Influence of the DAT gene knockout on exchange of essential and toxic trace elements in rats
The maintenance of energy homeostasis of the body according to modern data is carried out with the active participation of dopaminergic neurons of the central nervous system. The synthesis and metabolism of dopamine (DA) occurs both in the brain and in peripheral tissues. Violation of the synthesis and metabolism of DA is considered as a link in the vicious cycle which it formed during the development of diet-induced obesity. According to modern data, a number of essential and toxic trace elements, such as Cd, Al, As, Mn, Fe, Cu, Zn, are actively involved in the exchange of DA in the brain and peripheral organs and tissues. One way to assess this relationship is to compare changes in the microelement status of the organism when consuming hypercaloric diets in animals with normal and impaired DA transport. The latter can be animals with a knockout of the DAT transporter gene, which performs DA reabsorption with subsequent storage in the composition of secretory granules.
The aim is a comparative study of the content of a number of essential and toxic elements in the brain, liver, and kidneys of rats that differ in the allelic variants of the DAT gene fed balanced diet and the diet with an excess of energy value.
Material and methods. The study was carried out on 30 male rats of the DAT-KO knockout line (homozygotes DAT-/- and heterozygotes DAT+/-), 8-10 weeks old, and 13 males rats of the outbred Wistar line (DAT+/+) of the same age. For 62 days the animals (6 groups) received a semi-synthetic diet containing essential elements in the salt mixture or a similar high-fat-high-carbohydrate diet (HFCD) with 30% fat and 20% fructose solution instead of drinking water. The content of 16 trace elements (Fe, Mg, Cu, Mn, Co, Se, Zn, Cr, V, Cs, Ag, Al, Cd, As, Pb, Ni) were determined by inductively coupled plasma mass spectrometry in the liver, kidneys, and brain of rats with a knockout of the dopamine DAT transporter gene: homozygotes (DAT -/-) and heterozygotes (DAT+/-), as well as wild-type rats (DAT+/+) of the Wistar strain.
Results and discussion. In the liver, DAT knockout led to an increase in the content of As, Cd, Co, and Cs and a decrease in Fe; in the kidneys - to an increase in the levels of Pb, As, Cd and Se, in the brain - an increase in the content of most of the studied trace elements, including Pb, As, Cs, Al and Cu.
Conclusion. Against the background of consumption of HFCD, the effect of DAT knockout on the content of a number of elements was more pronounced compared with the consumption of the control diet. The revealed changes in the trace element content in DAT knockout rats are considered in terms of the effect of DA metabolism in the central nervous system and in peripheral tissues on the status of trace elements.
Keywords:dopamine transporter, knockout, rats, trace elements, liver, kidney, brain, ICP-MS
Funding. The work was supported by the Russian Scientific Foundation (grant No. 17-16-01043).
Conflict of interest. The authors declare that they have no conflicts of interest.
For citation: Shumakova A.A., Apryatin S.A., Shipelin V.A., Efimova E.V., Fesenko Z.S., Gmoshinski I.V. Influence of the DAT gene knockout on exchange of essential and toxic trace elements in rats. Voprosy pitaniia [Problems of Nutrition]. 2020; 89 (5): 17-27. DOI: https://www.doi.org/10.24411/0042-8833-2020-10062 (in Russian)
1. Volkow N.D., Wang G.J., Baler R.D. Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn Sci. 2011; 15 (1): 37–46. DOI: https://doi.org/10.1016/j.tics.2010.11.001
2. Rada P., Bocarsly M.E., Barson J.R., Hoebel B.G., Leibowitz S.F. Reduced accumbens dopamine in Sprague-Dawley rats prone to overeating a fat-rich diet. Physiol Behav. 2010; 101 (3): 394–400. DOI: https://doi.org/10.1016/j.physbeh.2010.07.005
3. Alsiö J., Olszewski P.K., Norbäck A.H., Gunnarsson Z.E.A., Levine A.S., Pickering C., et al. Dopamine D1 receptor gene expression decreases in the nucleus accumbens upon long-term exposure to palatable food and differs depending on diet-induced obesity phenotype in rats. Neuroscience. 2010; 171 (3): 779–87. DOI: https://doi.org/10.1016/j.neuroscience.2010.09.046
4. Gupta R., Shukla R.K., Pandey A., Sharma T., Dhuriya Y.K., Srivastava P., et al. Involvement of PKA/DARPP-32/PP1α and β- arrestin/Akt/GSK-3β signaling in cadmium-induced DA-D2 receptor-mediated motor dysfunctions: protective role of quercetin. Sci. Rep. 2018; 8 (1): 2528. DOI: https://doi.org/10.1038/s41598-018-20342-z
5. Srivastava P., Dhuriya Y.K., Gupta R., Shukla R.K., Yadav R.S., Dwivedi H.N., et al. Protective effect of curcumin by modulating BDNF/DARPP32/CREB in arsenic-induced alterations in dopaminergic signaling in rat corpus striatum. Mol Neurobiol. 2018; 55 (1): 445–61. DOI: https://doi.org/10.1007/s12035-016-0288-2
6. Ziomber A., Surowka A.D., Antkiewicz-Michaluk L., Romanska I., Wrobel P., Szczerbowska-Boruchowska M. Combined brain Fe, Cu, Zn and neurometabolite analysis - a new methodology for unraveling the efficacy of transcranial direct current stimulation (tDCS) in appetite control. Metallomics. 2018; 10 (3): 397–405. DOI: https://doi.org/10.1039/c7mt00329c
7. Hare D.J., Double K.L. Iron and dopamine: a toxic couple. Brain. 2016; 139 (pt 4): 1026–35. DOI: https://doi.org/10.1093/brain/aww022
8. Dalla Torre G., Mujika J.I., Lachowicz J.I., Ramos M.J., Lopez X. The interaction of aluminum with catecholamine-based neurotransmitters: can the formation of these species be considered a potential risk factor for neurodegenerative diseases? Dalton Trans. 2019; 48 (18): 6003–18. DOI: https://doi.org/10.1039/c8dt04216k
9. Van Duyn N., Settivari R., LeVora J., Zhou S., Unrine J., Nass R. The metal transporter SMF-3/DMT-1 mediates aluminum-induced dopamine neuron degeneration. J Neurochem. 2013; 124 (1): 147–57. DOI: https://doi.org/10.1111/jnc.12072
10. Skalnaya M.G., Skalny A.V., Grabeklis A.R., Serebryansky E.P., Demidov V.A., Tinkov A.A. Hair trace elements in overweight and obese adults in association with metabolic parameters. Biol Trace Elem Res. 2018; 186 (1): 12–20. DOI: https://doi.org/10.1007/s12011-018-1282-5
11. Leo D., Sukhanov I., Zoratto F., Illiano P., Caffino L., Sanna F., et al. Pronounced hyperactivity, cognitive dysfunctions, and BDNF dysregulation in dopamine transporter knock-out rats. J Neurosci. 2018; 38: 1959–72. DOI: https://doi.org/10.1523/J NEUROSCI.1931-17.2018
12. Apryatin S.A., Shipelin V.A., Trusov N.V., Mzhelskaya K.V., Evstratova V.S., Kirbaeva N.V., et al. Comparative analysis of the influence of a high-fat/high-carbohydrate diet on the level of anxiety and neuromotor and cognitive functions in Wistar and DAT-KO rats. Physiol Rep. 2019; 7 (4): e13987. DOI: https://doi.org/10.14814/phy2.13987
13. Reeves P.C. AIN-93 purified diets for the study of trace elements metabolism in rodents. In: R.R. Watson (ed.). Trace Elements in Laboratory Rodents. New York, etc: CRC Press, 2000.
14. Leggett R.W., Williams L.R., Melo D.R., Lipsztein J.L. A physiologically based biokinetic model for cesium in the human body. Sci Total Environ. 2003; 317 (1–3): 235–55.
15. Apryatin S.A., Shumakova A.A., Vrzhesinskaya O.A., Leonenko S.N., Kodentsova V.M., Gmoshinsky I.V. Alteration of mineral element status of rodents under combined group B vitamin deficiency. Trace Elem Electrolytes. 2018; 35 (10): 193–5.