Abstract
This case–control study explored the associations between autism spectrum disorder (ASD) and the serum concentration of nine chemical elements in children. The study recruited 92 Chinese children with ASD and 103 typically developing individuals. Serum concentrations of nine chemical elements (calcium, iodine, iron, lithium, magnesium, potassium, selenium, strontium, and zinc) were determined by inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma atomic emission spectrometry (ICP-AES). An unconditional logistic regression model was used to analyze the associations between the serum concentrations of the elements and the risk of ASD. After adjusting for confounders, the multivariate analysis results showed that zinc ≤ 837.70 ng/mL, potassium > 170.06 μg/mL, and strontium ≤ 52.46 ng/mL were associated with an increased risk of ASD, while selenium > 159.80 ng/mL was associated with a decreased risk of ASD. Furthermore, the degree of lithium and zinc deficiency was associated with ASD severity. The results indicated that metallomic profiles of some specific elements might play important roles in the development of ASD, a finding of scientific significance for understanding the etiology, and providing dietary guidance for certain ASD types.
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The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.
Abbreviations
- ASD:
-
Autism spectrum disorder
- CARS:
-
Childhood Autism Rating Scale
- TDI:
-
Typically developing individuals
- ICP-MS:
-
Inductively coupled plasma mass spectrometry
- ICP-AES:
-
Inductively coupled plasma atomic emission spectrometry
- OR:
-
Odds ratio
- aOR:
-
Adjusted odds ratio
- IQR:
-
Interquartile range
- CI:
-
Confidence interval
- I:
-
Iodine
- Li:
-
Lithium
- Se:
-
Selenium
- Sr:
-
Strontium
- Zn:
-
Zinc
- Ca:
-
Calcium
- Fe:
-
Iron
- K:
-
Potassium
- Mg:
-
Magnesium
References
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 110:193–209. https://doi.org/10.1385/bter:110:3:193
Adebayo OL, Salau BA, Sandhir R, Adenuga GA (2016) Dietary selenium or zinc supplementation restores brain lipid composition and membrane fluidity in protein-undernourished rats. Dev Neurosci 38:397–406. https://doi.org/10.1159/000462971
Battle DE (2013) Diagnostic and Statistical Manual of Mental Disorders (DSM). Codas 25:191–192. https://doi.org/10.1590/s2317-17822013000200017
Berding K, Donovan SM (2018) Diet can impact microbiota composition in children with autism spectrum disorder. Front Neurosci 12:515. https://doi.org/10.3389/fnins.2018.00515
Bhandari R, Paliwal JK, Kuhad A (2020) Neuropsychopathology of autism spectrum disorder: complex interplay of genetic, epigenetic, and environmental factors. Adv Neurobiol 24:97–141. https://doi.org/10.1007/978-3-030-30402-7_4
Bjorklund G (2013) The role of zinc and copper in autism spectrum disorders. Acta Neurobiol Exp (wars) 73:225–236
Bjørklund G, Dadar M, Chirumbolo S, Aaseth J, Peana M (2020) Metals, autoimmunity, and neuroendocrinology: is there a connection? Environ Res 187:109541. https://doi.org/10.1016/j.envres.2020.109541
Blaurock-Busch E, Amin OR, Rabah T (2011) Heavy metals and trace elements in hair and urine of a sample of arab children with autistic spectrum disorder. Maedica (bucur) 6:247–257
Blaurock-Busch E, Amin OR, Dessoki HH, Rabah T (2012) Toxic metals and essential elements in hair and severity of symptoms among children with autism. Maedica (bucur) 7:38–48
Bush AI (2000) Metals and neuroscience. Curr Opin Chem Biol 4:184–191. https://doi.org/10.1016/s1367-5931(99)00073-3
Caito S, Aschner M (2015) Neurotoxicity of metals. Handb Clin Neurol 131:169–189. https://doi.org/10.1016/b978-0-444-62627-1.00011-1
Chaste P, Leboyer M (2012) Autism risk factors: genes, environment, and gene-environment interactions. Dialogues Clin Neurosci 14:281–292. https://doi.org/10.31887/DCNS.2012.14.3/pchaste
Crompton M, Künzi M, Carafoli E (1977) The calcium-induced and sodium-induced effluxes of calcium from heart mitochondria. Evidence for a sodium-calcium carrier. Eur J Biochem 79:549–558. https://doi.org/10.1111/j.1432-1033.1977.tb11839.x
de Moura JE, de Moura EN, Alves CX, Vale SH, Dantas MM, Silva Ade A, Brandão-Neto J (2013) Oral zinc supplementation may improve cognitive function in schoolchildren. Biol Trace Elem Res 155:23–28. https://doi.org/10.1007/s12011-013-9766-9
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 42:342–353. https://doi.org/10.1007/s10803-011-1245-6
Delange F (2001) Iodine deficiency as a cause of brain damage. Postgrad Med J 77:217–220. https://doi.org/10.1136/pmj.77.906.217
Demling JH, Eglau MC, Autenrieth T (2001) On the physiological function of lithium from a psychiatric view point. Med Hypotheses 57:506–509. https://doi.org/10.1054/mehy.2001.1375
El-Ansary A, Al-Daihan S, Al-Dbass A, Al-Ayadhi L (2010) Measurement of selected ions related to oxidative stress and energy metabolism in Saudi autistic children. Clin Biochem 43:63–70. https://doi.org/10.1016/j.clinbiochem.2009.09.008
Fairweather-Tait SJ, Bao Y, Broadley MR, Collings R, Ford D, Hesketh JE, Hurst R (2011) Selenium in human health and disease. Antioxid Redox Signal 14:1337–1383. https://doi.org/10.1089/ars.2010.3275
Georgieff MK (2020) Iron deficiency in pregnancy. Am J Obstet Gynecol 223:516–524. https://doi.org/10.1016/j.ajog.2020.03.006
Grabrucker AM (2014) A role for synaptic zinc in ProSAP/Shank PSD scaffold malformation in autism spectrum disorders. Dev Neurobiol 74:136–146. https://doi.org/10.1002/dneu.22089
Grabrucker S, Jannetti L, Eckert M, Gaub S, Chhabra R, Pfaender S, Grabrucker AM (2014) Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders. Brain 137:137–152. https://doi.org/10.1093/brain/awt303
Guevara-Campos J, González-Guevara L, Cauli O (2015) Autism and intellectual disability associated with mitochondrial disease and hyperlactacidemia. Int J Mol Sci 16:3870–3884. https://doi.org/10.3390/ijms16023870
Guglielmi L, Servettini I, Caramia M, Catacuzzeno L, Franciolini F, D’Adamo MC, Pessia M (2015) Update on the implication of potassium channels in autism: K(+) channelautism spectrum disorder. Front Cell Neurosci 9:34. https://doi.org/10.3389/fncel.2015.00034
Hamza RT, Hewedi DH, Sallam MT (2013) Iodine deficiency in Egyptian autistic children and their mothers: relation to disease severity. Arch Med Res 44:555–561. https://doi.org/10.1016/j.arcmed.2013.09.012
Jackson MJ, Garrod PJ (1978) Plasma zinc, copper, and amino acid levels in the blood of autistic children. J Autism Child Schizophr 8:203–208. https://doi.org/10.1007/bf01537869
James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA (2004) Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 80:1611–1617. https://doi.org/10.1093/ajcn/80.6.1611
Kern JK, Jones AM (2006) Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev 9:485–499. https://doi.org/10.1080/10937400600882079
Koh JY, Lim JS, Byun HR, Yoo MH (2014) Abnormalities in the zinc-metalloprotease-BDNF axis may contribute to megalencephaly and cortical hyperconnectivity in young autism spectrum disorder patients. Mol Brain 7:64. https://doi.org/10.1186/s13041-014-0064-z
Krey JF, Dolmetsch RE (2007) Molecular mechanisms of autism: a possible role for Ca2+ signaling. Curr Opin Neurobiol 17:112–119. https://doi.org/10.1016/j.conb.2007.01.010
Kruppke B, Heinemann C, Wagner AS, Farack J, Wenisch S, Wiesmann HP, Hanke T (2019) Strontium ions promote in vitro human bone marrow stromal cell proliferation and differentiation in calcium-lacking media. Dev Growth Differ 61:166–175. https://doi.org/10.1111/dgd.12588
Lakshmi Priya MD, Geetha A (2011) Level of trace elements (copper, zinc, magnesium and selenium) and toxic elements (lead and mercury) in the hair and nail of children with autism. Biol Trace Elem Res 142:148–158. https://doi.org/10.1007/s12011-010-8766-2
Lee H, Lin MC, Kornblum HI, Papazian DM, Nelson SF (2014) Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum Mol Genet 23:3481–3489. https://doi.org/10.1093/hmg/ddu056
Li SO, Wang JL, Bjørklund G, Zhao WN, Yin CH (2014) Serum copper and zinc levels in individuals with autism spectrum disorders. NeuroReport 25:1216–1220. https://doi.org/10.1097/wnr.0000000000000251
Macedoni-Lukšič M, Gosar D, Bjørklund G, Oražem J, Kodrič J, Lešnik-Musek P, 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 163:2–10. https://doi.org/10.1007/s12011-014-0121-6
Oliveira G, Diogo L, Grazina M, Garcia P, Ataíde A, Marques C, Oliveira CR (2005) Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev Med Child Neurol 47:185–189. https://doi.org/10.1017/s0012162205000332
Prasad AS (2012) Discovery of human zinc deficiency: 50 years later. J Trace Elem Med Biol 26:66–69. https://doi.org/10.1016/j.jtemb.2012.04.004
Prohaska JR (1987) Functions of trace elements in brain metabolism. Physiol Rev 67:858–901. https://doi.org/10.1152/physrev.1987.67.3.858
Rayman MP (2012) Selenium and human health. Lancet 379:1256–1268. https://doi.org/10.1016/s0140-6736(11)61452-9
Rose S, Melnyk S, Pavliv O, Bai S, Nick TG, Frye RE, James SJ (2012) Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry 2:e134. https://doi.org/10.1038/tp.2012.61
Rossignol DA, Genuis SJ, Frye RE (2014) Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiatry 4:e360. https://doi.org/10.1038/tp.2014.4
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. https://doi.org/10.4137/bmi.S7286
Sandstead HH (1986) Nutrition and brain function: trace elements. Nutr Rev 44(Suppl):37–41. https://doi.org/10.1111/j.1753-4887.1986.tb07676.x
Schopler E, Reichler RJ, DeVellis RF, Daly K (1980) Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS). J Autism Dev Disord 10:91–103. https://doi.org/10.1007/bf02408436
Schrauzer GN (2002) Lithium: occurrence, dietary intakes, nutritional essentiality. J Am Coll Nutr 21:14–21. https://doi.org/10.1080/07315724.2002.10719188
Schrauzer GN, de Vroey E (1994) Effects of nutritional lithium supplementation on mood. A placebo-controlled study with former drug users. Biol Trace Elem Res 40:89–101. https://doi.org/10.1007/bf02916824
Sweetman DU, O’Donnell SM, Lalor A, Grant T, Greaney H (2019) Zinc and vitamin A deficiency in a cohort of children with autism spectrum disorder. Child Care Health Dev 45:380–386. https://doi.org/10.1111/cch.12655
Vela G, Stark P, Socha M, Sauer AK, Hagmeyer S, Grabrucker AM (2015) Zinc in gut-brain interaction in autism and neurological disorders. Neural Plast 2015:972791. https://doi.org/10.1155/2015/972791
Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, Murray CJL (2016) Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet 388:1545–1602. https://doi.org/10.1016/s0140-6736(16)31678-6
Whelton PK, He J (2014) Health effects of sodium and potassium in humans. Curr Opin Lipidol 25:75–79. https://doi.org/10.1097/mol.0000000000000033
Wu J, Liu DJ, Shou XJ, Zhang JS, Meng FC, Liu YQ, Han JS (2018) Chinese children with autism: a multiple chemical elements profile in erythrocytes. Autism Res 11:834–845. https://doi.org/10.1002/aur.1949
Yasuda H, Tsutsui T (2013) Assessment of infantile mineral imbalances in autism spectrum disorders (ASDs). Int J Environ Res Public Health 10:6027–6043. https://doi.org/10.3390/ijerph10116027
Yasuda H, Yoshida K, Yasuda Y, Tsutsui T (2011) Infantile zinc deficiency: association with autism spectrum disorders. Sci Rep 1:129. https://doi.org/10.1038/srep00129
Yeo JE, Kang SK (2007) Selenium effectively inhibits ROS-mediated apoptotic neural precursor cell death in vitro and in vivo in traumatic brain injury. Biochim Biophys Acta 1772:1199–1210. https://doi.org/10.1016/j.bbadis.2007.09.004
Yu HB, Li ZB, Zhang HX, Wang XL (2006) Role of potassium channels in Abeta(1–40)-activated apoptotic pathway in cultured cortical neurons. J Neurosci Res 84:1475–1484. https://doi.org/10.1002/jnr.21054
Zhou H, Xu X, Yan W, Zou X, Wu L, Luo X, Wang Y (2020) Prevalence of autism spectrum disorder in China: a nationwide multi-center population-based study among children aged 6 to 12 years. Neurosci Bull 36:961–971. https://doi.org/10.1007/s12264-020-00530-6
Mazahery H, Stonehouse W, Delshad M, Kruger MC, Conlon CA, Beck KL, von Hurst PR. (2017). Relationship between long chain n-3 polyunsaturated fatty acids and autism spectrum disorder: systematic review and meta-analysis of case-control and randomised controlled trials. Nutrients 9https://doi.org/10.3390/nu9020155
Rahbar MH, Samms-Vaughan M, Lee M, Zhang J, Hessabi M, Bressler J, Loveland KA. (2020). Interaction between a mixture of heavy metals (lead, mercury, arsenic, cadmium, manganese, aluminum) and GSTP1, GSTT1, and GSTM1 in relation to autism spectrum disorder. Res Autism Spectr Disord 79https://doi.org/10.1016/j.rasd.2020.101681
Sullivan KM. (2009). Iodine deficiency as a cause of autism. J Neurol Sci 276: 202; author reply 203. https://doi.org/10.1016/j.jns.2008.09.016
Tardy AL, Pouteau E, Marquez D, Yilmaz C, Scholey A. (2020). Vitamins and minerals for energy, fatigue and cognition: a narrative review of the biochemical and clinical evidence. Nutrients 12https://doi.org/10.3390/nu12010228
Acknowledgements
The authors offer their sincere thanks to all the study personnel from the Beijing Disabled Persons Federation, Wucailu Center, and Yangguangyouyi Center for their exceptional efforts in study subject recruitment, particularly to Li Li, Qingyun Wei, and Wei Zhao. Our gratitude also goes to the Neuroscience Research Institute, Peking University, particularly to Xiaojing Shou, Fanchao Meng, and Xinjie Xu, for their support in blood sampling, and to the Laboratory of Elementomics, School of Public Health, Peking University, particularly to Yaqiong Liu and Qing Xie, for their technical support in element analyses.
Funding
This research was funded by the Beijing Municipal Science & Technology Commission (Z181100001518005), the National Basic Research Program of China (2017YFA0105201), and the Key Realm R&D Program of Guangdong Province (2019B030335001).
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Conceptualization: Songping Han, Jisheng Han, Jingyu Wang, Xi Chen, and Rong Zhang; methodology: Xi Chen; formal analysis: Jing Wu and Dongfang Wang; investigation: Jing Wu, Laikai Yan, Meixiang Jia, and Jishui Zhang; writing—original draft preparation: Jing Wu; writing—review and editing, Xi Chen; funding acquisition: Rong Zhang. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee for Human Studies at Peking University Health Science Center (Permit Number: IRB00001052-13064, 25 Dec 2013).
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Wu, J., Wang, D., Yan, L. et al. Associations of essential element serum concentrations with autism spectrum disorder. Environ Sci Pollut Res 29, 88962–88971 (2022). https://doi.org/10.1007/s11356-022-21978-1
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DOI: https://doi.org/10.1007/s11356-022-21978-1