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Anti-Doping
EDITORIAL

Could Nickel Become a Novel Erythropoiesis-Stimulating Compound for Cheating Athletes?

Könnte Nickel ein neues erythropoietisch wirksames Dopingmittel werden?

Rude and violent behavior in sports is sometimes called “nickelig” in German language. Ironically, recent evidence suggests that nickel may be misused in sports (19). Nickel belongs to group 10 of the current IUPAC (International Union of Pure and Applied Chemistry) periodic classification of elements. It shares properties with iron and cobalt, the latter being a prohibited substance according to the regulations of the World Anti-Doping Agency (WADA) (7, 21). Under experimental conditions, ionic nickel can induce hypoxia-like responses, possibly promoting red blood cell production (1). This knowledge calls into question whether the recent detection of a nickel-enriched product claiming performance-enhancing properties, is indicative of attempts to undermine current human and animal doping controls (19, 20).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

THE HYPOXIA INDUCIBLE TRANSCRIPTION FACTORS (HIFs)

The erythropoietin gene (EPO) is controlled by the hypoxia-inducible transcription factors (HIFs). HIFs are heterodimeric proteins composed of α- and β-subunits. There are different HIF-αsubunits. HIF-1α is rather ubiquitously expressed, with HIF-1 (HIF-1α/HIF-1β) playing important roles in metabolic processes, such as glucose metabolism (15). In contrast, HIF-2α is restricted to specific cell types, including renal and extra-renal cells producing EPO, and endothelial cells producing vascular endothelial growth factor (VEGF) (9). Hence, HIF-2 (HIF-2α/HIF-1β) promotes erythropoiesis and angiogenesis. Distinct prolyl residues of the HIF-αsubunits are hydroxylated in an O2-pressure-dependent manner by specific enzymes, the prolyl-4-hydroxylase domain proteins (PHD-1, -2 and -3). PHDs are iron- and 2-oxoglutarate-dependent dioxygenases. Prolyl hydroxylated HIF-αis immediately ubiquitinated by the so-called SCF complex (S-phase kinase-associated protein 1, Cullin, F-box containing complex) to undergo immediate proteasomal degradation. Salnikow et al. were the first to demonstrate that nickel exposure activates HIF-1 (13). Subsequent studies have shown that Ni2+ does not only stabilize HIF-1α but also HIF-2α (11). Nickel is less potent than cobalt as a HIF-stabilizer (4).
Several hypotheses have been proposed to explain the stabilization of HIF-α by nickel. Ni2+ can enter cells via the divalent metal transporter-1 (DMT1) and thereby compete with Fe2+ for entry into cells (2). Of note, however, simple competitive inhibition of the HIF-αPHDs has been considered unlikely (4). It has been suggested that divalent metals such as Ni2+ or Co2+ may stabilize HIF-α by binding to Cullin-2 (8).

EFFECTS OF NICKEL ON EPO PRODUCTION

Almost 40 years ago the group of Hopfer discovered that the intra-renal injection of nickel compounds (αNi3S2, NiO, NiS2, βNiS, Ni dust) produces an increase in circulating EPO and erythrocytosis in rats (6). The intra-renal injection of Ni3S2 was also effective in guinea pigs but not in in hamsters or gerbils, indicating significant species-specificity (18). Importantly, NiCl2 proved to increase EPO mRNA expression and EPO production in the human hepatoma cell line, Hep3B (5). The intraperitoneal infusion of NiCl2 failed to stimulate EPO production in rats (17). Likewise, the subcutaneous injection of nickel failed to stimulate renal EPO mRNA expression in mice (10).
Note, here, that dietary nickel was found to increase the blood hemoglobin concentration and to cause pulmonary hypertension in broiler chickens (12). No such effect has been reported with respect to increased nickel supplementation in mammals. It can be stated that the effect of Ni2+ differs from that of Co2+, as the latter clearly stimulates EPO synthesis and erythropoiesis following oral administration (7).

EFFECTS OF NICKEL ON OTHER HIF-DEPENDENT GENES

HIFs do not only stimulate erythropoiesis, but are involved in a number of other processes which protect the cells from oxygen and glucose deprivation. More than 1000 HIF target genes have been identified so far (15). For example, hypoxia, nickel, and cobalt stimulate VEGF expression in osteoblast cell cultures by a similar mechanism (16). GeneChip analysis of mouse embryonic fibroblasts exposed to Ni2+ has demonstrated increased expression of genes involved in glucose metabolism, including glycolytic enzymes and genes responsible for glucose transport (14).

CONCLUSION

Nickel can stimulate HIF-dependent processes. However, there are no data in support of the assumption that nickel can stimulate EPO production when administered systemically (oral, subcutaneous, or intravenous routes). Actually, nickel is contained in numerous food products including corn, nuts, fruits, tea, etc. and thus an integral part of the human diet. Increased nickel supplementation, however, can cause severe side effects. Extensive nickel consumption can result in allergic reactions and (irreversible) nickel sensitivity, digestion problems, increased red blood cell counts, kidney failure and cancer, primarily lung cancer (3). These facts alone should discourage athletes from a potentially deleterious doping practice with nickel. In addition, anti-doping laboratories have established methods for detection of transition metals including nickel in biological samples (19, 20).

REFERENCES

  1. CHEN H, COSTA M. : Iron- and 2-oxoglutarate-dependent dioxygenases: an emerging group of molecular targets for nickel toxicity and carcinogenicity. Biometals. 2009; 22: 191-196.
    doi:10.1007/s10534-008-9190-3
  2. CHEN H, DAVIDSON T, SINGLETON S, GARRICK MD, COSTA M. : Nickel decreases cellular iron level and converts cytosolic aconitase to iron-regulatory protein 1 in A549 cells. Toxicol Appl Pharmacol. 2005; 206: 275-287.
    doi:10.1016/j.taap.2004.11.011
  3. COSTA M, DAVIDSON TL, CHEN H, KE Q, ZHANG P, YAN Y, HUANG C, KLUZ T.: Nickel carcinogenesis: epigenetics and hypoxia signaling. Mutat Res. 2005; 592: 79-88.
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  5. HO VT, BUNN HF. : Effects of transition metals on the expression of the erythropoietin gene: further evidence that the oxygen sensor is a heme protein. Biochem Biophys Res Commun. 1996; 223: 175-180.
    doi:10.1006/bbrc.1996.0865
  6. HOPFER SM, SUNDERMAN FW JR, FREDRICKSON TN, MORSE EE.: Increased serum erythropoietin activity in rats following intrarenal injection of nickel subsulfide. Res Commun Chem Pathol Pharmacol. 1979; 23: 155-170.
  7. JELKMANN W. : The disparate roles of cobalt in erythropoiesis, and doping relevance. Open J Hematol. 2012; 3: 1-9.
    doi:10.13055/ojhmt_3_1_6.121211
  8. KANAYA K, TSAI AL, KAMITANI T. : Cobalt- and nickel-binding property of cullin-2. Biochem Biophys Res Commun. 2002; 290: 294-299.
    doi:10.1006/bbrc.2001.6207
  9. KOURY MJ, HAASE VH. : Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol. 2015; 11: 394-410.
    doi:10.1038/nrneph.2015.82
  10. LATUNDE-DADA GO, SHIRALI S, MCKIE AT, SIMPSON RJ, PETERS TJ.: Effect of transition metal ions (cobalt and nickel chlorides) on intestinal iron absorption. Eur J Clin Invest. 2004; 34: 626-630.
    doi:10.1111/j.1365-2362.2004.01396.x
  11. LI Q, KLUZ T, SUN H, COSTA M. : Mechanisms of c-myc degradation by nickel compounds and hypoxia. PLoS ONE. 2009; 4: e8531.
    doi:10.1371/journal.pone.0008531
  12. MARTINEZ DA, DIAZ GJ. : Effect of graded levels of dietary nickel and manganese on blood haemoglobin content and pulmonary hypertension in broiler chickens. Avian Pathol. 1996; 25: 537-549.
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  13. SALNIKOW K, BLAGOSKLONNY MV, RYAN H, JOHNSON R, COSTA M.: Carcinogenic nickel induces genes involved with hypoxic stress. Cancer Res. 2000; 60: 38-41.
  14. SALNIKOW K, DAVIDSON T, KLUZ T, CHEN H, ZHOU D, COSTA M. : GeneChip analysis of signaling pathways effected by nickel. J Environ Monit. 2003; 5: 206-209.
    doi:10.1039/b210262p
  15. SEMENZA GL. : HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest. 2013; 123: 3664-3671.
    doi:10.1172/JCI67230
  16. STEINBRECH DS, MEHRARA BJ, SAADEH PB, GREENWALD JA, SPECTOR JA, GITTES GK, LONGAKER MT. : VEGF expression in an osteoblast-like cell line is regulated by a hypoxia response mechanism. Am J Physiol Cell Physiol. 2000; 278: C853-C860.
  17. SUNDERMAN FW JR, MCCULLY KS, HOPFER SM. : Association between erythrocytosis and renal cancers in rats following intrarenal injection of nickel compounds. Carcinogenesis. 1984; 5: 1511-1517.
    doi:10.1093/carcin/5.11.1511
  18. SUNDERMAN FW JR, HOPFER SM, REID MC, SHEN SK, KEVORKIAN CB.: Erythropoietin-mediated erythrocytosis in rodents after intrarenal injection of nickel subsulfide. Yale J Biol Med. 1982; 55: 123-136.
  19. THEVIS M, KRUG O, PIPER T, GEYER H, SCHÄNZER W. : Solutions advertised as erythropoiesis-stimulating products were found to contain undeclared cobalt and nickel species. Int J Sports Med. 2016; 37 :82-84.
    doi:10.1055/s-0035-1569350
  20. THEVIS, M, MACHNIK, M, SCHENK, I, KRUG O, PIPER T, SCHÄNZER W, DÜE M, BONDESSON U, HEDELAND M. : Nickel in equine sports drug testing - pilot study results on urinary Ni concentrations. Rapid Commun Mass Spectrom. 2016; 30: 982-984.
    doi:10.1002/rcm.7528
  21. WORLD ANTI-DOPING AGENCY (WADA). : The 2016 Prohibited List. [17th October 2016].
    https://www.wada-ama.org/en/what-we-do/prohibited-list
 
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