Evaluation of Whole Blood Trace Element Levels in Chinese Children with Autism Spectrum Disorder

  • Ling-ling Wu
  • Shan-shan Mao
  • Xu Lin
  • Rong-wang Yang
  • Zhi-wei ZhuEmail author


Autism spectrum disorder (ASD) is a neurodevelopmental disorder, which has increased markedly during the last decades. Essential trace elements play an important role in neurological function and their imbalances are common in children with ASD. The objective of the present study was to investigate whole blood levels of trace elements including zinc (Zn), copper (Cu), iron (Fe), and magnesium (Mg) in Chinese children with ASD. In total, 113 children diagnosed with ASD and 141 age-matched and gender-matched neurotypical children, divided into two gender and age groups of preschool age (2–5 years old) and school (6–10 years old) age, were examined. The quantitative analyses of whole blood trace element contents were performed by using flame atomic absorption spectroscopy. In the present study, the children with ASD generally had lower whole blood levels of Zn than the neurotypical controls. No significant differences in the whole blood Cu, Zn/Cu ratio, Fe, or Mg was detected between the ASD group and the control group. It is notable that whole blood Fe level in boys with ASD was significantly higher than in girls with ASD, and was nearly significant when compared with the control level of boys. After stratification for age, a significant 6% decrease in whole blood Zn levels was detected in preschool-aged children with ASD as compared to the control values. However, this significant ASD-related change was not detected in school-aged children. The whole blood Zn level and Zn/Cu ratio were significantly increased in school-aged children than in preschool-aged children in both ASD and control group. In addition, school-aged children with ASD had a significantly higher level of whole blood Fe than preschool-aged children with ASD. The results of the present study suggest an association between whole blood levels of Zn in Chinese children with ASD.


Autism spectrum disorder Trace elements Zinc Copper Iron Magnesium 



We are very grateful to Zheng Shen in the Department of Laboratory for the technical assistance.


This work was supported by the National Natural Science Foundation of China [grant number 81373015]; and the Health and Family Planning Commission of Zhejiang province [grant number H2014KYA125].

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Zablotsky B, Black LI, Maenner MJ, Schieve LA, Blumberg SJ (2015) Estimated prevalence of autism and other developmental disabilities following questionnaire changes in the 2014 National Health Interview Survey. Natl Health Stat Report 87:1–20 Accessed 10/18/2018
  2. 2.
    Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z, Kurzius-Spencer M, Zahorodny W, Robinson C, Rosenberg, White T, Durkin MS, Imm P, Nikolaou L, Yeargin-Allsopp M, Lee LC, Harrington R, Lopez M, Fitzgerald RT, Hewitt A, Pettygrove S, Constantino JN, Vehorn A, Shenouda J, Hall-Lande J, van K, Naarden, Braun, Dowling NF (2018) Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill Summ 67(6):1–23. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bhat S, Acharya UR, Adeli H, Bairy GM, Adeli A (2014) Autism: cause factors, early diagnosis and therapies. Rev Neurosci 25(6):841–850. ReviewCrossRefPubMedGoogle Scholar
  4. 4.
    Sharp WG, Postorino V, McCracken CE, Berry RC, Criado KK, Burrell TL, Scahill L (2018) Dietary intake, nutrient status, and growth parameters in children with autism spectrum disorder and severe food selectivity: an electronic medical record review. J Acad Nutr Diet 118(10):1943–1950. CrossRefPubMedGoogle Scholar
  5. 5.
    Saghazadeh A, Ahangari N, Hendi K, Saleh F, Rezaei N (2017) Status of essential elements in autism spectrum disorder: systematic review and meta-analysis. Rev Neurosci 28(7):783–809. ReviewCrossRefPubMedGoogle Scholar
  6. 6.
    Bjorklund G (2013) The role of zinc and copper in autism spectrum disorders. Acta Neurobiol Exp (Wars) 73(2):225–236 Review. Accessed 7/30/2018
  7. 7.
    Russo AJ, Bazin AP, Bigega R, Carlson RS III, Cole MG, Contreras DC, Galvin MB, Gaydorus SS, Holik SD, Jenkins GP, Jones BM, Languell PA, Lyman PJ, March KP, Meuer KA, Peterson SR, Piedmonte MT, Quinn MG, Smaranda NC, Steves PL, Taylor HP, Waddingham TE, Warren JS (2012) Plasma copper and zinc concentration in individuals with autism correlate with selected symptom severity. Nutr Metab Insights 5:41–47. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Russo AJ, Devito R (2011) Analysis of copper and zinc plasma concentration and the efficacy of zinc therapy in individuals with Asperger’s syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS) and autism. Biomark Insights 6:127–133. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hagmeyer S, Sauer AK, Grabrucker AM (2018) Prospects of zinc supplementation in autism spectrum disorders and shankopathies such as Phelan McDermid syndrome. Front Synaptic Neurosci 10(11).
  10. 10.
    Kirsten TB, Queiroz-Hazarbassanov N, Bernardi MM, Felicio LF (2015) Prenatal zinc prevents communication impairments and BDNF disturbance in a rat model of autism induced by prenatal lipopolysaccharide exposure. Life Sci 130:12–17. CrossRefPubMedGoogle Scholar
  11. 11.
    Prasad AS (2014) Impact of the discovery of human zinc deficiency on health. J Trace Elem Med Biol 28(4):357–363. CrossRefPubMedGoogle Scholar
  12. 12.
    Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, Gehn E, Loresto M, Mitchell J, Atwood S, Barnhouse S, Lee W (2011) Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutr Metab (Lond) 8(1):34. CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Li SO, Wang JL, Bjørklund G, Zhao WN, Yin CH (2014) Serum copper and zinc levels in individuals with autism spectrum disorders. Neuroreport 25(15):1216–1220. CrossRefPubMedGoogle Scholar
  14. 14.
    Crăciun EC, Bjørklund G, Tinkov AA, Urbina MA, Skalny AV, Rad F, Dronca E (2016) Evaluation of whole blood zinc and copper levels in children with autism spectrum disorder. Metab Brain Dis 31(4):887–890. CrossRefPubMedGoogle Scholar
  15. 15.
    Pfaender S, Sauer AK, Hagmeyer S, Mangus K, Linta L, Liebau S, Bockmann J, Huguet G, Bourgeron T, Boeckers TM, Grabrucker AM (2017) Zinc deficiency and low enterocyte zinc transporter expression in human patients with autism related mutations in SHANK3. Sci Rep 7(45190).
  16. 16.
    Skalny AV, Simashkova NV, Skalnaya AA, Klyushnik TP, Bjørklund G, Skalnaya MG, Tinkov AA (2017) Assessment of gender and age effects on serum and hair trace element levels in children with autism spectrum disorder. Metab Brain Dis 32(5):1675–1684. CrossRefPubMedGoogle Scholar
  17. 17.
    De Palma G, Catalani S, Franco A, Brighenti M, Apostoli P (2012) Lack of correlation between metallic elements analyzed in hair by ICP-MS and autism. J Autism Dev Disord 42(3):342–353. CrossRefPubMedGoogle Scholar
  18. 18.
    Babaknejad N, Sayehmiri F, Sayehmiri K, Mohamadkhani A, Bahrami S (2016) The relationship between zinc levels and autism: a systematic review and meta-analysis. Iran J Child Neurol 10(4):1–9 Review. Accessed 7/24/2018
  19. 19.
    Scheiber I, Dringen R, Mercer JF (2013) Copper: effects of deficiency and overload. Met Ions Life Sci 13:359–387. ReviewCrossRefPubMedGoogle Scholar
  20. 20.
    Macedoni-Lukšič M, Gosar D, Bjørklund G, Oražem J, Kodrič J, Lešnik-Musek P, Zupančič M, France-Štiglic A, Sešek-Briški A, Neubauer D, Osredkar J (2015) Levels of metals in the blood and specific porphyrins in the urine in children with autism spectrum disorders. Biol Trace Elem Res 163(1–2):2–10. CrossRefPubMedGoogle Scholar
  21. 21.
    Faber S, Zinn GM, Kern JC 2nd, Kingston HM (2009) The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders. Biomarkers 14(3):171–180. CrossRefPubMedGoogle Scholar
  22. 22.
    Sayehmiri F, Babaknejad N, Bahrami S, Sayehmiri K, Darabi M, Rezaei-Tavirani M (2015) Zn/Cu levels in the field of autism disorders: a systematic review and meta-analysis. Iran J Child Neurol 9(4):1–9 Review. Accessed 7/25/2018
  23. 23.
    Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L (2016) Iron deficiency anaemia. Lancet 387(10021):907–916. CrossRefPubMedGoogle Scholar
  24. 24.
    Wu LL, Zhang L, Shao J, Qin YF, Yang RW, Zhao ZY (2008) Effect of perinatal iron deficiency on myelination and associated behaviors in rat pups. Behav Brain Res 188(2):263–270
  25. 25.
    Ye Q, Trivedi M, Zhang Y, Böhlke M, Alsulimani H, Chang J, Maher T, Deth R, Kim J (2018) Brain iron loading impairs DNA methylation and alters GABAergic function in mice. FASEB J:fj201801116RR.
  26. 26.
    Imam MU, Zhang S, Ma J, Wang H, Wang F (2017) Antioxidants mediate both iron homeostasis and oxidative stress. Nutrients 9(7).
  27. 27.
    Smaga I, Niedzielska E, Gawlik M, Moniczewski A, Krzek J, Przegaliński E, Pera J, Filip M (2015) Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2. Depression, anxiety, schizophrenia and autism. Pharmacol Rep 67(3):569–580. CrossRefPubMedGoogle Scholar
  28. 28.
    Bener A, Khattab AO, Bhugra D, Hoffmann GF (2017) Iron and vitamin D levels among autism spectrum disorders children. Ann Afr Med 16(4):186–191CrossRefGoogle Scholar
  29. 29.
    Gunes S, Ekinci O, Celik T (2017) Iron deficiency parameters in autism spectrum disorder: clinical correlates and associated factors. Ital J Pediatr 43(1):86CrossRefGoogle Scholar
  30. 30.
    Liu X, Liu J, Xiong X, Yang T, Hou N, Liang X, Chen J, Cheng Q, Li T (2016) Correlation between nutrition and symptoms: nutritional survey of children with autism spectrum disorder in Chongqing, China. Nutrients 8(5).
  31. 31.
    Yui K, Imataka G, Kawasak Y, Yamada H (2016) Increased ω-3 polyunsaturated fatty acid/arachidonic acid ratios and upregulation of signaling mediator in individuals with autism spectrum disorders. Life Sci 145:205–212. CrossRefPubMedGoogle Scholar
  32. 32.
    Lane R, Kessler R, Buckley AW, Rodriguez A, Farmer C, Thurm A, Swedo S, Felt B (2015) Evaluation of periodic limb movements in sleep and Iron status in children with autism. Pediatr Neurol 53(4):343–349. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Tseng PT, Cheng YS, Chen YW, Stubbs B, Whiteley P, Carvalho AF, Li DJ, Chen TY, Yang WC, Tang CH, Chu CS, Yang WC, Liang HY, Wu CK, Yen CF, Lin PY (2018) Peripheral iron levels in children with autism spectrum disorders vs controls: a systematic review and meta-analysis. Nutr Res 50:44–52. CrossRefPubMedGoogle Scholar
  34. 34.
    Serefko A, Szopa A, Poleszak E (2016) Magnesium and depression. Magnes Res 29(3):112–119
  35. 35.
    Mousain-Bosc M, Roche M, Polge A, Pradal-Prat D, Rapin J, Bali JP (2006) Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6. II Pervasive developmental disorder-autism. Magnes Res 19(1):53–62 Accessed 7/31/2018
  36. 36.
    Adams JB, Holloway CE, George F, Quig D (2006) Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers. Biol Trace Elem Res 110(3):193–209
  37. 37.
    Skalny AV, Simashkova NV, Skalnaya AA, Klyushnik TP, Zhegalova IV, Grabeklis AR, Skalnaya MG, Tinkov AA (2018) Trace element levels are associated with neuroinflammatory markers in children with autistic spectrum disorder. J Trace Elem Med Biol.
  38. 38.
    Zhu ZW, Jin Y, Wu LL, Liu XL (2018) Current status and challenge in clinical work of autism spectrum disorders in China. World J Pediatr 14(3):209–211. CrossRefPubMedGoogle Scholar
  39. 39.
    Stewart-Knox BJ, Simpson EE, Parr H, Rae G, Polito A, Intorre F, Meunier N, Andriollo-Sanchez M, O'Connor JM, Coudray C, Strain JJ (2005) Zinc status and taste acuity in older Europeans: the ZENITH study. Eur J Clin Nutr 59(Suppl 2):S31–S36 CrossRefGoogle Scholar
  40. 40.
    Bandini LG, Curtin C, Phillips S, Anderson SE, Maslin M, Must A (2017) Changes in food selectivity in children with autism spectrum disorder. J Autism Dev Disord 47(2):439–446. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Prosperi M, Santocchi E, Balboni G, Narzisi A, Bozza M, Fulceri F, Apicella F, Igliozzi R, Cosenza A, Tancredi R, Calderoni S, Muratori F (2017) Behavioral phenotype of ASD preschoolers with gastrointestinal symptoms or food selectivity. J Autism Dev Disord 47(11):3574–3588. CrossRefPubMedGoogle Scholar
  42. 42.
    Zimmer MH, Hart LC, Manning-Courtney P, Murray DS, Bing NM, Summer S (2012) Food variety as a predictor of nutritional status among children with autism. J Autism Dev Disord 42(4):549–556. CrossRefPubMedGoogle Scholar
  43. 43.
    Xia W, Zhou Y, Sun C, Wang J, Wu L (2010) A preliminary study on nutritional status and intake in Chinese children with autism. Eur J Pediatr 169(10):1201–1206. CrossRefPubMedGoogle Scholar
  44. 44.
    Hsiao EY (2014) Gastrointestinal issues in autism spectrum disorder. Harv Rev Psychiatry 22(2):104–111. CrossRefPubMedGoogle Scholar
  45. 45.
    Rahman MM, Hossain KFB, Banik S, Sikder MT, Akter M, Bondad SEC, Rahaman MS, Hosokawa T, Saito T, Kurasaki M (2018) Selenium and zinc protections against metal-(loids)-induced toxicity and disease manifestations: a review. Ecotoxicol Environ Saf 168:146–163. CrossRefPubMedGoogle Scholar
  46. 46.
    Saghazadeh A, Rezaei N (2017) Systematic review and meta-analysis links autism and toxic metals and highlights the impact of country development status: higher blood and erythrocyte levels for mercury and lead, and higher hair antimony, cadmium, lead, and mercury. Prog Neuro-Psychopharmacol Biol Psychiatry 79:340–368. CrossRefGoogle Scholar
  47. 47.
    Fluegge Ba K (2017) Zinc and copper metabolism and risk of autism: a reply to Sayehmiri et al. Iran J Child Neurol 11(3):66–69 Accessed 7/18/2018
  48. 48.
    Yasuda H, Yoshida K, Yasuda Y, Tsutsui T (2011) Infantile zinc deficiency: association with autism spectrum disorders. Sci Rep 1(129).
  49. 49.
    Curtin P, Austin C, Curtin A, Gennings C, Arora M, (for the Emergent Dynamical Systems Group), Tammimies K, Willfors C, Berggren S, Siper P, Rai D, Meyering K, Kolevzon A, Mollon J, David AS, Lewis G, Zammit S, Heilbrun L, Palmer RF, Wright RO, Bölte S, Reichenberg A (2018) Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder. Sci Adv 4(5):eaat1293. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Padhye U (2003) Excess dietary iron is the root cause for increase in childhood autism and allergies. Med Hypotheses 61(2):220–222
  51. 51.
    Chang J, Kueon C, Kim J (2014) Influence of lead on repetitive behavior and dopamine metabolism in a mouse model of iron overload. Toxicol Res 30(4):267–276. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Gogou M, Kolios G (2017) The effect of dietary supplements on clinical aspects of autism spectrum disorder: a systematic review of the literature. Brain Dev 39(8):656–664. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Developmental and Behavioral Pediatrics, Children’s HospitalZhejiang University School of MedicineCity of HangzhouChina
  2. 2.Department of Neurology, Children’s HospitalZhejiang University School of MedicineCity of HangzhouChina
  3. 3.Department of Child Health Care, Children’s HospitalZhejiang University School of MedicineCity of HangzhouChina
  4. 4.Department of Psychology, Children’s HospitalZhejiang University School of MedicineCity of HangzhouChina

Personalised recommendations