On detecting omic-markers of negative effects associated with combined aerogenic exposure to aluminum and fluoride compounds

View or download the full article: 

M.A. Zemlyanova1,2,3, N.V. Zaitseva1, Yu.V. Koldibekova1, A.N. Perezhogin4, M.S. Stepankov1, N.I. Bulatova1


1Federal Scientific Center for Medical and Preventive Health Risk Management Technologies, 82 Monastyrskaya Str., Perm, 614045, Russian Federation
2Perm State National Research University, 15 Bukireva Str., Perm, 614990, Russian Federation
3Perm National Research Polytechnic University, 29 Komsomolsky prospekt, Perm, 614990, Russian Federation
4Irkutsk Antiplague Research Institute of Siberia and Far East awarded by the Labour Red Banner, 78 Trilissera Str., Irkutsk, 664047, Russian Federation


At present, it is relevant to study simultaneous combined impacts exerted by chemicals on developing adverse health effects. It is also becoming vital to search for molecular indicators of adverse effects with the altered expression level. This alteration makes it possible to determine peculiarities of molecular and cellular pathogenesis mechanisms regarding a number of non-communicable diseases under exposure to a mixture of chemicals.

Our research goal was to comparatively analyze and identify identical omic-markers of adverse effects under experimental and actual combined aerogenic exposure to aluminum and fluoride compounds. We substantiated molecular markers of prenosological changes by sequential implementation of an algorithm which included identifying altered proteins and peptides in blood plasma which were identical both under experimental and actual exposure; detecting and quantifying cause-effect relations between identical proteins and peptides and concentrations of aluminum and fluoride ion in urine.

The research results indicate that long-term combined aerogenic exposure to aluminum and fluoride compounds in low average daily doses (0.0005 mg/(kgday) and 0.002 mg/(kg*day) accordingly) causes elevated concentrations of aluminum (by 2.8 times higher) and fluoride-ion (by 1.8 times higher) in exposed children’s urine. This fact is verified by experimental research with its focus on combined exposure to the examined chemicals. We were able to substantiate identical omic-markers,
J-chain of immunoglobulin and Kelch-like protein 4 (KLHL4 gene), under simultaneous exposure to aluminum and fluoride compounds both under experimental and actual combined aerogenic exposure. We proved a cause-effect relation between levels of identical proteins and concentrations of aluminum and fluoride ion in urine under simultaneous exposure to the mixture of the examined chemicals. Identified protein markers in blood plasma give an opportunity to predict future adverse effects including developing immunoglobulins A and M deficiency with subsequent humoral immunity failure when J-chain of immunoglobulin is expressed; occurring sclerotic and inflammatory changes in vascular walls when Kelch-like protein 4 is expressed. These predicted adverse effects can be estimated as resulting from simple summated (additive) toxic impacts exerted by aluminum and fluoride under simultaneous combined aerogenic exposure to both chemicals.

aluminum and fluoride ion in urine, risk of adverse effects, isolated and combined exposure, blood plasma proteomic profile, immune system, cardiovascular system, immunoglobulin J-chain and Kelch-like protein 4
Zemlyanova M.A., Zaitseva N.V., Koldibekova Yu.V., Perezhogin A.N., Stepankov M.S., Bulatova N.I. On detecting omic-markers of negative effects associated with combined aerogenic exposure to aluminum and fluoride compounds. Health Risk Analysis, 2022, no. 1, pp. 113–122. DOI: 10.21668/health.risk/2022.1.13.eng
  1. Assessment of combined exposures to multiple chemicals: report of a WHO/IPCS interna-tional workshop on aggregate/cumulative risk assessment. World Health Organization, 2009, no. 7, 83 р.
  2. Considerations for Assessing the Risks of Combined Exposure to Multiple Chemicals, Series on Testing and Assessment. OECD, 2018, no. 296, 119 р.
  3. Hadley M.B., Baumgartner J., Vedanthan R. Developing a clinical approach to mitigating risks of air pollution and protecting cardiovascular health. Circulation, 2018, vol. 137, no. 7, pp. 725–742. DOI: 10.1161/CIRCULATIONAHA.117.030377
  4. WHO global air quality guidelines, Particulate matter (‎PM2.5 and PM10)‎, ozone, nitrogen dioxide, sulfur dioxide and carbon monoxide. World Health Organization, 2021. Available at: https://
    apps.who.int/iris/bit¬stream/handle/10665/345329/9789240034228-eng.pdf?sequence=1&isAllowed=y (12.11.2021).
  5. Zaitseva N.V., Zemlyanova M.A., Stepankov M.S., Ignatova A.M. Scientific forecasting of toxicity and evaluation of hazard potential of aluminum oxide nanoparticles for human health. Ekologiya cheloveka, 2018, no. 5, pp. 9–15. DOI: 10.33396/1728-0869-2018-5-9-15 (in Russian).
  6. Donskikh I.V. The influence of fluorine and its compounds on people’s health (literature review). Byulleten' VSNTs SO RAMN, 2013, vol. 91, no. 3, part 2, рр. 179–185 (in Russian).
  7. Mintel M.V., Zemlyanova М.А., Zhdanova-Zaplesvichko I.G. Some aspects of synergistic action of aluminum and fluorine on human body (literature review). Ekologiya cheloveka, 2018, no. 9, pp. 12–18. DOI: 10.33396/1728-0869-2018-9-12-17 (in Russian).
  8. Sazonova N.G., Makarenko T.A., Olovyannikova R.Ya., Kutyakov V.A., Salmina A.B. Proteomic analysis methods and their role in the diagnosis of obstetric and gynecological pathology. Zhurnal akusherstva i zhenskikh boleznei, 2019, vol. 68, no. 1, pp. 69–82. DOI: 10.17816/JOWD68169-82 (in Russian).
  9. Zhetisheva R.A., Kovaleva M.A., Kamenihina I.A., Kovalev L.I., Naumov V.G. The protein biomarkers search in atherosclerosis using proteomic technologies – as a promising area of science. Ateroskleroz i dislipidemii, 2020, no. 2, pp. 12–19. DOI: 10.34687/2219–8202.JAD.2020.02.0002 (in Russian).
  10. Drozdova E.V., Dudchik N.V., Sychik S.I., Shevlyakov V.V. Otsenka integral'noi toksichnosti faktorov i ob"ektov sredy obitaniya s ispol'zovaniem al'ternativnykh biologicheskikh test-modelei: metodologiya i tekhnologii [Integrated toxicity assessment of environmental factors and objects using alternative biological test models: methodology and technology]. Minsk, Belorusskii nauchno-issledovatel'skii institut transporta «Transtekhnika» Publ., 2017, 216 р. (in Russian).
  11. Xiao B., Li D., Dong Q., Li Q., Li S., Zhan C. [Effects of aluminum, fluorine and their mixtures on the enzyme activities of jejunal mucus membrane in the perfusion of small intestine of rats in vivo]. Journal of West China University of Medical Sciences, 1992, vol. 23, no. 1, рр. 79–82 (in Chinese).
  12. Strunecka A., Strunecky O., Patocka J. Fluoride plus aluminum: Useful tools in labo-ratory investigations, but messengers of false information. Physiol. Res., 2002, vol. 51, no. 6, pp. 557–564.
  13. Li L. The biochemistry and physiology of metallic fluoride: action, mechanism, and implications. Crit. Rev. Oral Biol. Med., vol. 14, no. 2, pp. 100–114. DOI: 10.1177/154411130301400204
  14. Suwalsky M., Norris B., Villena F., Cuevas F., Sotomayor P., Zatta P. Aluminum fluoride affects the structure and functions of cell membranes. Food Chem. Toxicol., 2004, vol. 42, no. 6, pp. 925–933. DOI: 10.1016/j.fct.2004.01.016
  15. Koshland M.E. The coming of age of the immunoglobulin J chain. Annu. Rev. Immunol., 1985, vol. 3, рр. 425–453. DOI: 10.1146/annurev.iy.03.040185.002233
  16. Johansen F.E., Braathen R., Brandtzaeg P. Role of J chain in secretory immunoglobulin formation. Scand. J. Immunol., 2000, vol. 52, no. 3, рр. 240–248. DOI: 10.1046/j.1365-3083.2000.00790.x
  17. Moskalets O.V. Immunoglobulin A and its selective deficiency. Kazanskii meditsinskii zhurnal, vol. 98, no. 5, pp. 809–813. DOI: 10.17750/KMJ2017-809 (in Russian).
  18. Choi S.-H., Cho S.-Y., Song J., Hur M.-W. KLHL4, a novel p53 target gene, inhibits cell proliferation by activating p21WAF/CDKN1A. Biochem. Biophys. Res. Commun., 2020, vol. 530, no. 3, pp. 588–596. DOI: 10.1016/j.bbrc.2020.07.100
  19. Shi X., Xiang S., Cao J., Zhu H., Yang B., He Q., Ying M. Kelch-like proteins: Physiolog-ical functions and relationships with diseases. Pharmacol. Res., 2019, vol. 148, pp. 104404. DOI: 10.1016/j.phrs.2019.104404
  20. Solodkov A.P., Belyaeva L.E., Lazuko S.S. Stress i arterial'naya gipertenziya [Stress and arterial hypertension]. Praktikuyuchii lіkar, 2013, no. 3, рр. 78–80 (in Russian).
Accepted for publication: 

You are here