifos workers: Characterization of biomarkers of exposure and response in relation to urinary TCPy. J Expo Sci Environ Epidemiol. 2008; 19(7):634-42. DOI: 10.1038/jes.2008.51. View