The role of the Inflammatory Cytokine Interleukin-6 (IL-6) in moderating the relationship between pesticide exposure and metabolic syndrome in vegetable farmers 10.55131/jphd/2026/240309
Article Sidebar
Main Article Content
Abstract
Pesticide exposure has been associated with metabolic syndrome (MetS). However, the moderating role of inflammatory cytokines, such as interleukin-6 (IL-6), remains unclear. This study examined how IL-6 moderates the relationship between acetylcholinesterase (AChE) activity, as a pesticide-exposure biomarker, and the risk of MetS among vegetable farmers. We conducted a case–control study involving 134 male farmers (44 MetS cases and 90 controls) selected from a 13-week population screening of 307 farmers in Kuningan, West Java from January to May 2025. Exposure was assessed through the measurement of acetylcholinesterase (AChE) activity, while IL-6 served as an inflammatory biomarker. MetS was diagnosed according to the International Diabetes Federation criteria. Venous blood samples were collected twice for AChE analysis and once for IL-6 measurement. Moderation analysis using linear regression with the PROCESS Macro SPSS revealed that IL-6 significantly moderated the effect of AChE on waist circumference (WC), systolic and diastolic blood pressure (BP), and MetS. The conditional effect of AChE on MetS according to IL-6 values increased with high inflammation (B = 0.0031, p = 0.0004 for WC; B = 0.0059, p = 0.0008 for systolic BP; B = 0.0027, p = 0.0064 for diastolic BP; and B =-0.0009, p = 0.0041 for MetS). Scatter plot patterns further supported the biological plausibility of this moderating mechanism. IL-6 modifies the strength and direction of the inflammatory response, enhancing the impact of pesticide exposure on key MetS components. These results underscore the central role of IL-6 in the cholinergic pathway and indicate that lowering chronic low-dose pesticide exposure may reduce inflammation-related metabolic risks.
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
References
Villeda-González JD, Gómez-Olivares JL, Baiza-Gutman LA, Manuel-Apolinar L, Damasio-Santana L, Millán-Pacheco C et al. Nicotinamide reduces inflammation and oxidative stress via the cholinergic system in fructose-induced metabolic syndrome in rats. Life Sci 2020; 250. doi:10.1016/ j.lfs.2020.117585.
Herningtyas EH, Ng TS. Prevalence and distribution of metabolic syndrome and its components among provinces and ethnic groups in Indonesia. BMC Public Health 2019; 19: 1–12.
Kim SK, Park S, Chang SJ, Kim SK, Song JS, Kim HR et al. Pesticides as a risk factor for metabolic syndrome: Population-based longitudinal study in Korea. Mol Cell Toxicol 2019; 15: 431–441.
Kruger MJ, Nell TA. The prevalence of the metabolic syndrome in a farm worker community in the Boland district, South Africa. BMC Public Health 2017; 17: 1–10.
ter Horst R, van den Munckhof ICL, Schraa K, Aguirre-Gamboa R, Jaeger M, Smeekens SP et al. Sex-specific regulation of inflammation and metabolic syndrome in obesity. Arterioscler Thromb Vasc Biol 2020; 40: 1787–1800.
Santillana N, Astudillo-Guerrero C, D’Espessailles A, Cruz G. White Adipose Tissue Dysfunction: Pathophysiology and Emergent Measurements. Nutrients 2023; 15: 1–15.
Cestonaro L V, Garcia SC, Nascimento S, Gauer B, Sauer E, Göethel G et al. Biochemical, hematological and immunological parameters and relationship with occupational exposure to pesticides and metals. Environ Sci Pollut Res 2020; 27: 29291–29302.
Mitteregger M, Steiner S, Willfort-Ehringer A, Gremmel T, Koppensteiner R, Gschwandtner M et al. Cholinesterase and Inflammation: Exploring Its Role and Associations with Inflammatory Markers in Patients with Lower Extremity Artery Disease. Biomedicines 2025; 13. doi:10.3390/ biomedicines13040823.
Aguilar-Bañuelos JA, Bernal-Hernández YY, Medina-Díaz IM, Ruiz-Arias MA, Herrera-Moreno JF, Barrón-Vivanco BS et al. Environmental exposure to pesticides is associated with oxidative stress, oxidative DNA damage, and elevated interleukin-8 in a child population. Environ Toxicol Pharmacol 2025; 114. doi:10.1016/ j.etap.2025.104656.
Jiang J, Wang J, Yao L, Lai S, Zhang X. What do we know about IL-6 in COVID-19 so far? Biophys Reports 2021; 7: 193–206.
Arab A, Mostafalou S. Neurotoxicity of pesticides in the context of CNS chronic diseases. Int J Environ Health Res 2022; 32: 2718–2755.
Lee Y, Tassey J, Sarkar A, Levi JN, Lee S, Liu NQ et al. Pharmacological inactivation of a non-canonical gp130 signaling arm attenuates chronic systemic inflammation and multimorbidity induced by a high-fat diet. Sci Rep 2024; 14. doi:10.1038/ s41598-024-82414-7.
Cui F, Sun J, Mi H, Li B, Tang L, Wang R et al. Chronic intermittent hypobaric hypoxia improves iron metabolism disorders via the IL-6/JAK2/STAT3 and Epo/STAT5/ERFE signaling pathways in metabolic syndrome rats. J Trace Elem Med Biol 2023; 79. doi:10.1016/j.jtemb.2023.127259.
Li X, Di C, Qiu S-T. Interleukin-6 in Skeletal Muscle Mass Regulation. Chinese J Biochem Mol Biol 2023; 39: 778–788.
Zanchi MM, Marafon F, Marins K, Bagatini MD, Zamoner A. Redox imbalance and inflammation: A link to depression risk in brazilian pesticide-exposed farmers. Toxicology 2024; 501. doi:10.1016/j.tox.2023.153706.
Eskenazi B, Gunier RB, Rauch S, Kogut K, Perito ER, Mendez X et al. Association of Lifetime Exposure to Glyphosate and Aminomethylphosphonic Acid (AMPA) with Liver Inflammation and Metabolic Syndrome at Young Adulthood: Findings from the CHAMACOS Study. Environ Health Perspect 2023; 131: 1–11.
Cestonaro LV, Macedo SMD, Piton YV, Garcia SC, Arbo MD. Toxic effects of pesticides on cellular and humoral immunity: an overview. Immunopharmacol Immunotoxicol 2022; 44: 816–831.
Alarcón-Aguilar FJ, de la Mora ID, Fortis-Barrera A. Anti-inflammatory action and effects on carbohydrate and lipid metabolism: an understudied role of interleukin-6. Eur Cytokine Netw 2024; 35: 48–55.
IDF. The IDF consensus worldwide definition of the Metabolic Syndrome. 2006 doi:10.1016/B978-0-323-85732-1.00044-X.
Kopańska M, Łagowska A, Kuduk B, Banaś-Ząbczyk A. Acrylamide Neurotoxicity as a Possible Factor Responsible for Inflammation in the Cholinergic Nervous System. Int J Mol Sci 2022; 23. doi:10.3390/ijms 23042030.
Jain MR, Joharapurkar AA. Inflammation Resolution and Its Relevance to Metabolic Syndrome. In: Advances in Biochemistry in Health and Disease. Springer Nature: Zydus Research Center, Zydus Lifesciences Ltd., Survey No. 396/403, Sarkhej-Bavla N.H. No. 8 A, Village Moraiya, Gujarat, Changodar, Ahmedabad, 382213, India, 2024, pp 161–177.
VanderVeen BN, Fix DK, Montalvo RN, Counts BR, Smuder AJ, Murphy EA et al. The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin-6. Exp Physiol 2019; 104: 385–397.
Forcina L, Franceschi C, Musarò A. The hormetic and hermetic role of IL-6. Ageing Res Rev 2022; 80. doi:10.1016/j.arr.2022.101697.
Kopańska M, Łagowska A, Kuduk B, Banaś-Ząbczyk A. Acrylamide Neurotoxicity as a Possible Factor Responsible for Inflammation in the Cholinergic Nervous System. Int J Mol Sci 2022; 23: 1–13.
Martins CC, Bagatini MD, Simões JLB, Cardoso AM, Baldissarelli J, Dalenogare DP et al. Increased oxidative stress and inflammatory markers contrasting with the activation of the cholinergic anti-inflammatory pathway in patients with metabolic syndrome. Clin Biochem 2021; 89: 63–69.
Minafra AR, Chadt A, Rafii P, Al-Hasani H, Behnke K, Scheller J. Interleukin 6 receptor is not directly involved in regulation of body weight in diet-induced obesity with and without physical exercise. Front Endocrinol (Lausanne) 2022; 13. doi:10.3389/ fendo.2022.1028808.
Lataro RM, Silva MAB, Mestriner FL, Cau SBA, Tostes RCA, Salgado HC. Chronic treatment with acetylcholinesterase inhibitors attenuates vascular dysfunction in spontaneously hypertensive rats. Am J Hypertens 2019; 32: 579–587.
Zambrano-Ganchozo G, Rodriguez-Ramos A, Escobar-Segovia K, Duque-Cordova L, Guzmán-Cadena D. Neurotoxic Effects on Banana Workers Exposed to Agrochemicals: Ecuador Case Study. In: M. B-T, H. C, A. DC, B. D (eds). Lecture Notes in Networks and Systems. Springer Science and Business Media Deutschland GmbH: Universidad Espíritu Santo, Samborondón, Ecuador, 2022, pp 327–337.
Lionetto MG, Caricato R, Calisi A, Giordano ME, Schettino T. Acetylcholinesterase as a biomarker in environmental and occupational medicine: New insights and future perspectives. Biomed Res Int 2013; 2013. doi:10.1155/2013/321213.
Ceja-Galvez HR, Torres-Sánchez ED, Torres-Jasso JH, Reyesuribe E, Salazar-Flores J. Relationship between PON-1 enzymatic activity and risk factors for pesticide poisoning in farmers from the Cienega, Jalisco, Mexico. Biocell 2021; 45: 1241–1250.
Walter J, Tanglay Y, du Fay de Lavallaz J, Strebel I, Boeddinghaus J, Twerenbold R et al. Clinical utility of circulating interleukin-6 concentrations in the detection of functionally relevant coronary artery disease. Int J Cardiol 2019; 275: 20–25.
Massey N, Vasanthi SS, Gimenez-Lirola LG, Tyler H, Thippeswamy T. Proinflammatory cytokines, oxidative stress, and organ function as biomarkers of soman (GD) chronic neurotoxicity. Sci Rep 2025; 15. doi: 10.1038/s41598-025-94190-z.
Cui J, Xiao S, Cao Y, Zhang Y, Yang J, Zheng L et al. Organophosphate Insecticide Malathion Induces Alzheimer’s Disease-Like Cognitive Impairment in Mice: Evidence of the Microbiota-Gut-Brain Axis. Environ Sci Technol 2024; 58: 21966–21977.
Yan R, Liu T, Peng Y, Peng X. Can statistical adjustment guided by causal inference improve the accuracy of effect estimation? A simulation and empirical research based on meta-analyses of case–control studies. BMC Med Inform Decis Mak 2020; 20. doi:10.1186/s12911-020-01343-3.
Hooshmand E, Akbarzade I, Delbari D, Niroomand M, Ghavidel F, Saatchi M. Prevalence of Metabolic Syndrome Among Adults Aged 50 and Above and Associated Factors: A Cross-Sectional Study From Ardakan Cohort Study on Aging (ACSA). Heal Sci Reports 2025; 8. doi:10.1002/hsr2.70508.
Staffa SJ, Zurakowski D. Five steps to successfully implement and evaluate propensity score matching in clinical research studies. Anesth Analg 2018; 127: 1066–1073.
Sandoval GJ, Bebu I, Lachin JM. Cost-Efficient Multiply Matched Case-Control Study Designs. Am J Epidemiol 2022; 191: 1970–1974.
Torales J, Barrios I. Research design: Classification algorithm and essential features. Med Clin y Soc 2023; 7: 210–235.
Diatta AER, Diatta AL, Gaye Fall MC, Ndiaye M. Workers’ exposure to organophosphorus pesticides in the community agricultural domain of Sefa, Sedhiou. Toxicol Anal Clin 2021; 33: 116–122.
