Abstract
Background
We evaluated: (1) associations of prenatal manganese (Mn) levels with child neurodevelopment at 4–6 years; (2) effect modification by maternal anemia and iron deficiency; and (3) sex-specific effects.
Methods
We measured blood Mn, hemoglobin, and serum ferritin in mothers at the second trimester, third trimester, and at birth, and in cord blood from a prospective birth cohort in Mexico City (n = 571). McCarthy Scales of Children’s Abilities were measured at 4–6 years. Using linear regression, we estimated associations between prenatal Mn and neurodevelopment, examined anemia and iron deficiency as effect modifiers, and analyzed associations by child sex.
Results
No direct associations were observed between Mn, anemia, or iron deficiency and McCarthy Scales. Second trimester iron deficiency and third trimester anemia modified the effect of Mn on child neurodevelopment. For instance, second trimester Mn was positively associated child memory scores in mother’s with normal ferritin (1.85 (0.02, 3.45)), but negatively associated in mother’s with low ferritin (−2.41 (−5.28, 0.47), interaction P value = 0.01), a pattern observed across scales. No effect modification at birth or in cord blood was observed.
Conclusions
Anemia/iron deficiency during pregnancy may modify Mn impacts on child neurodevelopment, particularly in boys.
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References
Freeland-Graves, J. H., Mousa, T. Y., Sanjeevi, N. in Manganese in Health and Disease 34–75 (2014). http://pubs.rsc.org/en/content/chapter/bk9781849739436-00034/978-1-84973-943-6
Hurley, L. S. The role of trace elements in foetal and neonatal development. Philos. Trans. R. Soc. Lond. Ser. B 294, 145–152 (1981).
Shaw, J. C. Trace metal requirements of preterm infants. Acta Paediatr. Scand. Suppl. 296, 93–100 (1982).
Ek, C. J., Dziegielewska, K. M., Habgood, M. D. & Saunders, N. R. Barriers in the developing brain and neurotoxicology. Neurotoxicology 33, 586–604 (2012).
Gunier, R. B. et al. Manganese in teeth and neurodevelopment in young Mexican–American children. Environ. Res. 142, 688–695 (2015).
Henn, B. C. et al. Early postnatal blood manganese levels and children’s neurodevelopment. Epidemiology 21, 433–439 (2010).
Muñoz-Rocha, T. V. et al. Prenatal co-exposure to manganese and depression and 24-months neurodevelopment. Neurotoxicology (2017). http://www.sciencedirect.com/science/article/pii/S0161813X17301201
Mora, A. M. et al. Prenatal and postnatal manganese teeth levels and neurodevelopment at 7, 9, and 10.5 years in the CHAMACOS cohort. Environ. Int. 84, 39–54 (2015).
Seo, Y. A., Li, Y. & Wessling-Resnick, M. Iron depletion increases manganese uptake and potentiates apoptosis through ER stress. Neurotoxicology 38, 67–73 (2013).
World Health Organization. Iron Deficiency Anaemia: Assessment, Prevention, and Control: A Guide For Programme Managers (WHO, Geneva, Switzerland, 2001).
Garcia-Valdes, L. et al. The impact of maternal obesity on iron status, placental transferrin receptor expression and hepcidin expression in human pregnancy. Int. J. Obes. 39, 571–578 (2015).
Balarajan, Y., Ramakrishnan, U., Özaltin, E., Shankar, A. H. & Subramanian, S. V. Anaemia in low-income and middle-income countries. Lancet 378, 2123–2135 (2011).
Claus Henn, B et al. Maternal and cord blood manganese concentrations and early childhood neurodevelopment among residents near a mining-impacted superfund site. Environ. Health Perspect. (2017). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743453/
Henn, B. C. et al. Associations of early childhood manganese and lead coexposure with neurodevelopment. Environ. Health Perspect. 120, 126–131 (2012).
Krachler, M., Rossipal, E. & Micetic-Turk, D. Trace element transfer from the mother to the newborn—investigations on triplets of colostrum, maternal and umbilical cord sera. Eur. J. Clin. Nutr. 53, 486–494 (1999).
Braun, J. M. et al. Relationships between lead biomarkers and diurnal salivary cortisol indices in pregnant women from Mexico City: a cross-sectional study. Environ. Health 13, 50 (2014).
Burris, H. H. et al. Association between birth weight and DNA methylation of IGF2, glucocorticoid receptor and repetitive elements LINE-1 and Alu. Epigenomics 5, 271–281 (2013).
Leifert, J. A. Anaemia and cigarette smoking. Int. J. Lab. Hematol. 30, 177–184 (2008).
Wehby, G. L., Prater, K., McCarthy, A. M., Castilla, E. E. & Murray, J. C. The impact of maternal smoking during pregnancy on early child neurodevelopment. J. Hum. Cap. 5, 207–254 (2011).
Renzetti, S. et al. The association of lead exposure during pregnancy and childhood anthropometry in the Mexican PROGRESS cohort. Environ. Res. 152, 226–232 (2017).
McCarthy, D. Manual for the McCarthy Scales of Children’s Abilities. New York, Psychological Corporation, 1972.
Hernández-Avila, M. et al. Validity and reproducibility of a food frequency questionnaire to assess dietary intake of women living in Mexico City. Sal. Pub. Mex. 40, 133–140 (1998).
Malin, A. J. et al. Quality of prenatal and childhood diet predicts neurodevelopmental outcomes among children in Mexico City. Nutrients (2018). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115750/
Rodríguez-Ramírez, S., Mundo-Rosas, V., Jiménez-Aguilar, A. & Shamah-Levy, T. Methodology for the analysis of dietary data from the Mexican National Health and Nutrition Survey 2006. Sal. Pub. Mex. 51(Suppl. 4), S523–S529 (2009).
Dirren, H., Logman, M. H., Barclay, D. V. & Freire, W. B. Altitude correction for hemoglobin. Eur. J. Clin. Nutr. 48, 625–632 (1994).
Carrasco, A. V. The AMAI System of Classifying Households by Socio-economic Level: The experience of Mexico and its comparison with Brazil and Argentina (ESOMAR, 2002).
R Core Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, Vienna, Austria, 2018). https://www.R-project.org/
Lin, C.-C. et al. In utero exposure to environmental lead and manganese and neurodevelopment at 2 years of age. Environ. Res. 123, 52–57 (2013).
Takser, L., Mergler, D., Hellier, G., Sahuquillo, J. & Huel, G. Manganese, monoamine metabolite levels at birth, and child psychomotor development. Neurotoxicology 24, 667–674 (2003).
Aschner, M. & Aschner, J. L. Manganese neurotoxicity: cellular effects and blood-brain barrier transport. Neurosci. Biobehav. Rev. 15, 333–340 (1991).
Nelson, C., Erikson, K., Piñero, D. J. & Beard, J. L. In vivo dopamine metabolism is altered in iron-deficient anemic rats. J. Nutr. 127, 2282–2288 (1997).
Kim, J. & Wessling-Resnick, M. Iron and mechanisms of emotional behavior. J. Nutr. Biochem. 25, 1101–1107 (2014).
Alcorn, J. & McNamara, P. J. Ontogeny of hepatic and renal systemic clearance pathways in infants. Part I. Clin. Pharmacokinet. 41, 959–998 (2002).
Di Renzo, G. C. et al. Iron deficiency anemia in pregnancy. Women’s Health (Lond. Engl.) 11, 891–900 (2015).
Menezes-Filho, J. A. et al. Elevated manganese exposure and school-aged children’s behavior: a gender-stratified analysis. Neurotoxicology 45, 293–300 (2014).
Zota, A. R. et al. Maternal blood manganese levels and infant birth weight. Epidemiology 20, 367–373 (2009).
Rudge, C. V. et al. The placenta as a barrier for toxic and essential elements in paired maternal and cord blood samples of South African delivering women. J. Environ. Monit. 11, 1322–1330 (2009).
Abdelouahab, N. et al. Monoamine oxidase activity in placenta in relation to manganese, cadmium, lead, and mercury at delivery. Neurotoxicol. Teratol. 32, 256–261 (2010).
Shamah-Levy, T. et al. Tendencia en la prevalencia de anemia entre mujeres mexicanas en edad reproductiva 2006-2016. Ensanut MC 2016. Sal. Púb. Méx. 60, 301–308 (2018).
Finley, J. W. Manganese absorption and retention by young women is associated with serum ferritin concentration. Am. J. Clin. Nutr. 70, 37–43 (1999).
Acknowledgements
We thank the American British Cowdray Hospital in Mexico City for providing research facilities. Work was supported by NIH grants: R01ES014930; R01ES013744; R01ES021357, P30ES009089, P30ES023515, and R24ES028522. Co-investigators at the INSP received partial funding from the National Institute of Public Health/Ministry of Health of Mexico.
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A.K. conceived the study design, performed the data analysis, interpreted the results, and drafted the manuscript. G.E.-G., A.C., L.S., I.P., C.A., and K.S. provided substantial contributions to data acquisition. D.C.B., M.M.T.-R., A.A.B., and R.O.W., each contributed substantially to study desgin and data interpretation, and critically revised the manuscript intelectual content. All authors provided final approval of the version to be published.
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Kupsco, A., Estrada-Gutierrez, G., Cantoral, A. et al. Modification of the effects of prenatal manganese exposure on child neurodevelopment by maternal anemia and iron deficiency. Pediatr Res 88, 325–333 (2020). https://doi.org/10.1038/s41390-020-0754-4
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DOI: https://doi.org/10.1038/s41390-020-0754-4
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