Skip to main content
Log in

Mediation effect of serum zinc on insulin secretion inhibited by methyl tert-butyl ether in gas station workers

  • Research Article
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

Methyl tert-butyl ether (MTBE), a type of gasoline additive, has been found to affect insulin function and glucose homeostasis in animal experiments, but there is still no epidemiological evidence. Zinc (Zn) is a key regulatory element of insulin secretion and function, and Zn homeostasis can be disrupted by MTBE exposure through inducing oxidative stress. Therefore, we suspected that Zn might be involved and play an important role in the process of insulin secretion inhibited by MTBE exposure. In this study, we recruited 201 male subjects including occupational and non-occupational MTBE exposure from Anhui Province, China in 2019. Serum insulin and functional analog fibroblast growth factor 1 (FGF1) and blood MTBE were detected by Elisa and headspace solid-phase microextraction and gas chromatography-high-resolution mass spectrometry. According to MTBE internal exposure level, the workers were divided into low- and high-exposed groups and found that the serum insulin level in the high-exposed group was significantly lower than that in the low-exposed group (p = 0.003) while fasting plasma glucose (FPG) level increased obviously in the high-exposed group compared to the low-exposed group (p = 0.001). Further analysis showed that MTBE exposure level was positively correlated with FPG level, but negatively correlated with serum insulin level, which suggested that the FPG level increase might be related to the decrease of serum insulin level induced by MTBE exposure. The results of further mediation effect analysis showed that changes in serum zinc levels played a major intermediary role in the process of insulin secretion inhibition and blood glucose elevation caused by MTBE exposure. In addition, a significant negative correlation was found between MTBE exposure and serum Zn level, which might play a strong mediating effect on the inhibition of insulin secretion induced by MTBE exposure. In conclusion, our study provided evidence that MTBE could inhibit insulin secretion and interfere with Zn metabolism in gas station workers for the first time, and found that Zn might play an important mediation effect during the process of inhibiting insulin secretion and interfering with glucose metabolism induced by MTBE exposure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

The data are available from the corresponding author on reasonable request.

References

  • Abiria SA, Krapivinsky G, Sah R, Santa-Cruz AG, Chaudhuri D, Zhang J, Adstamongkonkul P, DeCaen PG, Clapham DE (2017) TRPM7 senses oxidative stress to release Zn(2+) from unique intracellular vesicles. Proc Natl Acad Sci USA 114:E6079-e6088

    CAS  Google Scholar 

  • Achten C, Kolb A, Püttmann W, Seel P, Gihr R (2002) Methyl tert-butyl ether (MTBE) in river and wastewater in Germany. Environ Sci Technol 36:3652–3661

    CAS  Google Scholar 

  • Alghrably M, Czaban I, Jaremko Ł, Jaremko M (2019) Interaction of amylin species with transition metals and membranes. J Inorg Biochem 191:69–76

    CAS  Google Scholar 

  • Aung MT, Song Y, Ferguson KK, Cantonwine DE, Zeng L, McElrath TF, Pennathur S, Meeker JD, Mukherjee B (2020) Application of an analytical framework for multivariate mediation analysis of environmental data. Nat Commun 11:5624

    CAS  Google Scholar 

  • Baker PJ, Britton KL, Fisher M, Esclapez J, Pire C, Bonete MJ, Ferrer J, Rice DW (2009) Active site dynamics in the zinc-dependent medium chain alcohol dehydrogenase superfamily. Proc Natl Acad Sci USA 106:779–784

    CAS  Google Scholar 

  • Bellia F, Grasso G (2014) The role of copper(II) and zinc(II) in the degradation of human and murine IAPP by insulin-degrading enzyme. J Mass Spectrom: JMS 49:274–279

    CAS  Google Scholar 

  • Belpoggi F, Soffritti M, Maltoni C (1995) Methyl-tertiary-butyl ether (MTBE)–a gasoline additive–causes testicular and lymphohaematopoietic cancers in rats. Toxicol Ind Health 11:119–149

    CAS  Google Scholar 

  • Bermudez E, Willson G, Parkinson H, Dodd D (2012) Toxicity of methyl tertiary-butyl ether (MTBE) following exposure of Wistar rats for 13 weeks or one year via drinking water. J Appl Toxicol: JAT 32:687–706

    CAS  Google Scholar 

  • Biles RW, Schroeder RE, Holdsworth CE (1987) Methyl tertiary butyl ether inhalation in rats: a single generation reproduction study. Toxicol Ind Health 3:519–534

    CAS  Google Scholar 

  • Blundell TL, Cutfield JF, Cutfield SM, Dodson EJ, Dodson GG, Hodgkin DC, Mercola DA (1972) Three-dimensional atomic structure of insulin and its relationship to activity. Diabetes 21:492–505

    CAS  Google Scholar 

  • Bonventre JA, Kung TS, White LA, Cooper KR (2013) Manipulation of the HIF-Vegf pathway rescues methyl tert-butyl ether (MTBE)-induced vascular lesions. Toxicol Appl Pharmacol 273:623–634

    CAS  Google Scholar 

  • Boquist L, Lernmark A (1969) Effects on the endocrine pancreas in Chinese hamsters fed zinc deficient diets. Acta Pathol Microbiol Scand 76:215–228

    CAS  Google Scholar 

  • Bortolon C, Larøi F, Stephan Y, Capdevielle D, Yazbek H, Boulenger JP, Gely-Nargeot MC, Raffard S (2014) Further insight into the role of metacognitive beliefs in schizophrenia and OCD patients: testing a mediation model. Psychiatry Res 220:698–701

    Google Scholar 

  • Brand IA, Heinickel A (1991) Key enzymes of carbohydrate metabolism as targets of the 11.5-kDa Zn(2+)-binding protein (parathymosin). J Biol Chem 266:20984–20989

    CAS  Google Scholar 

  • Careghini A, Saponaro S, Sezenna E, Daghio M, Franzetti A, Gandolfi I, Bestetti G (2015) Lab-scale tests and numerical simulations for in situ treatment of polluted groundwater. J Hazard Mater 287:162–170

    CAS  Google Scholar 

  • Chabosseau P, Rutter GA (2016) Zinc and diabetes. Arch Biochem Biophys 611:79–85

    CAS  Google Scholar 

  • Chimienti F, Devergnas S, Pattou F, Schuit F, Garcia-Cuenca R, Vandewalle B, Kerr-Conte J, Van Lommel L, Grunwald D, Favier A, Seve M (2006) In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion. J Cell Sci 119:4199–4206

    CAS  Google Scholar 

  • Choi S, Liu X, Pan Z (2018) Zinc deficiency and cellular oxidative stress: prognostic implications in cardiovascular diseases. Acta Pharmacol Sin 39:1120–1132

    CAS  Google Scholar 

  • Daughtrey WC, Gill MW, Pritts IM, Douglas JF, Kneiss JJ, Andrews LS (1997) Neurotoxicological evaluation of methyl tertiary-butyl ether in rats. J Appl Toxicol: JAT 17(Suppl 1):S57-64

    CAS  Google Scholar 

  • Dunn MF (2005) Zinc-ligand interactions modulate assembly and stability of the insulin hexamer – a review. Biometals 18(4):295–303. https://doi.org/10.1007/s10534-005-3685-y

    Article  CAS  Google Scholar 

  • Eckers A, Klotz LO (2009) Heavy metal ion-induced insulin-mimetic signaling. Redox Rep: Communications in Free Radical Research 14:141–146

    CAS  Google Scholar 

  • Emdin SO, Dodson GG, Cutfield JM, Cutfield SM (1980) Role of zinc in insulin biosynthesis. Some possible zinc-insulin interactions in the pancreatic B-cell. Diabetologia 19:174–182

    CAS  Google Scholar 

  • Formby B, Schmid-Formby F, Grodsky GM (1984) Relationship between insulin release and 65zinc efflux from rat pancreatic islets maintained in tissue culture. Diabetes 33:229–234

    CAS  Google Scholar 

  • Fung EB, Gildengorin G, Talwar S, Hagar L, Lal A (2015) Zinc status affects glucose homeostasis and insulin secretion in patients with thalassemia. Nutrients 7:4296–4307

    CAS  Google Scholar 

  • Gasser E, Moutos CP, Downes M, Evans RM (2017) FGF1 - a new weapon to control type 2 diabetes mellitus. Nat Rev Endocrinol 13:599–609

    Google Scholar 

  • Gomot MJ, Faure P, Roussel AM, Coudray C, Osman M, Favier A (1992) Effect of acute zinc deficiency on insulin receptor binding in rat adipocytes. Biol Trace Elem Res 32:331–335

    CAS  Google Scholar 

  • Guo A, Zhang J, He B, Li A, Sun T, Li W, Wang J, Tai R, Liu Y, Qian Z, Fan J, Sali A, Stevens RC, Jiang H (2022) Quantitative, in situ visualization of intracellular insulin vesicles in pancreatic beta cells. Proc Natl Acad Sci USA 119:e2202695119

    CAS  Google Scholar 

  • Huber AM, Gershoff SN (1973) Effect of zinc deficiency in rats on insulin release from the pancreas. J Nutr 103:1739–1744

    CAS  Google Scholar 

  • Islam MS, du Loots T (2007) Diabetes, metallothionein, and zinc interactions: a review. BioFactors (oxford, England) 29:203–212

    CAS  Google Scholar 

  • Izaguirre M, Gil MJ, Monreal I, Montecucco F, Frühbeck G, Catalán V (2017) The role and potential therapeutic implications of the fibroblast growth factors in energy balance and type 2 diabetes. Curr DiabRep 17:43

    Google Scholar 

  • Kinlaw WB, Levine AS, Morley JE, Silvis SE, McClain CJ (1983) Abnormal zinc metabolism in type II diabetes mellitus. Am J Med 75:273–277

    CAS  Google Scholar 

  • Kolb A, Püttmann W (2006) Comparison of MTBE concentrations in groundwater of urban and nonurban areas in Germany. Water Res 40:3551–3558

    CAS  Google Scholar 

  • Kucharzyk KH, Rectanus HV, Bartling CM, Rosansky S, Minard-Smith A, Mullins LA, Neil K (2019) Use of omic tools to assess methyl tert-butyl ether (MTBE) degradation in groundwater. J Hazard Mater 378:120618

    CAS  Google Scholar 

  • Laur N, Kinscherf R, Pomytkin K, Kaiser L, Knes O, Deigner HP (2020) ICP-MS trace element analysis in serum and whole blood. PLoS One 15:e0233357

    CAS  Google Scholar 

  • Li YV (2014) Zinc and insulin in pancreatic beta-cells. Endocrine 45:178–189

    CAS  Google Scholar 

  • Li D, Yin D, Han X (2007) Methyl tert-butyl ether (MTBE)-induced cytotoxicity and oxidative stress in isolated rat spermatogenic cells. J Appl Toxicol 27:10–17

    Google Scholar 

  • Li D, Yuan C, Gong Y, Huang Y, Han X (2008) The effects of methyl tert-butyl ether (MTBE) on the male rat reproductive system. Food Chem Toxicol: An International Journal Published for the British Industrial Biological Research Association 46:2402–2408

    CAS  Google Scholar 

  • Li D, Liu Q, Gong Y, Huang Y, Han X (2009) Cytotoxicity and oxidative stress study in cultured rat Sertoli cells with methyl tert-butyl ether (MTBE) exposure. Reprod Toxicol (Elmsford, N.Y) 27:170–176

    CAS  Google Scholar 

  • Ma J, Chen L, Song D, Zhang Y, Chen T, Niu P (2017) SIRT1 attenuated oxidative stress induced by methyl tert-butyl ether in HT22 cells. Toxicol Res 6:290–296

    CAS  Google Scholar 

  • Mascolo G, Ciannarella R, Balest L, Lopez A (2008) Effectiveness of UV-based advanced oxidation processes for the remediation of hydrocarbon pollution in the groundwater: a laboratory investigation. J Hazard Mater 152:1138–1145

    CAS  Google Scholar 

  • McGregor D (2006) Methyl tertiary-butyl ether: studies for potential human health hazards. Crit Rev Toxicol 36:319–358

    CAS  Google Scholar 

  • Mehlman MA (1999) Cancer risk from exposure to motor fuel containing MTBE: “reasonably anticipated to be a human carcinogen.” Int J Occup Environ Health 5:323–324

    CAS  Google Scholar 

  • Miao X, Sun W, Fu Y, Miao L, Cai L (2013) Zinc homeostasis in the metabolic syndrome and diabetes. Front Med 7:31–52

    Google Scholar 

  • Mowri HO, Frei B, Keaney JF Jr (2000) Glucose enhancement of LDL oxidation is strictly metal ion dependent. Free Radical Biol Med 29:814–824

    CAS  Google Scholar 

  • Nies VJM, Struik D, Liu S, Liu W, Kruit JK, Downes M, van Zutphen T, Verkade HJ, Evans RM, Jonker JW (2022) Autocrine FGF1 signaling promotes glucose uptake in adipocytes. Proc Natl Acad Sci USA 119:e2122382119

    CAS  Google Scholar 

  • Olechnowicz J, Tinkov A, Skalny A, Suliburska J (2018) Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism. J Physiol Sci: JPS 68:19–31

    CAS  Google Scholar 

  • Philipp A, Kralisch S, Bachmann A, Lossner U, Kratzsch J, Blüher M, Stumvoll M, Fasshauer M (2011) Serum levels of the adipokine zinc-α2-glycoprotein are increased in chronic hemodialysis. Metabolism: Clinical and Experimental 60:669–672

    CAS  Google Scholar 

  • Phillips GB, Safrit HF (1971) Alcoholic diabetes. Induction of glucose intolerance with alcohol. JAMA 217:1513–1519

    CAS  Google Scholar 

  • Preacher KJ, Hayes AF (2008) Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav Res Methods 40:879–891

    Google Scholar 

  • Qiu J, Zhang C, Borgquist A, Nestor CC, Smith AW, Bosch MA, Ku S, Wagner EJ, Rønnekleiv OK, Kelly MJ (2014) Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metab 19:682–693

    CAS  Google Scholar 

  • Ramdas Nayak VK, Satheesh P, Shenoy MT, Kalra S (2022) Triglyceride Glucose (TyG) Index: a surrogate biomarker of insulin resistance. JPMA. J Pak Med Assoc 72:986–988

    Google Scholar 

  • Roth HP, Kirchgessner M (1981) Zinc and insulin metabolism. Biol Trace Elem Res 3:13–32

    CAS  Google Scholar 

  • Rutter GA, Chabosseau P, Bellomo EA, Maret W, Mitchell RK, Hodson DJ, Solomou A, Hu M (2016) Intracellular zinc in insulin secretion and action: a determinant of diabetes risk? Proc Nutr Soc 75:61–72

    CAS  Google Scholar 

  • Saeedi A, Fardid R, Khoshnoud MJ, Kazemi E, Omidi M, Mohammadi-Bardbori A (2017a) Disturbance of zinc and glucose homeostasis by methyl tert-butyl ether (MTBE); evidence for type 2 diabetes. Xenobiotica; the Fate of Foreign Compounds in Biological Systems 47:547–552

    CAS  Google Scholar 

  • Saeedi A, Omidi M, Khoshnoud MJ, Mohammadi-Bardbori A (2017b) Exposure to methyl tert-butyl ether (MTBE) is associated with mitochondrial dysfunction in rat. Xenobiotica; the Fate of Foreign Compounds in Biological Systems 47:423–430

    CAS  Google Scholar 

  • Salimi A, Vaghar-Moussavi M, Seydi E, Pourahmad J (2016) Toxicity of methyl tertiary-butyl ether on human blood lymphocytes. Environ Sci Pollut Res Int 23:8556–8564

    CAS  Google Scholar 

  • Savelenko VD, Ershov MA, Kapustin VM, Chernysheva EA, Abdellatief TMM, Makhova UA, Makhmudova AE, Abdelkareem MA, Olabi AG (2022) Pathways resilient future for developing a sustainable E85 fuel and prospects towards its applications. Sci Total Environ 844:157069

    CAS  Google Scholar 

  • Scarlett JM, Rojas JM, Matsen ME, Kaiyala KJ, Stefanovski D, Bergman RN, Nguyen HT, Dorfman MD, Lantier L, Wasserman DH, Mirzadeh Z, Unterman TG, Morton GJ, Schwartz MW (2016) Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. Nat Med 22:800–806

    CAS  Google Scholar 

  • Smith GD, Swenson DC, Dodson EJ, Dodson GG, Reynolds CD (1984) Structural stability in the 4-zinc human insulin hexamer. Proc Natl Acad Sci USA 81:7093–7097

    CAS  Google Scholar 

  • Soinio M, Marniemi J, Laakso M, Pyörälä K, Lehto S, Rönnemaa T (2007) Serum zinc level and coronary heart disease events in patients with type 2 diabetes. Diabetes Care 30:523–528

    CAS  Google Scholar 

  • Steiner DF (1976) Editorial: Errors in insulin biosynthesis. N Engl J Med 294:952–953

    CAS  Google Scholar 

  • Steiner DF (2011) Adventures with insulin in the islets of Langerhans. J Biol Chem 286:17399–17421

    CAS  Google Scholar 

  • Stout RW (1994) Glucose tolerance and ageing. J R Soc Med 87:608–609

    CAS  Google Scholar 

  • Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Järvinen H, Van Haeften T, Renn W, Gerich J (2000) Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care 23:295–301

    CAS  Google Scholar 

  • Tamaki M, Fujitani Y, Hara A, Uchida T, Tamura Y, Takeno K, Kawaguchi M, Watanabe T, Ogihara T, Fukunaka A, Shimizu T, Mita T, Kanazawa A, Imaizumi MO, Abe T, Kiyonari H, Hojyo S, Fukada T, Kawauchi T, Nagamatsu S, Hirano T, Kawamori R, Watada H (2013) The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J Clin Investig 123:4513–4524

    CAS  Google Scholar 

  • Tang Y, Ren Q, Wen Q, Yu C, Xie X, Hu Q, Du Y (2019) Effect of methyl tert-butyl ether on adipogenesis and glucose metabolism in vitro and in vivo. J Environ Sci (china) 85:208–219

    CAS  Google Scholar 

  • Valipour M, Maghami P, Habibi-Rezaei M, Sadeghpour M, Khademian MA, Mosavi K, Sheibani N, Moosavi-Movahedi AA (2015) Interaction of insulin with methyl tert-butyl ether promotes molten globule-like state and production of reactive oxygen species. Int J Biol Macromol 80:610–614

    CAS  Google Scholar 

  • Wang B, Wang P, Zheng E, Chen X, Zhao H, Song P, Su R, Li X, Zhu G (2011) Biochemical properties and physiological roles of NADP-dependent malic enzyme in Escherichia coli. J Microbiol (seoul, Korea) 49:797–802

    CAS  Google Scholar 

  • Wu L, Cui F, Zhang S, Ding X, Gao W, Chen L, Ma J, Niu P (2023) Associations between multiple heavy metals exposure and neural damage biomarkers in welders: a cross-sectional study. Sci Total Environ 869:161812

    CAS  Google Scholar 

  • Yang HK, Lee SH, Han K, Kang B, Lee SY, Yoon KH, Kwon HS, Park YM (2015) Lower serum zinc levels are associated with unhealthy metabolic status in normal-weight adults: the 2010 Korea National Health and Nutrition Examination Survey. Diabetes Metab 41:282–290

    CAS  Google Scholar 

Download references

Funding

This research was supported by the National Natural Science Foundation of China (NSFC No.81973009).

Author information

Authors and Affiliations

Authors

Contributions

Mingxiao Guo performed laboratory measurements, statistical analysis, drafting, and editing of the final manuscript; Mengdi Li participated in the investigation, laboratory measurements, sample collection, and the face-to-face interview; Fengtao Cui, Xinping Ding, Xingqiang Fang, and Wei Gao performed the investigation, data curation, and sample collection; Hanyun Wang performed the sample collection and laboratory measurements; Li Chen provided suggestions for statistical analysis; Piye Niu performed the investigation, data curation, methodology, supervision, and manuscript—review and editing; Junxiang Ma performed the design, methodology, supervision, writing—review and editing, project administration, and resources.

Corresponding author

Correspondence to Junxiang Ma.

Ethics declarations

Ethics approval

The protocol and operating procedures of this study were approved by the Ethics Committee of Capital Medical University (No.8197120404).

Consent to participate

All participants in this study had signed informed consent forms and all consented to participate in the research.

Consent for publication

The manuscript has not been submitted nor is under consideration for publication by another journal and none of its contents have been previously published. All authors participated in formulating the hypothesis, executing the work, analyzing the data, and writing the manuscript and have approved the final version for submission to your journal. All authors agreed to publication in the Journal of Environmental Science and Pollution Research.

Competing interests

The authors declare no competing interests.

Additional information

Responsible Editor: Lotfi Aleya

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

11356_2023_31772_MOESM1_ESM.pdf

Supplementary file1. The distribution of internal exposure levels among participants. The distribution of (A) MTBE, (B) TBA levels among participants. (PDF 1230 KB)

Supplementary file2 (DOCX 20 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, M., Li, M., Cui, F. et al. Mediation effect of serum zinc on insulin secretion inhibited by methyl tert-butyl ether in gas station workers. Environ Sci Pollut Res 31, 8952–8962 (2024). https://doi.org/10.1007/s11356-023-31772-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-023-31772-2

Keywords

Navigation