Sex-Specific Differences in Cognitive Abilities Associated with Childhood Cadmium and Manganese Exposures in School-Age Children: a Prospective Cohort Study

  • Tong Zhou
  • Jianqiu Guo
  • Jiming Zhang
  • Hongxi Xiao
  • Xiaojuan Qi
  • Chunhua Wu
  • Xiuli Chang
  • Yubin Zhang
  • Qiang Liu
  • Zhijun ZhouEmail author


To examine sex-specific associations of neonatal and childhood exposure to eight trace elements with cognitive abilities of school-age children. The association between exposure and effects was assessed among 296 school-age children from a population-based birth cohort study, who had manganese (Mn), cadmium (Cd), and lead (Pb) exposure measured in cord blood and chromium (Cr), manganese, cobalt (Co), copper (Cu), arsenic (As), selenium (Se), cadmium, and lead exposure quantified in spot urine. Cognitive abilities were assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models were performed to analyze associations of intelligence quotient (IQ) with trace element concentrations in cord blood and urinary trace element levels. General linear models were used to evaluate association between exposure fluctuation and children’s IQ. Urinary Cd concentrations were negatively associated with full-scale IQ (β = − 3.469, 95% confidence interval (CI) − 6.291, − 0.647; p = 0.016) and performance IQ (β = − 4.012, 95% CI − 7.088, − 0.936; p = 0.011) in girls; however, neonatal Cd exposure expressed as Cd concentrations in cord blood was in inverse associations with verbal IQ (β = − 2.590, 95% CI − 4.570, − 0.609; p = 0.010) only in boys. Positive association between urinary Mn concentrations and performance IQ (β = 1.305, 95% CI 0.035, 2.575; p = 0.044) of children was observed, especially in girls. In addition, inverse association of urinary Cu concentrations with verbal IQ (β = − 2.200, 95% CI − 4.360, − 0.039; p = 0.046) was only found in boys. Childhood Cd exposure may adversely affect cognitive abilities, while Mn exposure may beneficially modify cognitive abilities of school-age children, particularly in girls.


Trace element Neonatal exposure Childhood exposure Cognitive ability Sex-specific difference 



We are very grateful to pregnant women and their children in Sheyang Mini Birth Cohort Study and the staffs in Sheyang County People’s Hospital. We also thank doctors worked in Sheyang Maternal and Child Health Care Centre for their support for follow-up.

Funding Information

This study was financially supported by Shanghai “3-Year Action” Project (GWIV- 27.3).

Compliance with Ethical Standards

The study had been performed in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study protocol was approved by the Ethics Committee of the School of Public Health, Fudan University. Written informed consent was obtained from pregnant women and children’s caregivers (parents or grandparents).

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12011_2019_1703_MOESM1_ESM.pdf (294 kb)
ESM 1 (PDF 294 kb)


  1. 1.
    Grandjean P, Landrigan PJ (2014) Neurobehavioural effects of developmental toxicity. Lancet Neurol 13:330–338. CrossRefGoogle Scholar
  2. 2.
    ATSDR (2007) Toxicological profile for lead. Agency for Toxic Substances and Disease Registry, AtlantaGoogle Scholar
  3. 3.
    ATSDR (2012) Toxicological profile for cadmium. Agency for Toxic Substances and Disease Registry, AtlantaGoogle Scholar
  4. 4.
    Wu X, Cobbina SJ, Mao G, Xu H, Zhang Z, Yang L (2016) A review of toxicity and mechanisms of individual and mixtures of heavy metals in the environment. Environ Sci Pollut Res Int 23:8244–8259. CrossRefGoogle Scholar
  5. 5.
    Czarnecki LA, Moberly AH, Turkel DJ, Rubinstein T, Pottackal J, Rosenthal MC, McCandlish EF, Buckley B, McGann JP (2012) Functional rehabilitation of cadmium-induced neurotoxicity despite persistent peripheral pathophysiology in the olfactory system. Toxicol Sci 126:534–544. CrossRefGoogle Scholar
  6. 6.
    Neal AP, Guilarte TR (2013) Mechanisms of lead and manganese neurotoxicity. Toxicol Res (Camb) 2:99–114. CrossRefGoogle Scholar
  7. 7.
    Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, Canfield RL, Dietrich KN, Bornschein R, Greene T, Rothenberg SJ, Needleman HL, Schnaas L, Wasserman G, Graziano J, Roberts R (2005) Low-level environmental lead exposure and children’s intellectual function: an international pooled analysis. Environ Health Perspect 113:894–899. CrossRefGoogle Scholar
  8. 8.
    Rodrigues EG, Bellinger DC, Valeri L, Hasan MO, Quamruzzaman Q, Golam M, Kile ML, Christiani DC, Wright RO, Mazumdar M (2016) Neurodevelopmental outcomes among 2- to 3-year-old children in Bangladesh with elevated blood lead and exposure to arsenic and manganese in drinking water. Environ Health 15:44. CrossRefGoogle Scholar
  9. 9.
    Lucchini RG, Zoni S, Guazzetti S, Bontempi E, Micheletti S, Broberg K, Parrinello G, Smith DR (2012) Inverse association of intellectual function with very low blood lead but not with manganese exposure in Italian adolescents. Environ Res 118:65–71. CrossRefGoogle Scholar
  10. 10.
    Rodriguez-Barranco M, Lacasana M, Gil F, Lorca A, Alguacil J, Rohlman DS, Gonzalez-Alzaga B, Molina-Villalba I, Mendoza R, Aguilar-Garduno C (2014) Cadmium exposure and neuropsychological development in school children in southwestern Spain. Environ Res 134:66–73. CrossRefGoogle Scholar
  11. 11.
    Hamadani J, Tofail F, Nermell B, Gardner R, Shiraji S, Bottai M, Arifeen SE, Huda SN, Vahter M (2011) Critical windows of exposure for arsenic-associated impairment of cognitive function in pre-school girls and boys: a population-based cohort study. Int J Epidemiol 40:1593–1604. CrossRefGoogle Scholar
  12. 12.
    Hamadani JD, Grantham-Mcgregor SM, Tofail F, Nermell B, Fangstrom B (2010) Pre- and postnatal arsenic exposure and child development at 18 months of age: a cohort study in rural Bangladesh. Int J Epidemiol 39:1206–1216. CrossRefGoogle Scholar
  13. 13.
    Kohrle J (2015) Selenium and the thyroid. Curr Opin Endocrinol Diabetes Obes 22:392–401. CrossRefGoogle Scholar
  14. 14.
    Soldin OP, Aschner M (2007) Effects of manganese on thyroid hormone homeostasis: potential links. Neurotoxicology 28:951–956. CrossRefGoogle Scholar
  15. 15.
    Rayman MP (2012) Selenium and human health. Lancet 379:1256–1268. CrossRefGoogle Scholar
  16. 16.
    ATSDR (2004) Toxicological profile for copper. Agency for Toxic Substances and Disease Registry, AtlantaGoogle Scholar
  17. 17.
    ATSDR (2004) Toxicological profile for cobalt. Agency for Toxic Substances and Disease Registry, AtlantaGoogle Scholar
  18. 18.
    Karri V, Schuhmacher M, Kumar V (2016) Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: a general review of metal mixture mechanism in brain. Environ Toxicol Pharmacol 48:203–213. CrossRefGoogle Scholar
  19. 19.
    Llop S, Lopez-Espinosa MJ, Rebagliato M, Ballester F (2013) Gender differences in the neurotoxicity of metals in children. Toxicology 311:3–12. CrossRefGoogle Scholar
  20. 20.
    Qi X, Zheng M, Wu C, Wang G, Feng C, Zhou Z (2012) Urinary pyrethroid metabolites among pregnant women in an agricultural area of the Province of Jiangsu, China. Int J Hyg Environ Health 215:487–495. CrossRefGoogle Scholar
  21. 21.
    Guo J, Wu C, Qi X, Jiang S, Liu Q, Zhang J, Cao Y, Chang X, Zhou Z (2017) Adverse associations between maternal and neonatal cadmium exposure and birth outcomes. Sci Total Environ 575:581–587. CrossRefGoogle Scholar
  22. 22.
    Li D, Jin Y, Vandenberg SG, Zhu YM, Tang CH (1990) Report on Shanghai norms for the Chinese translation of the Wechsler Intelligence Scale for Children-Revised. Psychol Rep 67:531–541. Google Scholar
  23. 23.
    Zhang GQ, Gong Q, Zhang FL, Chen SM, Hu LQ, Liu F, Cui RH, He L (2009) Effects of auditory integrative training on autistic children. Beijing Da Xue Xue Bao 41:426–431 (in Chinese)Google Scholar
  24. 24.
    Liu J, Lynn R (2013) An increase of intelligence in China 1986-2012. Intelligence 41:479–481. CrossRefGoogle Scholar
  25. 25.
    Fan ZJ, Wu YL, He BY, Wang GM (2002) [Intelligence evaluation of 22 patients with congenital velopharyngeal incompetence]. Shanghai Kou Qiang Yi Xue 11:314–315 (in Chinese)Google Scholar
  26. 26.
    Ciesielski T, Weuve J, Bellinger DC, Schwartz J, Lanphear B, Wright RO (2012) Cadmium exposure and neurodevelopmental outcomes in U.S. children. Environ Health Perspect 120:758–763. CrossRefGoogle Scholar
  27. 27.
    Tian LL, Zhao YC, Wang XC, Gu JL, Sun ZJ, Zhang YL, Wang JX (2009) Effects of gestational cadmium exposure on pregnancy outcome and development in the offspring at age 4.5 years. Biol Trace Elem Res 132:51–59. CrossRefGoogle Scholar
  28. 28.
    Sakamoto M, Chan HM, Domingo JL, Koriyama C, Murata K (2018) Placental transfer and levels of mercury, selenium, vitamin E, and docosahexaenoic acid in maternal and umbilical cord blood. Environ Int 111:309–315. CrossRefGoogle Scholar
  29. 29.
    Arbuckle TE, Liang CL, Morisset AS, Fisher M, Weiler H, Cirtiu CM, Legrand M, Davis K, Ettinger AS, Fraser WD (2016) Maternal and fetal exposure to cadmium, lead, manganese and mercury: the MIREC study. Chemosphere 163:270–282. CrossRefGoogle Scholar
  30. 30.
    Garcia-Esquinas E, Perez-Gomez B, Fernandez-Navarro P, Fernandez MA, de Paz C, Perez-Meixeira AM, Gil E, Iriso A, Sanz JC, Astray J, Cisneros M, de Santos A, Asensio A, Garcia-Sagredo JM, Garcia JF, Vioque J, Lopez-Abente G, Pollan M, Gonzalez MJ, Martinez M, Aragones N (2013) Lead, mercury and cadmium in umbilical cord blood and its association with parental epidemiological variables and birth factors. BMC Public Health 13:841. CrossRefGoogle Scholar
  31. 31.
    Protano C, Astolfi ML, Canepari S, Vitali M (2016) Urinary levels of trace elements among primary school-aged children from Italy: the contribution of smoking habits of family members. Sci Total Environ 557-558:378–385. CrossRefGoogle Scholar
  32. 32.
    Burm E, Song I, Ha M, Kim YM, Lee KJ, Kim HC, Lim S, Kim SY, Lee CG, Kim SY, Cheong HK, Sakong J, Kang HT, Son M, Oh GJ, Kim Y, Yang JY, Hong SJ, Seo JH, Kim J, Oh S, Yu J, Chang SS, Kwon HJ, Choi YH, Choi W, Kim S, Yu SD (2016) Representative levels of blood lead, mercury, and urinary cadmium in youth: Korean Environmental Health Survey in Children and Adolescents (KorEHS-C), 2012-2014. Int J Hyg Environ Health 219:412–418. CrossRefGoogle Scholar
  33. 33.
    CDC (Centers for Disease Control and Prevention) (2018) Fourth National Report on Human Exposure to Environmental Chemicals Updated Tables, March 2018, Volume OneGoogle Scholar
  34. 34.
    Perez R, Domenech E, Conchado A, Sanchez A, Coscolla C, Yusa V (2018) Influence of diet in urinary levels of metals in a biomonitoring study of a child population of the Valencian region (Spain). Sci Total Environ 618:1647–1657. CrossRefGoogle Scholar
  35. 35.
    Claus Henn B, Bellinger DC, Hopkins MR, Coull BA, Ettinger AS, Jim R, Hatley E, Christiani DC, Wright RO (2017) Maternal and cord blood manganese concentrations and early childhood neurodevelopment among residents near a mining-impacted superfund site. Environ Health Perspect 125:067020. CrossRefGoogle Scholar
  36. 36.
    Lee JJ, Valeri L, Kapur K, Ibne Hasan MOS, Quamruzzaman Q, Wright RO, Bellinger DC, Christiani DC, Mazumdar M (2018) Growth parameters at birth mediate the relationship between prenatal manganese exposure and cognitive test scores among a cohort of 2- to 3-year-old Bangladeshi children. Int J Epidemiol 47:1169–1179. CrossRefGoogle Scholar
  37. 37.
    Munoz-Rocha TV, Tamayo YOM, Romero M, Pantic I, Schnaas L, Bellinger D, Claus-Henn B, Wright R, Wright RO, Tellez-Rojo MM (2018) Prenatal co-exposure to manganese and depression and 24-months neurodevelopment. Neurotoxicology 64:134–141. CrossRefGoogle Scholar
  38. 38.
    Kopp RS, Kumbartski M, Harth V, Bruning T, Kafferlein HU (2012) Partition of metals in the maternal/fetal unit and lead-associated decreases of fetal iron and manganese: an observational biomonitoring approach. Arch Toxicol 86:1571–1581. CrossRefGoogle Scholar
  39. 39.
    Abdelouahab N, Huel G, Suvorov A, Foliguet B, Goua V, Debotte G, Sahuquillo J, Charles MA, Takser L (2010) Monoamine oxidase activity in placenta in relation to manganese, cadmium, lead, and mercury at delivery. Neurotoxicol Teratol 32:256–261. CrossRefGoogle Scholar
  40. 40.
    Lewis RC, Meeker JD, Basu N, Gauthier AM, Cantoral A, Mercado-Garcia A, Peterson KE, Tellez-Rojo MM, Watkins DJ (2018) Urinary metal concentrations among mothers and children in a Mexico City birth cohort study. Int J Hyg Environ Health 221:609–615. CrossRefGoogle Scholar
  41. 41.
    Lee MJ, Chou MC, Chou WJ, Huang CW, Kuo HC (2018) Heavy metals’ effect on susceptibility to attention-deficit/hyperactivity disorder: implication of lead, cadmium, and antimony. Int J Environ Res Public Health 15(6):1221. CrossRefGoogle Scholar
  42. 42.
    Zhang X, Cui X, Lin C, Ma J, Liu X, Zhu Y (2017) Reference levels and relationships of nine elements in first-spot morning urine and 24-h urine from 210 Chinese children. Int J Hyg Environ Health 220:227–234. CrossRefGoogle Scholar
  43. 43.
    Kippler M, Tofail F, Hamadani JD, Gardner RM, Grantham-McGregor SM, Bottai M, Vahter M (2012) Early-life cadmium exposure and child development in 5-year-old girls and boys: a cohort study in rural Bangladesh. Environ Health Perspect 120:1462–1468. CrossRefGoogle Scholar
  44. 44.
    Takser L, Mergler D, Hellier G, Sahuquillo J, Huel G (2003) Manganese, monoamine metabolite levels at birth, and child psychomotor development. Neurotoxicology 24:667–674. CrossRefGoogle Scholar
  45. 45.
    Lin CC, Chen YC, Su FC, Lin CM, Liao HF, Hwang YH, Hsieh WS, Jeng SF, Su YN, Chen PC (2013) In utero exposure to environmental lead and manganese and neurodevelopment at 2 years of age. Environ Res 123:52–57. CrossRefGoogle Scholar
  46. 46.
    Chung SE, Cheong HK, Ha EH, Kim BN, Ha M, Kim Y, Hong YC, Park H, Oh SY (2015) Maternal blood manganese and early neurodevelopment: the Mothers and Children’s Environmental Health (MOCEH) Study. Environ Health Perspect 123:717–722. CrossRefGoogle Scholar
  47. 47.
    Claus Henn B, Ettinger AS, Schwartz J, Tellez-Rojo MM, Lamadrid-Figueroa H, Hernandez-Avila M, Schnaas L, Amarasiriwardena C, Bellinger DC, Hu H, Wright RO (2010) Early postnatal blood manganese levels and children’s neurodevelopment. Epidemiology 21:433–439. CrossRefGoogle Scholar
  48. 48.
    Gunier RB, Arora M, Jerrett M, Bradman A, Harley KG, Mora AM, Kogut K, Hubbard A, Austin C, Holland N, Eskenazi B (2015) Manganese in teeth and neurodevelopment in young Mexican-American children. Environ Res 142:688–695. CrossRefGoogle Scholar
  49. 49.
    Haynes EN, Sucharew H, Kuhnell P, Alden J, Barnas M, Wright RO, Parsons PJ, Aldous KM, Praamsma ML, Beidler C, Dietrich KN (2015) Manganese exposure and neurocognitive outcomes in rural school-age children: the Communities Actively Researching Exposure Study (Ohio, USA). Environ Health Perspect 123:1066–1071. CrossRefGoogle Scholar
  50. 50.
    Forns J, Fort M, Casas M, Caceres A, Guxens M, Gascon M, Garcia-Esteban R, Julvez J, Grimalt JO, Sunyer J (2014) Exposure to metals during pregnancy and neuropsychological development at the age of 4 years. Neurotoxicology 40:16–22. CrossRefGoogle Scholar
  51. 51.
    Skroder H, Kippler M, Tofail F, Vahter M (2017) Early-life selenium status and cognitive function at 5 and 10 years of age in Bangladeshi children. Environ Health Perspect 125:117003. CrossRefGoogle Scholar
  52. 52.
    Bouchard MF, Sauve S, Barbeau B, Legrand M, Brodeur ME, Bouffard T, Limoges E, Bellinger DC, Mergler D (2011) Intellectual impairment in school-age children exposed to manganese from drinking water. Environ Health Perspect 119:138–143. CrossRefGoogle Scholar
  53. 53.
    Wahlberg K, Arora M, Curtin A, Curtin P, Wright RO, Smith DR, Lucchini RG, Broberg K, Austin C (2018) Polymorphisms in manganese transporters show developmental stage and sex specific associations with manganese concentrations in primary teeth. NeuroToxicology 64:103–109. CrossRefGoogle Scholar
  54. 54.
    Mohanty AF, Farin FM, Bammler TK, MacDonald JW, Afsharinejad Z, Burbacher TM, Siscovick DS, Williams MA, Enquobahrie DA (2015) Infant sex-specific placental cadmium and DNA methylation associations. Environ Res 138:74–81. CrossRefGoogle Scholar
  55. 55.
    Kippler M, Engstrom K, Mlakar SJ, Bottai M, Ahmed S, Hossain MB, Raqib R, Vahter M, Broberg K (2013) Sex-specific effects of early life cadmium exposure on DNA methylation and implications for birth weight. Epigenetics 8:494–503. CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Tong Zhou
    • 1
  • Jianqiu Guo
    • 1
  • Jiming Zhang
    • 1
  • Hongxi Xiao
    • 1
  • Xiaojuan Qi
    • 1
    • 2
  • Chunhua Wu
    • 1
  • Xiuli Chang
    • 1
  • Yubin Zhang
    • 1
  • Qiang Liu
    • 1
  • Zhijun Zhou
    • 1
    Email author
  1. 1.School of Public Health/Key Laboratory of Public Health Safety of Ministry of Education/Key Lab of Health Technology Assessment, National Health Commission of the People’s Republic of ChinaFudan UniversityShanghaiChina
  2. 2.Zhejiang Provincial Center for Disease Control and PreventionHangzhouChina

Personalised recommendations