Association between serum copper and childhood asthma: A systematic review and meta-analysis
Main Article Content
Keywords
asthma, copper, child, meta-analysis
Abstract
Background: Asthma is a chronic respiratory disease with complex pathogenesis. Some studies suggest that certain trace metals may be associated with asthma. However, the relationship between serum copper (Cu) and childhood asthma remains unclear. This meta-analysis evaluates the association between Cu and childhood asthma.
Methods: Studies of multiple databases were searched from inception to 2024. We recorded the standardized mean difference (SMD), 95% confidence intervals (CIs), and other data. The analysis was performed using Stata 18.0 software. Two independent reviewers appraised methodological quality using the Newcastle–Ottawa Scale. Sensitivity analysis was used to test robustness. To evaluate publication bias, we used Begg’s funnel plots and Egger’s regression test.
Results: A total of 11 studies with a combined 1006 participants were included. There was no significant difference in the level of serum Cu between children with asthma cases and controls (SMD = −0.032, 95% CI: −0.291–0.228, P = 0.811). There was significant heterogeneity among the studies (I2 = 73.5%, P < 0.0001). Subgroup analysis demonstrated that heterogeneity was not caused by the continent of origin, publication year, sample size, detection methods, and the mean age of participants. No publication bias was found.
Conclusion: There is no statistically significant association between serum Cu levels and childhood asthma. Further research, particularly large-scale prospective cohort studies, is needed to clarify this relationship.
References
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2 Cheng F, He L, Deng D, Zhang J, Liu C. Analysis of asthma incidence and mortality rates among children aged –14 in 204 countries from 1990 to 2019. J Asthma. 2024:1–11. 10.1080/02770903.2024.2386442
3 Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204–22.
4 Healy C, Munoz-Wolf N, Strydom J, Faherty L, Williams NC, Kenny S, et al. Nutritional immunity: The impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease. Respir Res. 2021;22:133. 10.1186/s12931-021-01722-y
5 Liu X, Ali MK, Dua K, Xu R. The role of zinc in the pathogenesis of lung disease. Nutrients. 2022;14. 10.3390/nu14102115
6 Wu CC, Wang CC, Chung WY, Sheu CC, Yang YH, Cheng MY, et al. Environmental risks and sphingolipid signatures in adult asthma and its phenotypic clusters: A multicentre study. Thorax. 2023;78:225–32. 10.1136/thoraxjnl-2021-218396
7 Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology. 2011;283:65–87. 10.1016/j.tox.2011.03.001
8 Zheng L, Yu Y, Tian X, He L, Shan X, Niu J, et al. The association between multi-heavy metals exposure and lung function in a typical rural population of Northwest China. Environ Sci Pollut Res Int. 2023;30:65646–58. 10.1007/s11356-023-26881-x
9 Ali MK, Kim RY, Karim R, Mayall JR, Martin KL, Shahandeh A, et al. Role of iron in the pathogenesis of respiratory disease. Int J Biochem Cell Biol. 2017;88:181–95. 10.1016/j.biocel.2017.05.003
10 Nowak JE, Harmon K, Caldwell CC, Wong HR. Prophylactic zinc supplementation reduces bacterial load and improves survival in a murine model of sepsis. Pediatr Crit Care Med. 2012;13:e323–9. 10.1097/PCC.0b013e31824fbd90
11 Hamon R, Homan CC, Tran HB, Mukaro VR, Lester SE, Roscioli E, et al. Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD. PLoS One. 2014;9:e110056. 10.1371/journal.pone.0110056
12 El Brouzi MY, Adadi N, Lamtai M, Boulahfa H, Zghari O, Fath N, et al. Effects of nickel bioaccumulation on hematological, biochemical, immune responses, neuroinflammatory, oxidative stress parameters, and neurotoxicity in rats. Biol Trace Elem Res. 2025. 10.1007/s12011-025-04528-x
13 Tuo Y, Li Y, Guo T. Association between blood total mercury and psoriasis: The NHANES 2005–2006 and 2013–2014: A cross-sectional study. PLoS One. 2024;19:e0309147. 10.1371/journal.pone.0309147
14 Brigham EP, McCormack MC, Takemoto CM, Matsui EC. Iron status is associated with asthma and lung function in US women. PLoS One. 2015;10:e0117545. 10.1371/journal.pone.0117545
15 Agoro R, Taleb M, Quesniaux VFJ, Mura C. Cell iron status influences macrophage polarization. PLoS One. 2018;13:e0196921. 10.1371/journal.pone.0196921
16 Eleutherio ECA, Silva Magalhães RS, de Araújo Brasil A, Monteiro Neto JR, de Holanda Paranhos L. SOD1, more than just an antioxidant. Arch Biochem Biophys. 2021;697:108701. 10.1016/j.abb.2020.108701
17 Mattie MD, McElwee MK, Freedman JH. Mechanism of copper-activated transcription: Activation of AP-1, and the JNK/SAPK and p38 signal transduction pathways. J Mol Biol. 2008;383:1008–18. 10.1016/j.jmb.2008.08.080
18 Liu H, Guo H, Deng H, Cui H, Fang J, Zuo Z, et al. Copper induces hepatic inflammatory responses by activation of MAPKs and NF-κB signalling pathways in the mouse. Ecotoxicol Environ Saf. 2020;201:110806. 10.1016/j.ecoenv.2020.110806
19 Falah S. Al-Fartusie* SNM. Essential trace elements and their vital roles in human body. Indian Journal of Advances in Chemical Science. January 2017.
20 da Silva DA, De Luca A, Squitti R, Rongioletti M, Rossi L, Machado CML, et al. Copper in tumors and the use of copper-based compounds in cancer treatment. J Inorg Biochem. 2022;226:111634. 10.1016/j.jinorgbio.2021.111634
21 Fukai T, Ushio-Fukai M, Kaplan JH. Copper transporters and copper chaperones: Roles in cardiovascular physiology and disease. Am J Physiol Cell Physiol. 2018;315:C186–201. 10.1152/ajpcell.00132.2018
22 Culbertson EM, Culotta VC. Copper in infectious disease: Using both sides of the penny. Semin Cell Dev Biol. 2021;115:19–26. 10.1016/j.semcdb.2020.12.003
23 Podlecka D, Jerzyńska J, Sanad K, Polańska K, Bobrowska-Korzeniowska M, Stelmach I, et al. Micronutrients and the risk of allergic diseases in school children. Int J Environ Res Public Health. 2022;19(19):12187. 10.3390/ijerph191912187
24 Zajac D. Mineral micronutrients in asthma. Nutrients. 2021; 10.3390/nu13114001
25 Song W, Yue Y, Zhang Q, Wang X. Copper homeostasis dysregulation in respiratory diseases: A review of current knowledge. Front Physiol. 2024;15:1243629. 10.3389/fphys.2024.1243629
26 Wang J, Yin J, Hong X, Liu R. Exposure to heavy metals and allergic outcomes in children: A systematic review and meta-analysis. Biol Trace Elem Res. 2022;200:4615–31. 10.1007/s12011-021-03070-w
27 Kinnula VL, Crapo JD. Superoxide dismutases in the lung and human lung diseases. Am J Respir Crit Care Med. 2003;167:1600–19. 10.1164/rccm.200212-1479SO
28 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. 10.1136/bmj.n71
29 Di Toro R, Galdo Capotorti G, Gialanella G, Miraglia del Giudice M, Moro R, Perrone L. Zinc and copper status of allergic children. Acta Paediatr Scand. 1987;76:612–7. 10.1111/j.1651-2227.1987.tb10530.x
30 Li S, Rao RJ. Determination of serum copper and zinc in children with respiratory diseases and its clinical significance. Zhejiang Med J. 1995;(01):27–8.
31 Kocyigit A, Armutcu F, Gurel A, Ermis B. Alterations in plasma essential trace elements selenium, manganese, zinc, copper, and iron concentrations and the possible role of these elements on oxidative status in patients with childhood asthma. Biol Trace Elem Res. 2004;97:31–41. 10.1385/BTER:97:1:31
32 Guo JX, Li XH, Yang ZX. Relationship between serum IgE and trace elements in asthmatic children. J Taishan Med Coll. 2006 (01):58.
33 Peng PY, Sun XJ. Analysis of 6 serum elements in children with bronchial asthma and healthy children. J Fourth Mil Med Univ. 2007 (23):2199.
34 Oluwole O, Arinola OG, Adu MD, Adepoju A, Adedokun BO, Olopade OI, et al. Relationships between plasma micronutrients, serum IgE, and skin test reactivity and asthma among school children in rural Southwest Nigeria. J Biomark. 2014;2014:106150. 10.1155/2014/106150
35 Uysalol M, Uysalol EP, Yilmaz Y, Parlakgul G, Ozden TA, Ertem HV, et al. Serum level of vitamin D and trace elements in children with recurrent wheezing: A cross-sectional study. BMC Pediatr. 2014;14:270. 10.1186/1471-2431-14-270
36 ElSayed MMESaOGABaOIMaA. Serum levels of lead and copper in a group of Egyptian children with bronchial asthma. Egypt J Pediatr Allergy Immunol. 2016;14:47–52.
37 Yalçın SS, Emiralioğlu N, Yalçın S. Evaluation of blood and tooth element status in asthma cases: A preliminary case-control study. BMC Pulm Med. 2021;21:201. 10.1186/s12890-021-01565-9
38 Srivastava S, Tiwari V, Singh S, Karoli R, Bhattacharya P, Gupta N. Low serum levels of zinc, selenium, and vitamin D3 are biomarkers of airway inflammation and poor asthma control: A two-centre study. Cureus. 2023;15:e41082. 10.7759/cureus.41082
39 Peters ZJ, Nykamp JA, Passaperuma K, Carlson JC, DeWitte-Orr SJ, Greenberg BM, et al. Effect of copper on the cytotoxicity of phenanthrene and 9,10-phenanthrenequinone to the human placental cell line, JEG-3. Reprod Toxicol. 2007;23:513–20. 10.1016/j.reprotox.2007.01.008
40 Sul OJ, Ra SW. Quercetin prevents LPS-induced oxidative stress and inflammation by modulating NOX2/ROS/NF-kB in lung epithelial cells. Molecules. 2021;26. 10.3390/molecules26226949
41 Liu K, Hua S, Song L. PM2.5 exposure and asthma development: The key role of oxidative stress. Oxid Med Cell Longev. 2022;2022:3618806. 10.1155/2022/3618806
42 Neveu WA, Allard JB, Dienz O, Wargo MJ, Ciliberto G, Whittaker LA, et al. IL-6 is required for airway mucus production induced by inhaled fungal allergens. J Immunol. 2009;183:1732–8. 10.4049/jimmunol.0802923
43 Guo H, Jian Z, Liu H, Cui H, Deng H, Fang J, et al. TGF-β1-induced EMT activation via both Smad-dependent and MAPK signaling pathways in Cu-induced pulmonary fibrosis. Toxicol Appl Pharmacol. 2021;418:115500. 10.1016/j.taap.2021.115500
44 Ostrakhovitch EA, Lordnejad MR, Schliess F, Sies H, Klotz LO. Copper ions strongly activate the phosphoinositide-3-kinase/Akt pathway independent of the generation of reactive oxygen species. Arch Biochem Biophys. 2002;397:232–9. 10.1006/abbi.2001.2559
45 Athari SS. Targeting cell signaling in allergic asthma. Signal Transduct Target Ther. 2019;4:45. 10.1038/s41392-019-0079-0
46 Meng Y, Xu X, Xie G, Zhang Y, Chen S, Qiu Y, et al. Alkyl organophosphate flame retardants (OPFRs) induce lung inflammation and aggravate OVA-simulated asthmatic response via the NF-кB signaling pathway. Environ Int. 2022;163:107209. 10.1016/j.envint.2022.107209
47 He L, Norris C, Cui X, Li Z, Barkjohn KK, Teng Y, et al. Role of endogenous melatonin in pathophysiologic and oxidative stress responses to personal air pollutant exposures in asthmatic children. Sci Total Environ. 2021;773:145709. 10.1016/j.scitotenv.2021.145709
48 Zhou X, Zhao L, Luo J, Tang H, Xu M, Wang Y, et al. The toxic effects and mechanisms of Nano-Cu on the spleen of rats. Int J Mol Sci. 2019;20. 10.3390/ijms20061469
49 Mao S, Wu L, Shi W. Association between trace elements levels and asthma susceptibility. Respir Med. 2018;145:110 9. 10.1016/j.rmed.2018.10.028
50 Al-Fartusie FS, Abood MJ, Al-Bairmani HK, Mohammed AS. Evaluation of some trace elements in sera of asthma patients: A case control study. Folia Med 2021;63:797–804. 10.3897/folmed.63.e60506
51 Gagliardo R, Chanez P, Mathieu M, Bruno A, Costanzo G, Gougat C, et al. Persistent activation of nuclear factor-kappaB signaling pathway in severe uncontrolled asthma. Am J Respir Crit Care Med. 2003; 168:1190–8. 10.1164/rccm.200205-479OC
52 Alsharnoubi J, Alkharbotly A, Waheed H, Elkhayat Z, Hussein DY. Could we diagnose childhood asthma by LIBS technique? Lasers Med Sci. 2020;35:807–12. 10.1007/s10103-019-02866-6
53 Yang F, Liao J, Yu W, Qiao N, Guo J, Han Q, et al. Exposure to copper induces mitochondria-mediated apoptosis by inhibiting mitophagy and the PINK1/parkin pathway in chicken (Gallus gallus) livers. J Hazard Mater. 2021;408:124888. 10.1016/j.jhazmat.2020.124888
54 To T, Terebessy E, Zhu J, Zhang K, Lakey PS, Shiraiwa M, et al. Does early life exposure to exogenous sources of reactive oxygen species (ROS) increase the risk of respiratory and allergic diseases in children? A longitudinal cohort study. Environ Health. 2022;21. 10.1186/s12940-022-00902-7
2 Cheng F, He L, Deng D, Zhang J, Liu C. Analysis of asthma incidence and mortality rates among children aged –14 in 204 countries from 1990 to 2019. J Asthma. 2024:1–11. 10.1080/02770903.2024.2386442
3 Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204–22.
4 Healy C, Munoz-Wolf N, Strydom J, Faherty L, Williams NC, Kenny S, et al. Nutritional immunity: The impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease. Respir Res. 2021;22:133. 10.1186/s12931-021-01722-y
5 Liu X, Ali MK, Dua K, Xu R. The role of zinc in the pathogenesis of lung disease. Nutrients. 2022;14. 10.3390/nu14102115
6 Wu CC, Wang CC, Chung WY, Sheu CC, Yang YH, Cheng MY, et al. Environmental risks and sphingolipid signatures in adult asthma and its phenotypic clusters: A multicentre study. Thorax. 2023;78:225–32. 10.1136/thoraxjnl-2021-218396
7 Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology. 2011;283:65–87. 10.1016/j.tox.2011.03.001
8 Zheng L, Yu Y, Tian X, He L, Shan X, Niu J, et al. The association between multi-heavy metals exposure and lung function in a typical rural population of Northwest China. Environ Sci Pollut Res Int. 2023;30:65646–58. 10.1007/s11356-023-26881-x
9 Ali MK, Kim RY, Karim R, Mayall JR, Martin KL, Shahandeh A, et al. Role of iron in the pathogenesis of respiratory disease. Int J Biochem Cell Biol. 2017;88:181–95. 10.1016/j.biocel.2017.05.003
10 Nowak JE, Harmon K, Caldwell CC, Wong HR. Prophylactic zinc supplementation reduces bacterial load and improves survival in a murine model of sepsis. Pediatr Crit Care Med. 2012;13:e323–9. 10.1097/PCC.0b013e31824fbd90
11 Hamon R, Homan CC, Tran HB, Mukaro VR, Lester SE, Roscioli E, et al. Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD. PLoS One. 2014;9:e110056. 10.1371/journal.pone.0110056
12 El Brouzi MY, Adadi N, Lamtai M, Boulahfa H, Zghari O, Fath N, et al. Effects of nickel bioaccumulation on hematological, biochemical, immune responses, neuroinflammatory, oxidative stress parameters, and neurotoxicity in rats. Biol Trace Elem Res. 2025. 10.1007/s12011-025-04528-x
13 Tuo Y, Li Y, Guo T. Association between blood total mercury and psoriasis: The NHANES 2005–2006 and 2013–2014: A cross-sectional study. PLoS One. 2024;19:e0309147. 10.1371/journal.pone.0309147
14 Brigham EP, McCormack MC, Takemoto CM, Matsui EC. Iron status is associated with asthma and lung function in US women. PLoS One. 2015;10:e0117545. 10.1371/journal.pone.0117545
15 Agoro R, Taleb M, Quesniaux VFJ, Mura C. Cell iron status influences macrophage polarization. PLoS One. 2018;13:e0196921. 10.1371/journal.pone.0196921
16 Eleutherio ECA, Silva Magalhães RS, de Araújo Brasil A, Monteiro Neto JR, de Holanda Paranhos L. SOD1, more than just an antioxidant. Arch Biochem Biophys. 2021;697:108701. 10.1016/j.abb.2020.108701
17 Mattie MD, McElwee MK, Freedman JH. Mechanism of copper-activated transcription: Activation of AP-1, and the JNK/SAPK and p38 signal transduction pathways. J Mol Biol. 2008;383:1008–18. 10.1016/j.jmb.2008.08.080
18 Liu H, Guo H, Deng H, Cui H, Fang J, Zuo Z, et al. Copper induces hepatic inflammatory responses by activation of MAPKs and NF-κB signalling pathways in the mouse. Ecotoxicol Environ Saf. 2020;201:110806. 10.1016/j.ecoenv.2020.110806
19 Falah S. Al-Fartusie* SNM. Essential trace elements and their vital roles in human body. Indian Journal of Advances in Chemical Science. January 2017.
20 da Silva DA, De Luca A, Squitti R, Rongioletti M, Rossi L, Machado CML, et al. Copper in tumors and the use of copper-based compounds in cancer treatment. J Inorg Biochem. 2022;226:111634. 10.1016/j.jinorgbio.2021.111634
21 Fukai T, Ushio-Fukai M, Kaplan JH. Copper transporters and copper chaperones: Roles in cardiovascular physiology and disease. Am J Physiol Cell Physiol. 2018;315:C186–201. 10.1152/ajpcell.00132.2018
22 Culbertson EM, Culotta VC. Copper in infectious disease: Using both sides of the penny. Semin Cell Dev Biol. 2021;115:19–26. 10.1016/j.semcdb.2020.12.003
23 Podlecka D, Jerzyńska J, Sanad K, Polańska K, Bobrowska-Korzeniowska M, Stelmach I, et al. Micronutrients and the risk of allergic diseases in school children. Int J Environ Res Public Health. 2022;19(19):12187. 10.3390/ijerph191912187
24 Zajac D. Mineral micronutrients in asthma. Nutrients. 2021; 10.3390/nu13114001
25 Song W, Yue Y, Zhang Q, Wang X. Copper homeostasis dysregulation in respiratory diseases: A review of current knowledge. Front Physiol. 2024;15:1243629. 10.3389/fphys.2024.1243629
26 Wang J, Yin J, Hong X, Liu R. Exposure to heavy metals and allergic outcomes in children: A systematic review and meta-analysis. Biol Trace Elem Res. 2022;200:4615–31. 10.1007/s12011-021-03070-w
27 Kinnula VL, Crapo JD. Superoxide dismutases in the lung and human lung diseases. Am J Respir Crit Care Med. 2003;167:1600–19. 10.1164/rccm.200212-1479SO
28 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. 10.1136/bmj.n71
29 Di Toro R, Galdo Capotorti G, Gialanella G, Miraglia del Giudice M, Moro R, Perrone L. Zinc and copper status of allergic children. Acta Paediatr Scand. 1987;76:612–7. 10.1111/j.1651-2227.1987.tb10530.x
30 Li S, Rao RJ. Determination of serum copper and zinc in children with respiratory diseases and its clinical significance. Zhejiang Med J. 1995;(01):27–8.
31 Kocyigit A, Armutcu F, Gurel A, Ermis B. Alterations in plasma essential trace elements selenium, manganese, zinc, copper, and iron concentrations and the possible role of these elements on oxidative status in patients with childhood asthma. Biol Trace Elem Res. 2004;97:31–41. 10.1385/BTER:97:1:31
32 Guo JX, Li XH, Yang ZX. Relationship between serum IgE and trace elements in asthmatic children. J Taishan Med Coll. 2006 (01):58.
33 Peng PY, Sun XJ. Analysis of 6 serum elements in children with bronchial asthma and healthy children. J Fourth Mil Med Univ. 2007 (23):2199.
34 Oluwole O, Arinola OG, Adu MD, Adepoju A, Adedokun BO, Olopade OI, et al. Relationships between plasma micronutrients, serum IgE, and skin test reactivity and asthma among school children in rural Southwest Nigeria. J Biomark. 2014;2014:106150. 10.1155/2014/106150
35 Uysalol M, Uysalol EP, Yilmaz Y, Parlakgul G, Ozden TA, Ertem HV, et al. Serum level of vitamin D and trace elements in children with recurrent wheezing: A cross-sectional study. BMC Pediatr. 2014;14:270. 10.1186/1471-2431-14-270
36 ElSayed MMESaOGABaOIMaA. Serum levels of lead and copper in a group of Egyptian children with bronchial asthma. Egypt J Pediatr Allergy Immunol. 2016;14:47–52.
37 Yalçın SS, Emiralioğlu N, Yalçın S. Evaluation of blood and tooth element status in asthma cases: A preliminary case-control study. BMC Pulm Med. 2021;21:201. 10.1186/s12890-021-01565-9
38 Srivastava S, Tiwari V, Singh S, Karoli R, Bhattacharya P, Gupta N. Low serum levels of zinc, selenium, and vitamin D3 are biomarkers of airway inflammation and poor asthma control: A two-centre study. Cureus. 2023;15:e41082. 10.7759/cureus.41082
39 Peters ZJ, Nykamp JA, Passaperuma K, Carlson JC, DeWitte-Orr SJ, Greenberg BM, et al. Effect of copper on the cytotoxicity of phenanthrene and 9,10-phenanthrenequinone to the human placental cell line, JEG-3. Reprod Toxicol. 2007;23:513–20. 10.1016/j.reprotox.2007.01.008
40 Sul OJ, Ra SW. Quercetin prevents LPS-induced oxidative stress and inflammation by modulating NOX2/ROS/NF-kB in lung epithelial cells. Molecules. 2021;26. 10.3390/molecules26226949
41 Liu K, Hua S, Song L. PM2.5 exposure and asthma development: The key role of oxidative stress. Oxid Med Cell Longev. 2022;2022:3618806. 10.1155/2022/3618806
42 Neveu WA, Allard JB, Dienz O, Wargo MJ, Ciliberto G, Whittaker LA, et al. IL-6 is required for airway mucus production induced by inhaled fungal allergens. J Immunol. 2009;183:1732–8. 10.4049/jimmunol.0802923
43 Guo H, Jian Z, Liu H, Cui H, Deng H, Fang J, et al. TGF-β1-induced EMT activation via both Smad-dependent and MAPK signaling pathways in Cu-induced pulmonary fibrosis. Toxicol Appl Pharmacol. 2021;418:115500. 10.1016/j.taap.2021.115500
44 Ostrakhovitch EA, Lordnejad MR, Schliess F, Sies H, Klotz LO. Copper ions strongly activate the phosphoinositide-3-kinase/Akt pathway independent of the generation of reactive oxygen species. Arch Biochem Biophys. 2002;397:232–9. 10.1006/abbi.2001.2559
45 Athari SS. Targeting cell signaling in allergic asthma. Signal Transduct Target Ther. 2019;4:45. 10.1038/s41392-019-0079-0
46 Meng Y, Xu X, Xie G, Zhang Y, Chen S, Qiu Y, et al. Alkyl organophosphate flame retardants (OPFRs) induce lung inflammation and aggravate OVA-simulated asthmatic response via the NF-кB signaling pathway. Environ Int. 2022;163:107209. 10.1016/j.envint.2022.107209
47 He L, Norris C, Cui X, Li Z, Barkjohn KK, Teng Y, et al. Role of endogenous melatonin in pathophysiologic and oxidative stress responses to personal air pollutant exposures in asthmatic children. Sci Total Environ. 2021;773:145709. 10.1016/j.scitotenv.2021.145709
48 Zhou X, Zhao L, Luo J, Tang H, Xu M, Wang Y, et al. The toxic effects and mechanisms of Nano-Cu on the spleen of rats. Int J Mol Sci. 2019;20. 10.3390/ijms20061469
49 Mao S, Wu L, Shi W. Association between trace elements levels and asthma susceptibility. Respir Med. 2018;145:110 9. 10.1016/j.rmed.2018.10.028
50 Al-Fartusie FS, Abood MJ, Al-Bairmani HK, Mohammed AS. Evaluation of some trace elements in sera of asthma patients: A case control study. Folia Med 2021;63:797–804. 10.3897/folmed.63.e60506
51 Gagliardo R, Chanez P, Mathieu M, Bruno A, Costanzo G, Gougat C, et al. Persistent activation of nuclear factor-kappaB signaling pathway in severe uncontrolled asthma. Am J Respir Crit Care Med. 2003; 168:1190–8. 10.1164/rccm.200205-479OC
52 Alsharnoubi J, Alkharbotly A, Waheed H, Elkhayat Z, Hussein DY. Could we diagnose childhood asthma by LIBS technique? Lasers Med Sci. 2020;35:807–12. 10.1007/s10103-019-02866-6
53 Yang F, Liao J, Yu W, Qiao N, Guo J, Han Q, et al. Exposure to copper induces mitochondria-mediated apoptosis by inhibiting mitophagy and the PINK1/parkin pathway in chicken (Gallus gallus) livers. J Hazard Mater. 2021;408:124888. 10.1016/j.jhazmat.2020.124888
54 To T, Terebessy E, Zhu J, Zhang K, Lakey PS, Shiraiwa M, et al. Does early life exposure to exogenous sources of reactive oxygen species (ROS) increase the risk of respiratory and allergic diseases in children? A longitudinal cohort study. Environ Health. 2022;21. 10.1186/s12940-022-00902-7