Elevated Urinary 3-OH-BaP Levels and CYP1A1 Enzyme Activity in Pediatric Acute Lymphoblastic Leukemia: A Case-Control Study in a High-Pollution Region
DOI:
https://doi.org/10.56294/saludcyt20262555Keywords:
Urinary 3-OH-BaP, CYP1A1, acute lymphoblastic, leukemiaAbstract
Introduction: pollutants related to acute lymphoblastic leukemia (ALL) include polycyclic aromatic hydrocarbons (PAHs), such as the carcinogenic benzo[a]pyrene (BaP). Urinary 3-hydroxybenzo[a]pyrene (3-OH-BaP) is a key biomarker for BaP exposure. Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE-dG), the ultimate metabolite of BaP, correlates with CYP1A1 activity. However, the correlation with urinary 3-OH-BaP remains unexplored in ALL. Exploring the relationship between urinary 3-OH-BaP and CYP1A1 enzyme levels in ALL patients, the present study makes a valuable contribution to global research, addressing the lack of non-Western data on urinary PAH biomarkers in pediatric ALL.
Method: this was a case-control study including 68 subjects (33 patients and 35 healthy controls). Urine was collected for 3-OH-BaP detection via HPLC, and isolate of peripheral blood mononuclear cell (PBMC) for CYP1A1 enzyme levels via an ELISA kit.
Results: mean urinary 3-OH-BaP levels were 623 ± 463 ng/mL in ALL cases vs. 286 ± 155 ng/mL in controls (p = 0,000). Mean CYP1A1 levels were 0,4817 ± 0,17 ng/mL in ALL cases vs. 0,3018 ± 0,03 ng/mL in controls (p = 0,000). A positive correlation was found between urinary 3-OH-BaP and PBMC CYP1A1 levels (r = 0,417, p < 0,001).
Conclusion: the association between elevated urinary 3-OH-BaP and PBMC CYP1A1 levels in ALL patients compared to healthy controls suggests a role of CYP1A1 in BaP detoxification during carcinogenesis in pollution-exposed children.
References
[1] Gökbuget, N.; Boissel, N.; Chiaretti, S.; Dombret, H.; Doubek, M.; Fielding, A.; Foà, R.; Giebel, S.; Hoelzer, D.; Hunault, M.; et al. Special Report Management of ALL in Adults : 2024 ELN Recommendations from a European Expert Panel. Blood, 2024, 143 (19), 1903–1930. https://doi.org/10.1182/blood.2023023568. DOI: https://doi.org/10.1182/blood.2023023568
[2] Dzhambov, A. M. Comments on The Association between Road Traffic Noise and Type 2 Diabetes: A Systematic Review and Meta-Analysis of Cohort Studies. Environ. Sci. Pollut. Res., 2023, 30 (37), 88235–88237. https://doi.org/10.1007/s11356-023-28830-0. DOI: https://doi.org/10.1007/s11356-023-28830-0
[3] Nematollahi, P.; Enayati, S.; Ebrahimpour, K.; Yousefian, S.; Moafi, A.; Ebrahimi, A. Association of Exposure to Benzene Compounds and Organochlorine Pesticides with Pediatric Acute Leukemia. Discov. Public Heal., 2025, 22 (1). https://doi.org/0.1186/s12982-025-00809-x. DOI: https://doi.org/10.1186/s12982-025-00809-x
[4] D.Barbeau; R.Persoons; M.Marques; A.Maitre. Biomonitoring of PAH Carcinogenic Exposure Using Urinary 3-Hydroxybenzo[a]Pyrene Instead of 1-Hydroxypyrene. Toxicol. Lett., 2011, 205, S72. https://doi.org/10.1016/j.toxlet.2011.05.271. DOI: https://doi.org/10.1016/j.toxlet.2011.05.272
[5] Lee, S. H. R.; Yang, W.; Gocho, Y.; John, A.; Rowland, L.; Smart, B.; Williams, H.; Maxwell, D.; Hunt, J.; Yang, W. Pharmacotypes across the Genomic Landscape of Pediatric Acute Lymphoblastic Leukemia and Impact on Treatment Response. Nat. Med., 2023, 29 (1), 170–179. https://doi.org/10.1038/s41591-022-02112-7. DOI: https://doi.org/10.1038/s41591-022-02112-7
[6] Pasquini, M. C.; Hu, Z.-H.; Curran, K.; Laetsch, T.; Locke, F.; Rouce, R.; Pulsipher, M. A.; Phillips, C. L.; Keating, A.; Frigault, M. J. Real-World Evidence of Tisagenlecleucel for Pediatric Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma. Blood Adv., 2020, 4 (21), 5414–5424. https://doi.org/10.1182/bloodadvances.2020003092. DOI: https://doi.org/10.1182/bloodadvances.2020003092
[7] Koukoulakis, K. G.; Kanellopoulos, P. G.; Chrysochou, E.; Koukoulas, V.; Minaidis, M.; Maropoulos, G.; Nikoleli, G. P.; Bakeas, E. Leukemia and PAHs Levels in Human Blood Serum: Preliminary Results from an Adult Cohort in Greece. Atmos. Pollut. Res., 2020, 11 (9), 1552–1565. https://doi.org/10.1016/j.apr.2020.06.018. DOI: https://doi.org/10.1016/j.apr.2020.06.018
[8] Bloom, M.; Maciaszek, J. L.; Clark, M. E.; Pui, C.-H.; Nichols, K. E. Recent Advances in Genetic Predisposition to Pediatric Acute Lymphoblastic Leukemia. Expert Rev. Hematol., 2020, 13 (1), 55–70. https://doi.org/10.1080/17474086.2020.1685866. DOI: https://doi.org/10.1080/17474086.2020.1685866
[9] Monick, M. M.; Beach, S. R. H.; Plume, J.; Sears, R.; Gerrard, M.; Brody, G. H.; Philibert, R. A. Coordinated Changes in AHRR Methylation in Lymphoblasts and Pulmonary Macrophages from Smokers. Am. J. Med. Genet. Part B Neuropsychiatr. Genet., 2012, 159B (2), 141–151. https://doi.org/10.1002/ajmg.b.32021. DOI: https://doi.org/10.1002/ajmg.b.32021
[10] Timms, J. A.; Relton, C. L.; Rankin, J.; Strathdee, G.; McKay, J. A. DNA Methylation as a Potential Mediator of Environmental Risks in the Development of Childhood Acute Lymphoblastic Leukemia. Epigenomics, 2016, 8 (4), 519–536. https://doi.org/10.2217/epi-2015-0011. DOI: https://doi.org/10.2217/epi-2015-0011
[11] Lu, J.; Zhao, Q.; Zhai, Y. J.; He, H. R.; Yang, L. H.; Gao, F.; Zhou, R. S.; Zheng, J.; Ma, X. C. Genetic Polymorphisms of CYP1A1 and Risk of Leukemia: A Meta-Analysis. Onco. Targets. Ther., 2015, 8, 2883–2902. https://doi.org/10.2147/OTT.S92259. DOI: https://doi.org/10.2147/OTT.S92259
[12] Takam, P.; Schäffer, A.; Laovitthayanggoon, S.; Charerntantanakul, W.; Sillapawattana, P. Toxic Effect of Polycyclic Aromatic Hydrocarbons (PAHs) on Co-Culture Model of Human Alveolar Epithelial Cells (A549) and Macrophages (THP-1). Environ. Sci. Eur., 2024, 36 (1). https://doi.org/10.1186/s12302-024-01003-7. DOI: https://doi.org/10.1186/s12302-024-01003-7
[13] Ahn, M. B.; Suh, B.-K. Bone Morbidity in Pediatric Acute Lymphoblastic Leukemia. Ann. Pediatr. Endocrinol. Metab., 2020, 25 (1), 1–9. https://doi.org/10.6065/apem.2020.25.1.1. DOI: https://doi.org/10.6065/apem.2020.25.1.1
[14] Akhtar, S.; Hourani, S.; Therachiyil, L.; Al-Dhfyan, A.; Agouni, A.; Zeidan, A.; Uddin, S.; Korashy, H. M. Epigenetic Regulation of Cancer Stem Cells by the Aryl Hydrocarbon Receptor Pathway. Semin. Cancer Biol., 2022, 83, 177–196. https://doi.org/10.1016/j.semcancer.2020.08.014. DOI: https://doi.org/10.1016/j.semcancer.2020.08.014
[15] Brillantino, C.; Rossi, E.; Bifano, D.; Minelli, R.; Tamasi, S.; Mamone, R.; Bignardi, E.; Zeccolini, R.; Zeccolini, M.; Vallone, G. An Unusual Onset of Pediatric Acute Lymphoblastic Leukemia. J. Ultrasound, 2021, 24 (4), 555–560. https://doi.org/10.1007/s40477-020-00461-y. DOI: https://doi.org/10.1007/s40477-020-00461-y
[16] Tran, T. H.; Hunger, S. P. The Genomic Landscape of Pediatric Acute Lymphoblastic Leukemia and Precision Medicine Opportunities. In Seminars in cancer biology; Elsevier, 2022; Vol. 84, pp 144–152. https://doi.org/10.1016/j.semcancer.2020.10.013. DOI: https://doi.org/10.1016/j.semcancer.2020.10.013
[17] Brown, P.; Inaba, H.; Annesley, C.; Beck, J.; Colace, S.; Dallas, M.; DeSantes, K.; Kelly, K.; Kitko, C.; Lacayo, N. Pediatric Acute Lymphoblastic Leukemia, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw., 2020, 18 (1), 81–112. https://doi.org/10.6004/jnccn.2020.0001. DOI: https://doi.org/10.6004/jnccn.2020.0001
[18] Barbeau, D.; Maître, A.; Marques, M. Highly Sensitive Routine Method for Urinary 3-Hydroxybenzo[a]Pyrene Quantitation Using Liquid Chromatography-Fluorescence Detection and Automated off-Line Solid Phase Extraction. Analyst, 2011, 136 (6), 1183. https://doi.org/10.1039/c0an00428f. DOI: https://doi.org/10.1039/c0an00428f
[19] Wang, X. H.; Hong, H. S.; Mu, J. L.; Lin, J. Q.; Wang, S. H. Polycyclic Aromatic Hydrocarbon (PAH) Metabolites in Marine Fishes as a Specific Biomarker to Indicate PAH Pollution in the Marine Coastal Environment. J. Environ. Sci. Heal. Part A, 2008, 43 (3), 219–226. https://doi.org/10.1080/10934520701792662. DOI: https://doi.org/10.1080/10934520701792662
[20] Moorthy, B.; Chu, C.; Carlin, D. J. Polycyclic Aromatic Hydrocarbons: From Metabolism to Lung Cancer. Toxicol. Sci., 2015, 145 (1), 5–15. https://doi.org/10.1093/toxsci/kfv040. DOI: https://doi.org/10.1093/toxsci/kfv040
[21] Marquès, M.; Persoons, R. Comparison of Urinary 3-Hydroxybenzo(a)Pyrene (3-OHBaP) and Trans-Anti-7,8,9,10-Tetrahydroxy-7,8,9,10-Tetrahydrobenzo(a)Pyrene (TetraolBaP) as Biomarkers of Exposure to Carcinogenic BaP. Int. J. Hyg. Environ. Health, 2025, 263, 114476. https://doi.org/10.1016/j.ijheh.2024.114476. DOI: https://doi.org/10.1016/j.ijheh.2024.114476
[22] Montano, L.; Baldini, G. M.; Piscopo, M.; Liguori, G.; Lombardi, R.; Ricciardi, M.; Esposito, G.; Pinto, G.; Fontanarosa, C.; Spinelli, M.; et al. Polycyclic Aromatic Hydrocarbons (PAHs) in the Environment: Occupational Exposure, Health Risks and Fertility Implications. Toxics, 2025, 13 (3), 151. https://doi.org/10.3390/toxics13030151. DOI: https://doi.org/10.3390/toxics13030151
[23] Styszko, K.; Pamuła, J.; Pac, A.; Sochacka-Tatara, E. Biomarkers for Polycyclic Aromatic Hydrocarbons in Human Excreta: Recent Advances in Analytical Techniques—a Review. Environ. Geochem. Health, 2023, 45 (10), 7099–7113. https://doi.org/10.1007/s10653-023-01699-1. DOI: https://doi.org/10.1007/s10653-023-01699-1
[24] Colvin, V. C.; Bastin, K. M.; Siddens, L. K.; Vermillion Maier, M. L.; Williams, D. E.; Smith, J. N.; Tilton, S. C. Building a Predictive Model for Polycyclic Aromatic Hydrocarbon Dosimetry in Organotypically Cultured Human Bronchial Epithelial Cells Using Benzo[a]Pyrene. Toxicol. Reports, 2025, 15, 102133. https://doi.org/10.1016/j.toxrep.2025.102133. DOI: https://doi.org/10.1016/j.toxrep.2025.102133
[25] Yang, P.; Ma, J.; Zhang, B.; Duan, H.; He, Z.; Zeng, J.; Zeng, X.; Li, D.; Wang, Q.; Xiao, Y.; et al. CpG Site–Specific Hypermethylation of P16INK4α in Peripheral Blood Lymphocytes of PAH-Exposed Workers. Cancer Epidemiol. Biomarkers Prev., 2012, 21 (1), 182–190. https://doi.org/10.1158/1055-9965.epi-11-0784. DOI: https://doi.org/10.1158/1055-9965.EPI-11-0784
[26] Wohak, L. E.; Krais, A. M.; Kucab, J. E.; Stertmann, J.; Øvrebø, S.; Seidel, A.; Phillips, D. H.; Arlt, V. M. Carcinogenic Polycyclic Aromatic Hydrocarbons Induce CYP1A1 in Human Cells via a P53-Dependent Mechanism. Arch. Toxicol., 2014, 90 (2), 291–304. https://doi.org/10.1007/s00204-014-1409-1. DOI: https://doi.org/10.1007/s00204-014-1409-1
[27] Hunger, S. P.; Raetz, E. A. How I Treat Relapsed Acute Lymphoblastic Leukemia in the Pediatric Population. Blood, J. Am. Soc. Hematol., 2020, 136 (16), 1803–1812. https://doi.org/10.1182/blood.2019004043. DOI: https://doi.org/10.1182/blood.2019004043
[28] Luo, K.; Stepanov, I.; Hecht, S. S. Chemical Biomarkers of Exposure and Early Damage from Potentially Carcinogenic Airborne Pollutants. Ann. Cancer Epidemiol., 2019, 3, 5. https://doi.org/10.21037/ace.2019.08.01. DOI: https://doi.org/10.21037/ace.2019.08.01
[29] Calderon-hernandez, J.; Jarquin-yañez, L.; Reyes-arreguin, L.; Diaz-padilla, L. A.; Gonzalez-compean, J. L.; Gonzalez-montalvo, P.; Rivera-gomez, R.; Villanueva-toledo, J. R. Childhood Acute Lymphoblastic Leukemia Survival and Spatial Analysis of Socio-Environmental Risks in Mexico. 2023, No. October, 1–12. https://doi.org/10.3389/fonc.2023.1236942. DOI: https://doi.org/10.1289/isee.2024.1657
[30] Cao, Y.; Lu, J.; Lu, J. Paternal Smoking Before Conception and During Pregnancy Is Associated With an Increased Risk of Childhood Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis of 17 Case-Control Studies. J. Pediatr. Hematol. Oncol., 2020, 42 (1). https://doi.org/10.1097/MPH.0000000000001657. DOI: https://doi.org/10.1097/MPH.0000000000001657
[31] Lejman, M.; Kuśmierczuk, K.; Bednarz, K.; Ostapińska, K.; Zawitkowska, J. Targeted Therapy in the Treatment of Pediatric Acute Lymphoblastic Leukemia—Therapy and Toxicity Mechanisms. Int. J. Mol. Sci., 2021, 22 (18), 9827. https://doi.org/10.3390/ijms22189827. DOI: https://doi.org/10.3390/ijms22189827
[32] Shiizaki, K.; Kawanishi, M.; Yagi, T. Modulation of Benzo[a]Pyrene–DNA Adduct Formation by CYP1 Inducer and Inhibitor. Genes Environ., 2017, 39 (1). https://doi.org/10.1186/s41021-017-0076-x. DOI: https://doi.org/10.1186/s41021-017-0076-x
[33] Rujkijyanont, P.; Inaba, H. Diagnostic and Treatment Strategies for Pediatric Acute Lymphoblastic Leukemia in Low-and Middle-Income Countries. Leukemia, 2024, 38 (8), 1649–1662. https://doi.org/10.1038/s41375-024-02277-9. DOI: https://doi.org/10.1038/s41375-024-02277-9
[34] Al-Mahayri, Z. N.; AlAhmad, M. M.; Ali, B. R. Long-Term Effects of Pediatric Acute Lymphoblastic Leukemia Chemotherapy: Can Recent Findings Inform Old Strategies? Front. Oncol., 2021, 11, 710163. https://doi.org/10.3389/fonc.2021.710163. DOI: https://doi.org/10.3389/fonc.2021.710163
[35] Zhang, X.; Hou, H.; Xiong, W.; Hu, Q. Development of a Method to Detect Three Monohydroxylated Polycyclic Aromatic Hydrocarbons in Human Urine by Liquid Chromatographic Tandem Mass Spectrometry. J. Anal. Methods Chem., 2015, 2015, 514320. https://doi.org/10.1155/2015/514320. DOI: https://doi.org/10.1155/2015/514320
[36] Lafontaine, M.; Gendre, C.; Delsaut, P.; Simon, P. Urinary 3-Hydroxybenzo[a]Pyrene as a Biomarker of Exposure to Polycyclic Aromatic Hydrocarbons: An Approach for Determining a Biological Limit Value. Polycycl. Aromat. Compd., 2004, 24 (4–5), 441–450. https://doi.org/10.1080/10406630490471447. DOI: https://doi.org/10.1080/10406630490471447
[37] Kato, M. Pediatric Acute Lymphoblastic Leukemia; Springer, 2020. DOI: https://doi.org/10.1007/978-981-15-0548-5
[38] Hayashi, H.; Makimoto, A.; Yuza, Y. Treatment of Pediatric Acute Lymphoblastic Leukemia: A Historical Perspective. Cancers (Basel)., 2024, 16 (4), 723. https://doi.org/10.3390/cancers16040723. DOI: https://doi.org/10.3390/cancers16040723
[39] Brady, S. W.; Roberts, K. G.; Gu, Z.; Shi, L.; Pounds, S.; Pei, D.; Cheng, C.; Dai, Y.; Devidas, M.; Qu, C. The Genomic Landscape of Pediatric Acute Lymphoblastic Leukemia. Nat. Genet., 2022, 54 (9), 1376–1389. https://doi.org/10.1038/s41588-022-01159-z. DOI: https://doi.org/10.1038/s41588-022-01159-z
[40] Navarrete-Aliaga, Ó.; Muriach, M.; Delgado-Saborit, J. M. Toxicological Effects of Air Pollutants on Human Airway Cell Models Using Air–Liquid Interface Systems: A Systematic Review. Curr. Environ. Heal. Reports, 2025, 12 (1), 10.1007. https://doi.org/10.1007/s40572-025-00491-w. DOI: https://doi.org/10.1007/s40572-025-00491-w
[41] Dinardo, C. D.; Gharibyan, V.; Yang, H.; Wei, Y.; Pierce, S.; Kantarjian, H. M.; Rytting, M. Impact of Aberrant DNA Methylation Patterns Including CYP1B1 Methylation in Adolescents and Young Adults with Acute Lymphocytic Leukemia. 2013, 784–789. https://doi.org/10.1002/ajh.23511. DOI: https://doi.org/10.1002/ajh.23511
[42] Inaba, H.; Pui, C.-H. Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia. J. Clin. Med., 2021, 10 (9), 1926. https://doi.org/10.3390/jcm10091926. DOI: https://doi.org/10.3390/jcm10091926
[43] Mahmood, N.; Shahid, S.; Bakhshi, T.; Riaz, S.; Ghufran, H.; Yaqoob, M. Identification of Significant Risks in Pediatric Acute Lymphoblastic Leukemia (ALL) through Machine Learning (ML) Approach. Med. Biol. Eng. Comput., 2020, 58 (11), 2631–2640. https://doi.org/10.1007/s11517-020-02245-2. DOI: https://doi.org/10.1007/s11517-020-02245-2
[44] Kurniawan, A.; Risanti, E. D.; Suhda, S.; Rinonce, H. T.; Dwianingsih, E. K.; Fachiroh, J. WIF1 Qualitative-Methylation from Peripheral Blood Could Not Be Used as Biomarker for The Risk of Nasopharyngeal Carcinoma or Smoking Behavior in Yogyakarta Panel. Indones. Biomed. J., 2019, 11 (3), 273–278. https://doi.org/10.18585/inabj.v11i3.810. DOI: https://doi.org/10.18585/inabj.v11i3.810
[45] Goswami, S.; Karmakar, S.; Brahmachari, K.; Sarkar, P.; Sharma, N.; Ghosh, M.; Maji, S.; Koley, S.; Shaw, S.; Goswami, D. Gastroprotective Potential of Indian Medicinal Plants-A Comprehensive Review. Mathews J. Gastroenterol. Hepatol., 2024, 9 (1), 1–37. https://doi.org/10.30654/MJGH.10023. DOI: https://doi.org/10.30654/MJGH.10023
[46] Risanti, E. D.; Kurniawan, A.; Wahyuningsih, L.; Dwianingsih, E. K.; Rinonce, H. T.; Fachiroh, J. Association of Peripheral Blood RASSF1A and CDKN2A Methylation Status with Smoking Behaviour in Nasopharyngeal Carcinoma. Indones. Biomed. J., 2018, 10 (2), 123–127. https://doi.org/10.18585/inabj.v10i2.381. DOI: https://doi.org/10.18585/inabj.v10i2.381
[47] Inaba, H.; Mullighan, C. G. Pediatric Acute Lymphoblastic Leukemia. Haematologica, 2020, 105 (11), 2524. https://doi.org/10.3324/haematol.2020.247031. DOI: https://doi.org/10.3324/haematol.2020.247031
[48] Förster, K.; Preuss, R.; Roßbach, B.; Brüning, T.; Angerer, J.; Simon, P. 3-Hydroxybenzo[a]Pyrene in the Urine of Workers with Occupational Exposure to Polycyclic Aromatic Hydrocarbons in Different Industries. Occup. Environ. Med., 2008, 65 (4), 224–229. https://doi.org/10.1136/oem.2006.030809. DOI: https://doi.org/10.1136/oem.2006.030809
[49] Ivanov, A. V.; Alecsa, M. S.; Popescu, R.; Starcea, M. I.; Mocanu, A. M.; Rusu, C.; Miron, I. C. Pediatric Acute Lymphoblastic Leukemia Emerging Therapies—From Pathway to Target. Int. J. Mol. Sci., 2023, 24 (5), 4661. https://doi.org/10.3390/ijms24054661. DOI: https://doi.org/10.3390/ijms24054661
[50] Zhang, T.; Zhou, X.; Wang, L.; Li, C.; Xu, Y.; Liu, Z. Vascular Toxicity of Benzene Series Released from Decorative Materials. Toxicol. Ind. Health, 2025, 41 (5–6), 346–364. https://doi.org/10.1177/07482337251340797. DOI: https://doi.org/10.1177/07482337251340797
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Loly. R. Siagian, Kusworini Handono, Hidayat Sujuti, Arinto Y. Ponco (Author)
This work is licensed under a Creative Commons Attribution 4.0 International License.
The article is distributed under the Creative Commons Attribution 4.0 License. Unless otherwise stated, associated published material is distributed under the same licence.
