普通人群有机氯农药暴露与心血管疾病风险的关联研究

Associations between organochlorine pesticide exposure and cardiovascular disease risk in the general population

摘要

目的：探讨普通人群中有机氯农药（organochlorine pesticides，OCPs）与心血管疾病（cardiovascular disease，CVD）之间的相关性。方法：采用横断面设计，选取2005-2016年美国国家健康与营养调查中符合纳入和排除标准的6 009例普通居民作为研究对象。收集研究对象的一般资料、体格检查和实验室检查指标，纳入7种OCPs，包括β-六氯环己烷（β-hexachlorocyclohexane，β-HCH）、六氯苯（hexachlorobenzene，HCB）、氧化氯丹（oxychlordane，OXY）、反式九氯（trans-nonachlor，T-NONA）、二氯二苯基二氯乙烯[2,2-Bis（4-chlorophenyl)-1,1-dichloroethene，p,p'-DDE]、二氯二苯基三氯乙烷[2,2-Bis（4-chlorophenyl）-1,1,1-trichloroethane，p,p'-DDT]和灭蚁灵（Mirex），并根据是否患CVD将研究对象分为正常组5 499例和CVD组510例。采用多因素logistic回归及限制性立方样条（restricted cubic spline，RCS）模型分析人群中单一OCPs暴露与CVD风险之间的相关性。使用贝叶斯核机器回归（Bayesian kernel machine regression，BKMR）和分位数-g运算（quantile g-computation，Qgcomp）模型进一步分析OCPs联合暴露与CVD风险的关联。结果：多因素logistic回归结果显示，调整混杂因素后，β-HCH、OXY、T-NONA、p,p'-DDE和Mirex浓度升高可增加CVD风险（P＜0.05），与第一分位数浓度相比，β-HCH、OXY、T-NONA、p,p'-DDE和Mirex在第四分位数浓度时CVD风险分别增加3.19、2.96、6.26、2.40和1.89倍。RCS模型显示，β-HCH、OXY、T-NONA和Mirex与CVD风险存在非线性剂量反应关系（P＜0.05）。BKMR模型结果显示，OCPs混合物与CVD风险具有正向联合效应，其中OXY可能是主要贡献物质之一；当其他OCPs浓度固定在第25、50和75百分位数时，OXY与CVD风险存在正相关关系；OXY和β-HCH、OXY和p,p'-DDE、OXY和Mirex之间可能存在交互作用。Qgcomp模型验证了BKMR的稳定性与真实性，仅p,p'-DDE具有负向效应，正向权重排序依次为OXY、T-NONA、Mirex和β-HCH。结论：OCPs混合暴露与CVD风险升高有关，OXY是驱动此关联的主要成分，提示OXY可能是CVD风险升高的独立危险因素。

Abstract

Objective: To explore the associations between organochlorine pesticides (OCPs) and cardiovascular disease (CVD) in the general population. Methods: A cross-sectional study was adopted, and 6,009 residents who met the inclusion and exclusion criteria from the National Health and Nutrition Examination Survey (NHANES) (2005-2016) were enrolled. General data, physical examination, and laboratory test results were collected from the participants. Seven types of OCPs were analyzed, including β-hexachlorocyclohexane (β-HCH), hexachlorobenzene (HCB), oxychlordane (OXY), trans-nonachlor (T-NONA), 2,2-Bis (4-chlorophenyl)-1,1-dichloroethene (p,p'-DDE), 2,2-Bis(4-chlorophenyl)-1,1,1-trichloroethane (p,p'-DDT) and Mirex. The participants were divided into a control group (n=5,499) and a CVD group (n=510) according to the presence or absence of CVD. Multivariate logistic regression analysis and restricted cubic spline (RCS) models were used to analyze the associations between individual exposure to OCPs and CVD risk in the population. The associations between the joint exposure to OCPs and CVD risk were further analyzed using Bayesian kernel machine regression (BKMR) and quantile g-computation (Qgcomp) models. Results: Results from the multivariate logistic regression analysis showed that, after adjusting for confounders, elevated concentrations of β-HCH, OXY, T-NONA, p,p'-DDE and Mirex were associated with an increased risk of CVD (P＜0.05). Compared with the first quartile of concentration, the CVD risk associated with β-HCH, OXY, T-NONA, p,p'-DDE and Mirex at the fourth quartile concentration increased by 3.19-fold, 2.96-fold, 6.26-fold, 2.40-fold and 1.89-fold, respectively. The RCS model revealed non-linear dose-response relationships between β-HCH, OXY, T-NONA, Mirex and CVD risk (P＜0.05). The results from the BKMR model indicated a positive joint effect of OCPs mixture on CVD risk, with OXY likely being one of the major contributors. When the concentrations of other OCPs were fixed at the 25th, 50th, and 75th percentiles, OXY was positively associated with CVD risk. Additionally, potential interactions were observed between OXY and β-HCH, OXY and p,p'-DDE, as well as OXY and Mirex. The Qgcomp model verified the stability and validity of the BKMR, with only p,p'-DDE exerting a negative effect. The positive weights were observed in the following order: OXY, T-NONA, Mirex, and β-HCH. Conclusion: Joint exposure to OCPs is associated with an increased risk of CVD. OXY is the major component driving the associations, suggesting that it may serve as an independent risk factor for increased CVD risk.

关键词

心血管疾病 / 有机氯农药 / 普通人群 / 暴露-效应关系 / 横断面研究 / logistic回归分析 / 贝叶斯核机器回归 / 分位数-g运算

Key words

cardiovascular disease / organochlorine pesticides / general population / exposure-effect relationship / cross-sectional study / logistic regression analysis / Bayesian kernel machine regression / quantile g-computation

参考文献

[1] Stark B A, Jihnson C O, Sobrinbo C A . Global, regional, and national burden of cardiovascular diseases and risk factors in 204 countries and territories, 1990-2023[J]. Journal of the American College of Cardiology, 2025, 86(22): 2167-2243.

[2] 《中国心血管健康与疾病报告》撰写委员会. 中国心血管健康与疾病报告2024概要[J]. 中国循环杂志, 2025, 40(6): 521-559.

[3] The Writing Committee of the Report on Cardiovascular Health. Report on cardiovascular health and diseases in China 2024：an updated summary[J]. Chinese Circulation Journal, 2025, 40(6): 521-559.

[4] 国家卫生健康委员会. 中国卫生健康统计年鉴-2022[M]. 北京： 中国协和医科大学出版社， 2022.

[5] National Health Commission . China Health Statistics Yearbook-2022[M]. Beijing: Peking Union Medical College Press， 2022.

[6] Wang J, Cao L L, Gao Z Y, et al. Relationship between thyroid hormone parameters and exposure to a mixture of organochlorine pesticides，mercury and nutrients in the cord blood of newborns[J]. Environmental Pollution, 2022, 292: 118362.

[7] 王茜, 尹瑜, 王豪, 等. 金属或类金属及持久性有机污染物暴露与心血管疾病的研究进展[J]. 中华流行病学杂志, 2023, 44(5): 705-712.

[8] Wang X, Yin Y, Wang H, et al. Progress in research of relationship between metal or metalloid and persistent organic pollutants exposures and cardiovascular disease[J]. Chinese Journal of Epidemiology, 2023, 44(5): 705-712.

[9] 尹杰, 王虎婷, 韩沐珂, 等. 2017年北京居民血清中有机氯农药暴露水平[J]. 卫生研究, 2025, 54(3): 471-477.

[10] Yin J, Wang H T, Han M K, et al. Level of organochlorine pesticides in serum of Beijing residents in 2017[J]. Journal of Hygiene Research, 2025, 54(3): 471-477.

[11] Yan L J, Liu Z L, Zhong X J, et al. Exposure to organochlorine pesticides and mortality risk among individuals with diabetes：a prospective cohort analysis and network pharmacology study[J]. Ecotoxicology and Environmental Safety, 2025, 305: 119274.

[12] Hernández-Mariano J Á, Baltazar-Reyes M C, Salazar-Martínez E, et al. Exposure to the pesticide DDT and risk of diabetes and hypertension：systematic review and meta-analysis of prospective studies[J]. International Journal of Hygiene and Environmental Health, 2022, 239: 113865.

[13] Donat-Vargas C, Schillemans T, Kiviranta H, et al. Blood levels of organochlorine contaminants mixtures and cardiovascular disease[J]. JAMA Network Open, 2023, 6(9): e2333347.

[14] Lim J E, Lee S, Lee S, et al. Serum persistent organic pollutants levels and stroke risk[J]. Environmental Pollution, 2018, 233: 855-861.

[15] Wang X, Mukherjee B, Park S K . Associations of cumulative exposure to heavy metal mixtures with obesity and its comorbidities among U. S. adults in NHANES 2003-2014[J]. Environment International, 2018, 121: 683-694.

[16] Yuan Y, Isasi C R, Al-Rousan T, et al. Associations of concurrent hypertension and type 2 diabetes with mortality outcomes: a prospective study of U.S. adults [J]. Diabetes Care, 2025, 48(7): 1241-50.

[17] Beydoun H A, Huang S Y, Beydoun M A, et al. Mediating-moderating effect of allostatic load on the association between dietary approaches to stop hypertension diet and all-cause and cause-specific mortality：2001-2010 National Health and Nutrition Examination surveys[J]. Nutrients, 2019, 11(10): 2311.

[18] Kario K, Okura A, Hoshide S, et al. The WHO global report 2023 on hypertension warning the emerging hypertension burden in globe and its treatment strategy[J]. Hypertension Research, 2024, 47(5): 1099-1102.

[19] Colagiuri S. Glycated haemoglobin（HbA1c）for the diagnosis of diabetes mellitus-practical implications[J]. Diabetes Research and Clinical Practice, 2011, 93(3): 312-313.

[20] Wang X H, Cao Y P, Chen X L, et al. Per- and polyfluoroalkyl substances（PFAS）exposure and cardiovascular risk：lipid profile as a mediator[J]. Lipids in Health and Disease, 2025, 24(1): 393.

[21] Wu X Y, Wei D D, Zhou Y L, et al. Pesticide exposures and 10-year atherosclerotic cardiovascular disease risk：integrated epidemiological and bioinformatics analysis[J]. Journal of Hazardous Materials, 2025, 485: 136835.

[22] Ali Mohammadkhani M, Shahrzad S, Haghighi M, et al. Insights into organochlorine pesticides exposure in the development of cardiovascular diseases：a systematic review[J]. Archives of Iranian Medicine, 2023, 26(10): 592-599.

[23] Kim S A, Kim K S, Lee Y M, et al. Associations of organochlorine pesticides and polychlorinated biphenyls with total，cardiovascular，and cancer mortality in elders with differing fat mass[J]. Environmental Research, 2015, 138: 1-7.

[24] Keswani C, Dilnashin H, Birla H, et al. Global footprints of organochlorine pesticides：a pan-global survey[J]. Environmental Geochemistry and Health, 2022, 44(1): 149-177.

[25] Ghosh R. Organochlorine pesticide-mediated induction of NADPH oxidase and nitric-oxide synthase in endothelial cell[J]. Journal of Clinical and Diagnostic Research, 2017, 11(1): BC09-BC12.

[26] Zhang B X, Li Q, Lu Y Y, et al. KCNQ1OT1/miR-140-5p/PTP4A3 axis is involved in endosulfan-induced vascular endothelial cell migration linking to atherosclerosis[J]. Toxicology Letters, 2025, 412: 44-54.

[27] Zhang L S, Wei J L, Ren L H, et al. Endosulfan induces autophagy and endothelial dysfunction via the AMPK/mTOR signaling pathway triggered by oxidative stress[J]. Environmental Pollution, 2017, 220: 843-852.

[28] Park C M, Kim K T, Rhyu D Y . Exposure to a low concentration of mixed organochlorine pesticides impairs glucose metabolism and mitochondrial function in L6 myotubes and zebrafish[J]. Journal of Hazardous Materials, 2021, 414: 125437.

[29] Magliano D J, Rancière F, Slama R, et al. Exposure to persistent organic pollutants and the risk of type 2 diabetes：a case-cohort study[J]. Diabetes & Metabolism, 2021, 47(5): 101234.

[30] Darvishian M, Bhatti P, Gaudreau É, et al. Persistent organic pollutants and risk of cutaneous malignant melanoma among women[J]. Cancer Reports, 2022, 5(8): e1536.

[31] Lee H S, Lee J C, Lee I K, et al. Associations among organochlorine pesticides，methanobacteriales，and obesity in Korean women[J]. PLoS One, 2011, 6(11): e27773.

[32] Itoh H, Iwasaki M, Kasuga Y, et al. Association between serum organochlorines and global methylation level of leukocyte DNA among Japanese women：a cross-sectional study[J]. Science of the Total Environment, 2014, 490: 603-609.

[33] Airaksinen R, Rantakokko P, Eriksson J G, et al. Association between type 2 diabetes and exposure to persistent organic pollutants[J]. Diabetes Care, 2011, 34(9): 1972-1979.

[34] Ugalde-Resano R, Mérida-Ortega Á, Barajas B, et al. Diabetes mellitus and serum organochlorine pesticides mixtures in Mexican women[J]. Environmental Health, 2024, 23(1): 57.

[35] Lamat H, Sauvant-Rochat M P, Tauveron I, et al. Metabolic syndrome and pesticides：a systematic review and meta-analysis[J]. Environmental Pollution, 2022, 305: 119288.

[36] Howell G E, Young D, Seo K S, et al. Alterations in murine macrophage reactivity and bactericidal efficacy following exposure to an environmentally relevant mixture of organochlorine pesticide compounds[J]. Food and Chemical Toxicology, 2025, 197: 115268.

[37] Li M M, Wang R, Su C, et al. Temporal trends of exposure to organochlorine pesticides in the United States：a population study from 2005 to 2016[J]. International Journal of Environmental Research and Public Health, 2022, 19(7): 3862.

[38] Kou J, Li X, Zhang M Y, et al. Accumulative levels，temporal and spatial distribution of common chemical pollutants in the blood of Chinese adults[J]. Environmental Pollution, 2022, 311: 119980.

[39] Wei D B, Kameya T, Urano K . Environmental management of pesticidal POPs in China：past，present and future[J]. Environment International, 2007, 33(7): 894-902.

[40] Ma Y, Yun X T, Ruan Z Y, et al. Review of hexachlorocyclohexane（HCH）and dichlorodiphenyltrichloroethane（DDT）contamination in Chinese soils[J]. Science of the Total Environment, 2020, 749: 141212.

基金资助

国家自然科学基金资助项目(81860570)

国家自然科学基金资助项目(82060088)