Iranian Journal of Child Neurology

Abstract

How to Cite This Article: Fluegge K. Zinc and copper metabolism and risk of autism: a reply to Sayehmiri et al. Iran J Child Neurol. Summer 2017; 11(3):66-69.

Abstract

Objective

Sayehmiri et al. recently conducted a meta-analysis to explore the relationship between zinc and copper metabolism and autism spectrum disorders (ASD).

Recent reports have elucidated a full behavioral profile of mice exposed to prenatal zinc deficiency and documented a phenotype similar to that found in autism spectrum disorders (ASD). These studies suggest that significant alterations in Zn metabolism may be an important nutritional component in the development of ASD.

Materials & Methods

The idea that prenatal zinc deficiency may be to blame is cursorily challenged. Epidemiological studies show that high-income countries with a low estimated prevalence of inadequate zinc intake report the highest prevalence of ASD.

Consistent with other reports indicating a link between air pollution and ASD, it has recently been proposed that use of the herbicide, glyphosate, in agriculture may serve as an instrumental variable in predicting later neurodevelopmental impairment via emissions of the agricultural air pollutant, nitrous oxide (N2O).

Results

Work in anesthesiology has demonstrated the neurological effects from subanesthetic doses of N2O, including its inhibition of the alpha 7 nicotinic acetylcholine receptor (α7), a receptor coupled to both central nitric oxide (NO) metabolism and peripheral anti-inflammation.

Conclusion

This correspondence explores how the aforementioned nutritional phenotypes found by Sayehmiri et al. in their systematic review may be a compensatory mechanism to counter the effects (namely, α7 inhibition) of air pollutant exposures occurring during the most critical stages of fetal development.

References

1. Sayehmiri F, Babaknejad N, Bahrami S, Sayehmiri K, Darabi M, Rezaei-Tavirani M. Zn/Cu Levels in the Field of Autism Disorders: A Systematic Review and Metaanalysis. Iran J Child Neurol. 2015;9(4):1-9.

2. Grabrucker S, Boeckers TM, Grabrucker AM. Gender Dependent Evaluation of Autism like Behavior in Mice Exposed to Prenatal Zinc Deficiency. Front Behav Neurosci. 2016;10: 37. doi.org/10.3389/fnbeh.2016.00037

3. Wessells KR, Brown KH. Estimating the Global Prevalence of Zinc Deficiency: Results Based on Zinc Availability in National Food Supplies and the Prevalence of Stunting. PLoS ONE. 2012;7(11): e50568. doi.org/10.1371/journal.pone.0050568.

4. Elsabbagh M, Divan G, Koh Y-J, Kim YS, Kauchali S, Marcín C, et al. Global Prevalence of Autism and Other Pervasive Developmental Disorders. Autism Res. 2012; 5:160–179. doi: 10.1002/aur.239.

5. Russo AJ, Bazin AP, Bigega R, Carlson RS, Cole MG, Contreras DC, et al. Plasma Copper and Zinc Concentration in Individuals with Autism Correlate with Selected Symptom Severity. Nutr Metab Insights. 2012; 5:41–47. doi.org/10.4137/NMI.S8761.

6. Fluegge K, Fluegge K. Glyphosate use predicts healthcare utilization for ADHD in the Healthcare Cost and Utilization Project net (HCUPnet): A two-way fixed effects analysis. Pol J Environ Stud. 2016;25(4): 1489-1503.

7. Fluegge K. Does environmental exposure to the greenhouse gas, N2O, contribute to etiological factors in neurodevelopmental disorders? A Mini-Review of the Evidence. Environ Toxicol Pharmacol. 2016; 47:6-18,

doi: 10.1016/j.etap.2016.08.013.

8. Suzuki T, Ueta K, Sugimoto M, Uchida I, Mashimo T. Nitrous oxide and xenon inhibit the human (alpha 7)5 nicotinic acetylcholine receptor expressed in Xenopus oocyte. Anesth Analg. 2003;96 (2):443-8.

9. Zayas RM, Qazi S, Morton DB,Trimmer BA. Nicotinicacetylcholine receptors are functionally coupled to the nitric oxide/cGMP-pathway in insect neurons. J Neurochem. 2002;83(2): 421-31.

10. Haberberger RV, Henrich M, Lips KS, Kummer W. Nicotinic receptor alpha 7-subunits are coupled to the stimulation of nitric oxide synthase in rat dorsal root ganglion neurons. Histochem Cell Biol. 2003;120(3):173-81.

11. Young JW, Crawford N, Kelly JS, Kerr LE, Marston HM, Spratt C, et al. Impaired attention is central to the cognitive deficits observed in alpha 7 deficient mice. Eur Neuropsychopharmacol. 2007;17(2):145-55.

12. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421(6921):384-8.

13. Fluegge K. A reply to ‘Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study.’ Transl Psychiatry. 2016; doi:10.1038/tp.2016.24.

14. Rabinovich D, Yaniv SP, Alyagor I, Schuldiner O. Nitric Oxide as a Switching Mechanism between Axon Degeneration and Regrowth during Developmental Remodeling. Cell. 2016;164(1-2):170-82. doi: 10.1016/j. cell.2015.11.047.

15. Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A, et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron. 2014;83(5):1131-43. doi: 10.1016/j. neuron.2014.07.040.

16. Gao Y, Heldt SA. Lack of neuronal nitric oxide synthase results in attention deficit hyperactivity disorder-like behaviors in mice. Behav Neurosci. 2015;129(1):50-61. doi: 10.1037/bne0000031.

17. Sweeten TL, Posey DJ, Shankar S, McDougle CJ. High nitric oxide production in autistic disorder: a possible role for interferon-gamma. Biol Psychiatry. 2004;55(4):434-7.

18. Cortese-Krott MM, Kulakov L, Opländer C, Kolb-Bachofen V, Kröncke K-D, Suschek CV. Zinc regulates iNOS-derived nitric oxide formation in endothelial cells. Redox Biology. 2014;2:945–954. doi.org/10.1016/j. redox.2014.06.011.

19. Cui L, Blanchard RK, Cousins RJ. The permissive effect of zinc deficiency on uroguanylin and inducible nitric oxide synthase gene upregulation in rat intestine induced by interleukin 1alpha is rapidly reversed by zinc repletion. J Nutr. 2003;33(1): 51-6.

20. Gomez NN, Davicino RC, Biaggio VS, Bianco GA, Alvarez SM, Fischer P, et al. Overexpression of inducible nitric oxide synthase and cyclooxygenase-2 in rat zinc deficient lung: Involvement of a NF-kappa B dependent pathway. Nitric Oxide. 2006;14 (1):30-8.

21. Chreifi G, Li H, McInnes CR, Gibson CL, Suckling CJ, Poulos TL. Communication between the Zinc and Tetrahydrobiopterin Binding Sites in Nitric Oxide Synthase. Biochemistry. 2014;53(25):4216–4223. doi. org/10.1021/bi5003986.

22. Panda K, Rosenfeld RJ, Ghosh S, Meade AL, Getzoff ED, Stuehr DJ. Distinct dimer interaction and regulation in nitric-oxide synthase types I, II, and III. J Biol Chem. 2002;277(34): 31020-30.

23. McNeill E, Crabtree MJ, Sahgal N, Patel J, Chuaiphichai S, Iqbal AJ, et al. Regulation of iNOS function and cellular redox state by macrophage Gch1 reveals specific requirements for tetrahydrobiopterin in NRF2 activation. Free Radic Biol Med. 2015;79: 206-16. doi: 10.1016/j. freeradbiomed.2014.10.575.

24. Prasad AS. Zinc is an Antioxidant and Anti-Inflammatory Agent: Its Role in Human Health. Front Nutr. 2014;1:14. doi.org/10.3389/fnut.2014.00014

25. Cuzzocrea S, Persichini T, Dugo L, Colasanti M, Musci G. Copper induces type II nitric oxide synthase in vivo. Free Radic Biol Med. 2003;34(10):1253-62.

26. Demura Y, Ishizaki T, Ameshima S, Okamura S, Hayashi T, Matsukawa S, Miyamori I. The activation of nitric oxide synthase by copper ion is mediated by intracellular Ca2+ mobilization in human pulmonary arterial endothelial cells. Br J Pharmacol. 1998;125 (6):1180-7.

27. Plane F, Wigmore S, Angelini GD, Jeremy JY. Effect of copper on nitric oxide synthase and guanylyl cyclase activity in the rat isolated aorta. Br J Pharmacol. 1997;121(2):345–350. doi.org/10.1038/sj.bjp.0701144.