Prenatal manganese exposure and neuropsychological development in early childhood in the INMA cohort

https://doi.org/10.1016/j.ijheh.2019.113443Get rights and content

Highlights

  • Prenatal Mn levels did not associate with neuropsychological development during the first year.

  • Maternal iron status and the child's sex did not modify the Mn effect.

  • Consumption of nuts was the only dietary factor associated with maternal Mn levels.

Abstract

Introduction

Manganese (Mn) is an essential element, diet being its main source. Some epidemiological studies have found that a prenatal excess of Mn could negatively affect neuropsychological development during infancy, but the evidence is inconclusive. The aim of this study was to explore the relationship between maternal serum Mn concentrations and child neuropsychological development assessed at 1 year of age.

Methods

study subjects were 1179 mother–child pairs from two Spanish cohorts (Valencia and Gipuzkoa) of the INMA (Environment and Childhood) Project. Mn was measured in serum samples collected during the first trimester of pregnancy. Child neuropsychological development was assessed using the Bayley Scales of Infant Development, composed of both mental and psychomotor scales. Sociodemographic, lifestyle and dietary information was collected through questionnaires during pregnancy and during the child's first year of life. Serum Mn was log-2 transformed. Multivariable linear regression models were built. Generalized additive models were used to assess the shape of the relation between prenatal exposure to Mn and the neuropsychological test scores.

Results

geometric mean and 95% confidence interval (95% CI) of maternal serum Mn was 1.50 (1.48–1.53) μg/L. Levels of Mn were higher among non-working mothers and in those with a higher consumption of nuts. The association between maternal Mn levels and child neuropsychological development was negative in the multivariable models for the mental (β [95% CI] = −0.39 [-2.73, 1.95]) and psychomotor scales (β [95% CI] = −0.92 [-3.48, 1.65]), although the coefficients were not statistically significant. The best shape describing the relationship between Mn and the Bayley scales was linear in both cases.

Conclusion

This study shows a null association between maternal prenatal levels of Mn and neuropsychological development at one year after birth in two cohorts within the INMA study.

Introduction

Manganese (Mn) is an essential element involved in numerous metabolic processes, such as the metabolism of fats and carbohydrates, the formation of connective tissue and bones, and the synthesis and metabolism of neurotransmitters (Agency for Toxic Substances and Disease Registry, 2012; Santamaria and Sulsky, 2010). Mn is a naturally occurring metal in the environment. However, anthropogenic sources such as pesticides, gasoline additives and industry, especially metallurgical processes, have made a substantial contribution to the presence of Mn in the atmosphere (Lucchini et al., 2015).

The main exposure route in the non-exposed population is through diet. The main contributors to Mn levels are cereals, legumes, and vegetables (Agence nationale de sécurité sanitaire de l'alimentation de l'environnement et du travail, 2011; Filippini et al., 2017; Rose et al., 2010), although relatively high levels of Mn have been detected in other foods such as nuts, eggs, and tea (Perelló et al., 2015; Rose et al., 2010). The intake of water has been observed to be another source of exposure, especially in regions with high levels of Mn in drinking water, such as Bangladesh (Wasserman et al., 2006), Japan or Australia (Freeland-Graves et al., 2016). Likewise, living close to agricultural or industrial areas (Gunier et al., 2014; Takser et al., 2004) also seems to be related to Mn exposure.

Levels of Mn are kept within physiological limits by a homeostatic mechanism. An increase in Mn concentration can occur on account of exposure to high levels of Mn or owing to the presence of conditions that can affect this homeostatic mechanism, such as iron deficiency or liver dysfunction (Agency for Toxic Substances and Disease Registry, 2012). There is scarce evidence about the neurological effects caused by exposure to Mn in the general population or in critical periods, as in prenatal development (Agency for Toxic Substances and Disease Registry, 2012).

Epidemiological studies have reported an increase in blood Mn levels during pregnancy (Spencer, 1999; Takser et al., 2004). Mn is transferred from the mother to the fetus via the placenta through active transport mechanisms in order to meet the fetal demand for this element (Nandakumaran et al., 2016). Mn is able to cross the blood-brain barrier and accumulate in the developing brain (Yoon et al., 2011). Although Mn is an essential element for fetal growth, the developing brain seems to be especially vulnerable to an excess of Mn (Grandjean and Landrigan, 2014).

Very few epidemiological studies have evaluated the relationship between prenatal Mn levels and neuropsychological development in infancy. Takser et al. (2003) found a negative relation between cord blood Mn levels and hand skills, attention and non-verbal memory scores at 3 years of age, but no association was observed between Mn and general cognitive scores at 3 (n = 126) and 6 (n = 100) years old. Claus-Henn et al. (2017) reported a significant negative association between maternal blood Mn levels and mental and psychomotor development in 2-year-old children from USA (n = 224). Some studies have observed an inverted U-shaped relationship between prenatal Mn levels and psychomotor, mental and/or language development in infancy (Chung et al., 2015; Muñoz-Rocha et al., 2018). Conversely, a recent study (n = 355) has found no significant relation between maternal blood Mn levels and neuropsychological development at 1 year of age (Mora et al., 2018).

Although the literature suggests that exposure to Mn during the prenatal period could affect children's neurodevelopment, this evidence is still too scarce to draw any definite conclusions. Therefore, the aim of this study was to explore the relationship between maternal Mn concentrations and child neuropsychological development assessed at around 12 months of age in a Spanish birth cohort study. We also described the maternal exposure to Mn and assessed the influence of sociodemographic, environmental and dietary characteristics on it.

Section snippets

Study population

The study population belongs to the INMA Project (Environment and Childhood), a multicentre birth cohort study that aims to investigate the effect of environmental exposures and diet during pregnancy and childhood on fetal and child development in different geographical areas of Spain (http://www.proyectoinma.org). Subjects were participants in the Gipuzkoa (northwest of Spain) and Valencia (east of Spain) areas.

The study protocol has been reported elsewhere (Guxens et al., 2012). Briefly, 1493

Results

In our population, 45% of the mothers were 30–34 years old, around 92% were born in Spain, around 40% had a university degree, and more than the 40% belonged to the lowest social class (Table 1).

Mn concentrations were detected in all maternal serum samples. The GM of serum Mn concentration was 1.50 (95%CI: 1.48–1.53) μg/L, with an interquartile range (IQR) from 1.30 to 1.67 μg/L and a median of 1.45 μg/L. Higher Mn levels were observed among mothers born in Spain, those who lived near an

Discussion

In this Spanish birth cohort study, a null association was found between maternal serum Mn and mental or psychomotor development at year of age. As far as we know, this is the largest epidemiological study to have analyzed the association between prenatal Mn and neuropsychological development in early childhood.

Evidence about prenatal Mn exposure and neuropsychological development is still inconclusive. In fact, a recent systematic review concluded that the available evidence does not

Conclusion

In conclusion, the results of the present study did not suggest any effect of the early prenatal levels of Mn on neuropsychological development during the first year after birth. It is possible that the prenatal Mn levels observed may be within physiological limits, below the cut-off point from which this element could cause neurological adverse effects. These findings add information to the body of scientific knowledge about the adequate prenatal Mn levels and the window of susceptibility to

Declaration of competing interest

The authors declared no conflict of interest.

The study protocol was approved by the Ethics Committee of the university hospital La Fe (Valencia), the Ethics Committee of the Public Health Research Centre in Valencia (CSISP) and the Ethics Committee of Donostia Hospital (Gipuzkoa).

All study participants were included in the study after being signed the informed consent form.

Acknowledgments and funding

We are grateful to all the participants and their families for taking part in this study. We also appreciate the generous contribution in the study of all INMA members. A full roster of the INMA Project Investigators can be found at http://www.proyectoinma.org/presentacion-inma/listado-investigadores/en_listado-investigadores.html. This study was supported by grants from Instituto de Salud Carlos III [FIS-FEDER: 06/0867, 09/00090, 13/22187, 13/1944, 16/1288, 17/00663 and 19/1338; Miguel Servet-

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