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Contents lists available at ScienceDirect

NeuroToxicology

Full Length Article

Prenatal co-exposure to manganese and depression and 24-months

neurodevelopment
Teresa Verenice Muñoz-Rochaa , Marcela Tamayo y Ortiza,b,* , Martín Romeroa ,
Ivan Panticc , Lourdes Schnaasc , David Bellingerd , Birgit Claus-Henne , Rosalind Wrightf ,
Robert O. Wrightg, Mara Téllez-Rojoa
a
National Institute of Public Health, Universidad No. 655 Colonia Santa María, Ahuacatitlán, Cerrada Los Pinos y Caminera, C.P. 62100, Cuernavaca, Morelos,
Mexico
b
CONACYT- National Council of Science and Technology, Avenida Insurgentes Sur 1582, D.F., Benito Juárez, Crédito Constructor, 03940, Ciudad de, Mexico
c
National Institute of Perinatology, Calle Montes Urales #800, D.F., Miguel Hidalgo, Lomas Virreyes, 11000 Ciudad de, Mexico
d
Department Environmental Health, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA 02115, United States,
e
Department of Environmental Health, Boston University School of Public Health, 715 Albany Street, Boston, MA 02118, United States,
f
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1428 Madison Ave, New York, NY 10029, United States
g
Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, 1428 Madison Ave, New York, NY 10029, United States

A R T I C L E I N F O A B S T R A C T

Article history: Background: Normal prenatal neurodevelopment follows stages that are potentially influenced by both
Received 31 January 2017 chemical and psychosocial environments. Exposure to elevated manganese during this critically
Received in revised form 12 July 2017 vulnerable period has been found to be neurotoxic. Independently, maternal prenatal depression has
Accepted 12 July 2017
been associated with subsequent neurodevelopmental decrements in children. The association between
Available online xxx
child neurodevelopment and prenatal co-exposure to manganese and maternal depression has not been
sufficiently studied.
Keywords:
Methods: During pregnancy and at birth, we measured maternal blood and cord blood manganese levels
Prenatal
Neurodevelopment
respectively. Maternal depression was assessed in the 3rd trimester of pregnancy using the Edinburgh
Depression Depression Scale. Neurodevelopment was evaluated at 24 months of age with the Bayley Scales of Infant
Manganese Development. A multivariate multiple regression model was used to analyze cognitive, language and
Co-exposure motor scores simultaneously for 473 children from the PROGRESS birth cohort in Mexico City.
Results: Over 25% of our study participants reported having depressive symptoms. 3rd trimester blood
manganese as well as depressive symptoms were independently negatively associated with all
neurodevelopment scores in adjusted models. In stratified analyses, the negative association between
manganese (maternal as well as cord blood) and 24-month language scores was stronger among women
with depressive symptoms. Receptive language was mostly affected. Inverted U-shaped curves were seen
for the association between with cord blood manganese and neurodevelopment scores.
Conclusions: Our findings are in line with previous studies of manganese and depression neurotoxicity.
The prenatal period may be particularly sensitive to manganese and depression co-exposures and should
be of interest for public health interventions to promote healthy emotional and nutritional pregnancies.
© 2017 Elsevier B.V. All rights reserved.

1. Background

The prenatal period is critical to neurodevelopment. During this

* Corresponding author at: Center for Nutrition Research and Health, Universidad
No. 655 Colonia Santa María, Ahuacatitlán, Cerrada Los Pinos y Caminera, C.P. 62100,
Cuernavaca, Morelos, Mexico.
E-mail addresses: verenice.munoz@insp.mx (T.V. Muñoz-Rocha),
marcela.tamayo@insp.mx (M. Tamayo y Ortiz), martin.romero@insp.mx
(M. Romero), ivandpantic@gmail.com (I. Pantic), lschnaas@hotmail.com
(L. Schnaas), david.bellinger@childrens.harvard.edu (D. Bellinger), bclaus@bu.edu
(B. Claus-Henn), rosalind.wright@mssm.edu (R. Wright), robert.wright@mssm.edu
(R.O. Wright), mmtellez@insp.mx (M. Téllez-Rojo).
time, the nervous system matures towards the achievement of the
cognitive, motor and language functions. Independently, exposure
to elevated manganese (Mn) and the presence of depression in
pregnant women are factors that can influence the neurodevelop-
ment of their offspring (Chung et al., 2015; Coetzee et al., 2016;
Glover, 2014; Nulman et al., 2015).
Manganese (Mn) is an essential nutrient that contributes
substantially to a variety of body functions including the

http://dx.doi.org/10.1016/j.neuro.2017.07.007
0161-813X/© 2017 Elsevier B.V. All rights reserved.

Please cite this article in press as: T.V. Muñoz-Rocha, et al., Prenatal co-exposure to manganese and depression and 24-months
neurodevelopment, Neurotoxicology (2017), http://dx.doi.org/10.1016/j.neuro.2017.07.007
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breakdown of cholesterol, carbohydrates and proteins and also
plays a key role in brain development and bone formation
(Freeland-Graves and Turnlund, 1996). Mn is a core component of
various metalloenzymes that ensure proper functioning of the
central nervous system (Aschner and Aschner, 1991). The general
population is exposed to Mn through food, water and air. Mn
absorbed from ambient air might occur in areas with heavy traffic
(Bueno-Brito et al., 2005). However, levels in ambient air are
considered negligible when compared to the natural abundance of
Mn in soil (Gulson et al., 2006). In food, its concentration is highest
in string beans, nuts, legumes, seeds, tea, whole grains and green-
leaf vegetables. Guidelines have been established for different
exposure routes: the WHO establishes 0.15 mg/m3 for air and
0.4 mg/L in water; the U.S. FDA establishes a limit of 0.05 mg/L in
bottled drinking water and as for food the EPA has a reference dose
of 0.14 mg/kg/day (ATSDR, 2012). According to the Food and
Nutrition Board of the Institute of Medicine, 2 mg of Mn per day
constitute an adequate intake for pregnant women, with the
tolerable upper intake level of 11 mg (Food and Nutrition Board,
2001). Notwithstanding its protective effect against oxidative
damage, in larger quantities Mn becomes an oxidizer itself (ATSDR,
2012) and is a known neurotoxicant. Mn accumulates in
mitochondria-rich membranes and penetrates the blood-brain
and placental barriers. Evidence of the neurotoxic effects of Mn is
increasing, specifically with regard to cognition, memory, behavior
and motor function (Claus Henn et al., 2012, 2010; Hernández-
Bonilla et al., 2011; Menezes-Filho et al., 2011, 2009; Rodríguez-
Barranco et al., 2013). Several studies have examined the neuro-
developmental effects of intrauterine Mn exposure, and results
suggest that environmental exposure to Mn in utero may affect the
psychomotor development of children at an early age (Gunier et al.,
2015; Lin et al., 2013a; Mora et al., 2015a).
Perinatal depression has also been identified as a risk factor for
inadequate infant neurodevelopment in the long term (Dossett,
2008). According to the World Health Organization, depression is a
disease that alters the mood, thoughts, appetite, sleep, perception
of self-esteem and overall lifestyle of individuals (WHO, 2016).
Feeling sad, apathetic and hurt, those who suffer from this
emotional disorder find it difficult to interact with the environ-
ment (Lara et al., 2006). Prenatal depression is differentiated by its
adverse effects on the baby, whose neuronal development during
this period is directly affected by context (Olhaberry et al., 2013).
Research performed during outpatient consultations at the
National Institute of Perinatology indicated that as many as 21.7%
of pregnant women in Mexico may experience probable depres-
sion episodes (Ortega et al., 2001). Another study revealed a 23.3%
prevalence of depression among pregnant users of primary
healthcare services at Family Medicine Unit 171 of the Mexican
Social Security Institute (Instituto Mexicano del Seguro Social, IMSS)
(Delgado-Quiñones et al., 2015). A recent study in the US estimated
that the prevalence of minor depression was higher among
pregnant women (16.6%) compared to non-pregnant women
(11.4%) (adjusted PR = 1.5, [95% confidence interval (CI): 1.2, 1.9]).
Studies have found that depression occurs particularly during
weeks 6 to 10 and in the third trimester of pregnancy, when the
body prepares for labor and delivery (Carter and Kostara, 2005).
Depression can affect the central nervous system through
anomalous levels of aminergic neurotransmitters (e.g., serotonin,
norepinephrine and dopamine) acting upon the neurons of the
central nervous system (Escobar Izquierdo et al., 2009). Mn is
essential to the proper functioning of the hypothalamus, a region of
the brain containing a large number of neurons. One of the primary
functions of the hypothalamus is to link the nervous and endocrine
systems by secreting neurohormones through the pituitary gland.
The molecular mechanisms by which Mn affects hypothalamic
processes are not fully understood, therefore determining exactly
Please cite this article in press as: T.V. Muñoz-Rocha, et al., Prenatal co-exposure to manganese and depression and 24-months
neurodevelopment, Neurotoxicology (2017), http://dx.doi.org/10.1016/j.neuro.2017.07.007
which mechanisms are at play in the interaction between Mn and
depression and consequently child neurodevelopment is not
completely clear (Tellerias and Paris, 2008). However, both could
be acting on the same dopamine pathway and epidemiologic
evidence is scarce.
Because both Mn and depression are common exposures in
pregnancy, we explored their joint associations with children’s
neurodevelopment at 24 months of age. We hypothesized that
depression could be an effect modifier of the association between
Mn and neurodevelopment.
2. Methods
2.1. Study population
The Programming Research in Obesity, Growth, Environment
and Social Stressors (PROGRESS) birth cohort recruited women
during their prenatal visit at four IMSS clinics in Mexico City,
between 2007 and 2011 and followed them since their 2nd
trimester. Inclusion criteria have been previously described in
more detail (Braun et al., 2014). Briefly, women had to be healthy,
at least 18 years old, between 12 and 24 weeks pregnant, and plan
to live in Mexico City. All protocols were approved by the
institutional review boards of the Icahn School of Medicine at
Mount Sinai, the Harvard T.H. Chan School of Public Health, the
National Institute of Public Health Mexico, the National Institute of
Perinatology Mexico, and the Mexican Social Security System.
Upon consent, women visited our research centers during their
2nd and 3rd trimesters, we collected samples and data at birth and
760 mother-infant pairs visited our research centers at 6, 12, 18 and
24 months postpartum. Our study analyzed data from 541 dyads
for which a neurodevelopmental assessment was administered to
the child at the 24 month visit. We excluded from analyses children
who were born at 32 weeks and/or weighed 1,500 g (n = 4).
2.2. Child neurodevelopment
Neurodevelopment was assessed at 24 months of age using the
Bayley Scales of Infant and Toddler Development 3rd edition
(Albers and Grieve, 2006). Trained psychologists blind to the
prenatal Mn and depression levels evaluated the cognitive,
language and motor development of children.
2.3. Maternal gestational depression
The Edinburgh Depression Scale (EDS) was administered during
the 3rd trimester of pregnancy. The questionnaire consists of ten
polytomous (four-option) response items exploring last-week
symptoms of a major depression episode. Each question is rated on
a scale of 0 to 3 points. Studies have found that a cut-off of 12
indicates a probable depressive disorder (Evans et al., 2001;
Murray and Cox, 1990). The scale was applied in a Chilean cohort
(Hispanic population, closer to our study population) and found
that a cut-off between 12 and 13 had an 87.4% correct classification
of cases and non-cases (Alvarado et al., 2012). For our main
analyses we had a conservative approach and used a dichotomous
variable with a cutoff of 13 for depressive symptoms. We also
explored using quartiles of the EDS for a secondary analysis.
2.4. Prenatal manganese
Mn was measured in maternal venous blood samples in the 3rd
trimester (between the 30th and 34th week) of pregnancy, from
here on referred to as BMn and during birth in umbilical cord blood
(CMn). Royal blue trace metal Vacutainer tubes (Becton-Dickinson
and Company, Franklin Lakes, New Jersey) containing EDTA were
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used to collect the samples which were stored at 4  C until shipped. models for each Mn predictor. All statistical analyses were
They were hence stored at 20  C until analyzed with a mass performed with STATA 13 software.
spectrometer (Elan 6100; PerkinElmer, Norwalk, CT) at the Trace
Element Lab of the Harvard T.H. Chan School of Public Health. All of 3. Results
the samples exceeded the 0.09 mg/dL limit of detection.
The mean (SD) BMn and CMn concentrations were 27.7 mg/L
2.5. Covariates (8.7) and 50.1 (16.5) mg/L respectively. The Spearman correlation
between them was 0.02 with a p = 0.68. On a scale of 0 to 28, our
We selected the following covariates for inclusion in models study participants averaged 8.6 SD (5.8) (median = 8, IQR = 9)
based on previous literature: infant sex, birth weight (kg), points on the EDS questionnaire. Based on the EDS cutoff point
gestational age (weeks) and maternal education (years of (13), 26.5% of pregnant women were found to suffer from
schooling), age at delivery (years), marital status (with/without depressive symptoms, and quartiles were distributed as follows:
a partner), 3rd trimester blood lead (mg/dL collected using the 1st quartile from 0 to 4 points, 2nd quartiles 5–8 points, 3rd
same methods described above for Mn) and the HOME (Home quartile 9–13 points and 4th quartile 14–28 points on the EDS
Observation Measurement of the Environment) score at 24 months scale. Characteristics of our analytic sample participants and non-
of age (Chung et al., 2015; Lin et al., 2013b; Mora et al., 2015b; participants can be found in Table 1. None of the differences
Nulman et al., 2012). between groups were statistically significant. Spearman correla-
Without considering the HOME evaluation, complete covariate tions with a p < 0.05 level of significance were observed between
information were obtained from 473 and 308 mother-child pairs neurodevelopment scores: 0.57 between the language and
for the BMn and CMn analysis respectively. Adjusting for the HOME cognitive functions, 0.45 between the language and motor
score reduced the sample size to 341 and 214 respectively and did functions, and 0.50 between the cognitive and motor functions.
not change the main effect estimates by more than 10%, therefore BMn and depression scores had a Spearman correlation of 0.05
our final models did not include this covariate. (p = 0.26). Mn (maternal or cord) and depression symptoms in
pregnancy had independently, statistically significant negative
2.6. Statistical analysis associations with neurodevelopment scores in unadjusted models.
Results from our model using BMn and depression are shown in
We first examined the distribution and summary statistics for Table 2. On average, 1 mg/L increase in maternal blood manganese
all variables using univariate and bivariate regression models. We (BMn) and the presence of depression symptoms in pregnancy
ran separate analyses for BMn and CMn concentrations. The were associated respectively, with a decrease of 0.12 (p < 0.01) and
distributions for both BMn and CMn were slightly skewed to the 2.40 (p < 0.01) points on cognitive scores, 0.20 (p < 0.01) and 2.47
right but were included without any transformation in the models. (p = 0.01) points on language scores, and 0.10 (p = 0.04) and 1.01
We included both Mn variables as continuous in analyses. (p = 0.19) points on motor scores adjusting for covariates (infant
Neurodevelopment scores were normally distributed and used sex, birth weight, gestational age and maternal education, age at
as continuous variables, as were the rest of the covariates except delivery, marital status, 3rd trimester blood lead). In the model
for depression symptoms, child’s sex and maternal marital status including an interaction term between BMn and depressive
which were analyzed as dichotomous variables. symptoms, the coefficients were statistically significant for
To assess non-linearity of the association between each variable language scores (cognitive b = 0.08 p = 0.25, language b = 0.25
and neurodevelopment, we first used lowess graphs for visual p < 0.01, motor b = 0.10 p = 0.89). The results of the model
examination. All covariates showed a linear relationship, however stratified by depression suggest an effect modification of the
both BMn and CMn suggested a quadratic relation. We then
generated models including a quadratic term for BMn and CMn,
Table 1
separately. The effect coefficients were only statistically significant
Characteristics of analytic sample participants and non-participants.
for CMn. We therefore decided to assume the association between
BMn and neurodevelopment scores as linear and as quadratic for Participants Non-participants
n = 473 n = 287
CMn.
mean (SD) mean (SD)
We used multivariate linear regression models, an extension of
Children
the multiple regression model that allows quantifying relations
Cord blood manganese (mg/L) a 50.1 (16.5) 51.9 (19.4)
between the multiple response and explanatory variables while Neurodevelopment—Bayley IIIb
controlling for covariates, taking into account residual correlations. Cognitive 92.5 (8.7) 90.8 (6.8)
Therefore, a single model with three response variables (cognitive, Language 90.0 (9.3) 87.3 (7.4)
language and motor scores) rather than three independent models Motor 94.1 (9.5) 92.5 (8.5)
Sex: Male (%) 51.7 55.6
was preferred. All models included either BMn or CMn, depressive
Birth weight (kg) 3.1 (0.4) 3.0 (0.4)
symptoms and were adjusted for covariates. We applied t-tests to HOMEc 31.7 (5.5) 30.9 (5.1)
detect inter-group variance, specifically in terms of significant Gestational age (weeks) 38.8 (1.3) 40.2 (1.2)
neurodevelopmental differences by maternal depression.
Mother
In order to examine a possible interaction between Mn and
3T blood manganese (mg/L) d 27.7 (8.7) 26.4 (8.7)
depression, we included an interaction term in the adjusted Symptoms of depression: Yes (%) e 26 28
models. If the interaction coefficients were statistically significant Age at delivery (years) 27.0 (5.5) 27.4 (5.2)
we also stratified our models by depression in order to assess its Education (total years of schooling) 11.9 (2.7) 11.8 (2.9)
possible role as an effect modifier of the Mn-neurodevelopment Marital status: With partner (%) 80.7 80.5
3rd trimester blood lead (mg/dL) 4.1 (2.8) 3.9 (2.6)
association. We verified that model assumptions had been met.
a
Lastly, we constructed graphs illustrating the association between Cord Blood Mn: participants = 308 non-participants = 125.
b
Bayley III: non-participants = 64.
Mn, depression and neurodevelopment scores by saving the c
HOME: participants = 341 non-participants = 106.
predicted values of the adjusted models and graphed by depressive d
3T Mn non-participants n = 201.
symptoms (yes/no). As a secondary analysis in order to verify the e
Depression non-participants: n = 183XYZ.
cut-off point for depression, we included the EDS as quartiles in our

Please cite this article in press as: T.V. Muñoz-Rocha, et al., Prenatal co-exposure to manganese and depression and 24-months
neurodevelopment, Neurotoxicology (2017), http://dx.doi.org/10.1016/j.neuro.2017.07.007
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Table 2
Multivariate regression model for 24 months of age neurodevelopmental scores and maternal 3rd trimester blood Mn (mg/L) (n=473).

Cognitive Language Motor

b (SE) p b (SE) p b (SE) p

3rd trimester blood Mn 0.12 (0.0) <0.01 0.20 (0.0) <0.01 0.10 (0.0) 0.04
Depression: Yes 2.40 (0.8) <0.01 2.47 (0.9) 0.01 1.01 (0.8) 0.19
Sex: Male 2.34 (0.7) <0.01 3.43 (0.8) <0.01 2.47 (0.8) < 0.01
Birth weight 1.31 (1.0) 0.09 2.34 (1.0) 0.03 1.01 (1.1) 0.38
Gestational age (weeks) 0.00 (0.3) 0.98 0.21 (0.3) 0.53 0.51 (0.3) 0.17
Marital status (with partner) 0.73 (0.9) 0.38 0.37 (1.0) 0.65 1.05 (1.1) 0.3
Maternal age 0.03 (0.0) 0.76 0.07 (0.1) 0.64 0.01 (0.0) 0.86
Education (yrs) 0.55 (0.1) <0.01 0.52 (0.2) <0.01 0.15 (0.1) 0.36
Blood lead (mg/dL) 0.97(0.1) 0.48 0.13 (0.1) 0.26 0.01 (0.1) 0.83

association between maternal blood BMn and neurodevelopment 4. Discussion

(Table 3). On average, language scores for children whose mothers
were depressed during pregnancy were lower than for children
whose mothers were not depressed during pregnancy (Fig. 1).
Results from the analysis using CMn are shown in Table 4. Mean
curves for the adjusted association between CMn and neuro-
development scores had an inverted U shape. The interaction term
between CMn and language scores was statistically significant (not
for cognitive or motor scores). In stratified analyses by depression,
CMn was most strongly associated with language scores (Fig. 2).
Cognitive scores also differed depending on depression; however,
associations were not statistically significant (Table 5).
Since our models showed a consistently strong association with
language scores and both BMn and CMn, as well as an effect
modification by depression, we generated separate models looking
at the receptive (comprehension) and expressive (ability to use
vocabulary and words to sentences) components of the language
score. We found that receptive language score ranged from 2 to 16
with a mean of 8.9 (95% CI: 8.76, 9.07). On average, 1 mg/L increase
of BMn was associated with a decrease of 0.02 receptive language
points for children whose mothers did not have depressive
symptoms during pregnancy (p = 0.02), compared to a decrease
of 0.05 receptive language points for children whose mothers had
depressive symptoms during pregnancy (p = 0.02). The interaction
term between BMn and depression for receptive language had a
p < 0.01. We also saw a negative association between BMn and
expressive language, however there was no difference between
children born to women with or without depressive symptoms
during pregnancy (p for interaction = 0.09).
Results from the secondary analysis using EDS quartiles in
adjusted models for BMn comparing the 4th EDS quartile to the 1st
showed: a decrease of 3.8 cognitive points (p < 0.01), a decrease of
2.6 language points (p = 0.03) and a decrease of 2.34 motor points
(p = 0.07). Associations for the 2nd and 3rd quartiles compared to
the 1st were not statistically significant. For the CMn analysis,
comparing the 4th EDS quartile to the 1st we saw: a decrease of 4.4
cognitive points (p < 0.01), a decrease of 2.2 language points
(p = 0.15) and a decrease of 2.9 motor points (p = 0.06). Negative
associations were also seen comparing the 2nd quartile to the 1st
for cognitive scores (decrease of 2.9 points, p = 0.03) and for motor
scores (decrease of 3.2 points, p = 0.02. All other associations were
not statistically significant but in the same negative direction.
Our findings support studies showing a negative association
between prenatal (in-utero) exposure to Mn and 24 month
neurodevelopment (Lin et al., 2013b). Likewise, they are in line
with the literature of maternal depressive symptoms during this
period and reduced cognitive, language and motor development in
their children (Field, 2011; Nulman et al., 2012). After adjusting for
covariates, we observed the strongest negative associations for Mn
with language scores, compared to associations with cognitive and
motor scores. Furthermore, only the association between BMn and
language was modified by depression. Together our results suggest
that the prenatal mechanism by which language is developed is
affected by the co-exposure to Mn and depression and should be
further explored.
Although manganese is an essential metal for our bodily
functions, there is evidence that both insufficiently low and
excessively high levels are harmful to our health (O’Neal and
Zheng, 2015; Shan et al., 2016). We explored the effects of maternal
Mn deficiency (through 3rd trimester blood) on infant neuro-
development; however we did not find a negative quadratic
relationship, but rather a negative linear association for higher
maternal Mn concentrations. These findings are similar to those
seen in the Tar Creek superfund site where authors found a
negative linear association for maternal blood Mn but null
association for cord blood Mn (Claus Henn et al., 2017). By
contrast, we found a negative quadratic relationship between CMn
and neurodevelopment scores, consistent with findings from other
studies of early childhood blood Mn (Claus Henn et al., 2010). In
their study of infant neurodevelopment, Chung et al. collected
maternal blood just before delivery and found the same inverted U
shape association (Chung et al., 2015). The difference in the shape
of the functions may be reflecting the rapid growth of the infant’s
brain in the last gestational stage, with a higher nutritional need
for manganese. In our study, CMn might be illustrating this
exposure time window better than BMn.
Mean BMn levels found in our study are higher, than those
reported by Oulhoute et al. from the NHANES 2001–2012 (27.6 vs
12.5 mg/L respectively)(Oulhote et al., 2014). This could be due to
the timing during pregnancy in the collection of the sample,
which is unspecified in the article. Compared to concentrations
found by other studies, our results for BMn and are closer to those

Table 3
Adjusted multivariate regression model coefficients for neurodevelopmental scores and maternal 3rd trimester blood Mn stratified by depression (n = 473, with depression
n = 124, 26.3%).

Cognitive Language Motor

Depression b [95% CI] b [95% CI] b [95% CI]
No -0.15 (-0.25 to 0.04) -0.18 (-0.29 to 0.07) -0.14 (-0.25 to 0.04)
Yes -0.13 (-0.32 to 0.06) -0.27 (-0.46 to 0.08) -0.13 (-0.22 to 0.10)
p interaction 0.25 <0.01 0.89

Please cite this article in press as: T.V. Muñoz-Rocha, et al., Prenatal co-exposure to manganese and depression and 24-months
neurodevelopment, Neurotoxicology (2017), http://dx.doi.org/10.1016/j.neuro.2017.07.007
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Fig. 1. Graphical depiction of depression (women with depression n = 124) as an effect modifier of the association between 3rd trimester manganese blood (n = 473) and 24
month neurodevelopmental Bayley scores.

Table 4
Multivariate regression model for 24 months of age neurodevelopment and cord blood manganese (mg/L) (n = 307).

Cognitive Language Motor

b (SE) p b (SE) p b (SE) p

Cord manganese 0.38 (.15) 0.01 .533 (.16) <0.01 .345 (.16) 0.03
Cord manganese2 0.003 (.0) 0.01 0.005 (.00) <0.01 0.003 (0.0) 0.05
Depression: Yes 2.2 (1.1) 0.06 2.17 (1.2) 0.08 0.92 (1.1) 0.35
Sex: Male 2.6 (0.9) 0.01 3.93 (1.0) <0.01 3.16 (1.0) <0.01
Birth weight 1.6 (1.2) 0.01 3.38 (1.4) 0.01 0.76 (1.5) 0.56
Gestational age 0.1 (0.3) 0.85 0.15 (0.4) 0.73 0.08 (0.4) 0.83
Marital status (w/partner) -0.0 (1.2) 0.99 0.26 (1.4) 0.84 0.42 (1.4)
Maternal age 0.0 (0.0) 0.95 0.04 (0.1) 0.61 0.11 (0.1) 0.23
Education (total years) 0.6 (0.1) 0.04 0.61 (0.2) 0.05 0.14 (0.2) 0.46
Blood Lead (mg/dL) 0.3 (0.1) 0.06 0.24 (0.1) 0.17 0.25 (0.1) 0.15

Fig. 2. Graphical depiction of depression (women with depression n = 124) as an effect modifier of the association between cord blood manganese (n = 307) and 24 month
neurodevelopmental Bayley scores.

found by by Zota et al. in Tar Creek, BMn: 24 mg/L or by Mora et al.
in Costa Rica banana plantation workers: BMn 24.4 mg/L, and
lower than those found by Guan in China BMn: 54.98 mg/L. With
respect to CMn, our results (mean 50.1 mg/L) were lower than
those found by Guan: 78.75 mg/L, closer to those found by
Zota: 42 mg/L, but higher than those found by Tasker at el in
Southwest Quebec of 34.4 mg/L (Guan et al., 2014; Mora et al.,
2014; Takser et al., 2004; Zota et al., 2009). These differences
could be due to a variety of reasons including exposure to Mn in
the different populations, the timing in collection of the sample,
or even genetic/epigenetic characteristics of the specific
populations.

Please cite this article in press as: T.V. Muñoz-Rocha, et al., Prenatal co-exposure to manganese and depression and 24-months
neurodevelopment, Neurotoxicology (2017), http://dx.doi.org/10.1016/j.neuro.2017.07.007
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Table 5
Adjusted multivariate regression model coefficients for 24-month neurodevelopment scores and cord manganese (mg/L) stratified by depression (n = 307).
Cognitive
Depression: No (n = 235) b (SE) p b (SE)
Cord manganese 0.32 (.17) 0.05
Cord manganese2 0.003 (0.0) 0.05
Depression: Yes (n = 72)
Cord manganese .501 (.33) 0.14
Cord manganese2 0.004 (.00) 0.17
p interaction Mn 0.14
p interaction Mn2 0.17
We found a weak and non-significant correlation between BMn
and CMn, these finding are in line with those reported by Rudge
et al. who studied the placental permeability of Mn and found
twice as high BMn concentrations than CMn, as in our study (Rudge
et al., 2009). However many other studies have found positive
correlations (Guan et al., 2014; Takser et al., 2004; Zota et al., 2009).
One important difference is the timing of the sample collection, in
our study BMn was collected in the third trimester, whereas the
mentioned studies collected BMn at the moment of birth. Maternal
blood Mn during pregnancy may not adequately represent levels in
the fetus, which may be due to immature fetal liver function and
Mn tending to accumulate (Yoon et al., 2011). In line with the
above, we saw a positive correlation (Spearman 0.16, p < 0.01)
between CMn and Mn in samples of maternal blood collected
within the 24 h after delivery, which we did not consider in our
analysis to respect the timing of exposure (postnatal Mn levels may
not be an adequate reflection of gestational exposure, even if only
24 h had elapsed).
Our finding of significant associations between maternal blood
Mn and child neurodevelopment may indicate a role for the
placenta in influencing child neurodevelopment. The different
ranges of concentrations for maternal vs. cord blood might also be
influencing the ability to find an inverted U shaped association
since BMn ranged from 9.8–50.3 mg/L and CMn ranged from 11.5–
106.6 mg/L.
Higher Mn blood levels might be a reflection of women’s
exposure to higher concentrations of Mn in air, water or food,
however all the women in our cohort lived in Mexico City
throughout the period of this study, therefore, although we do not
have a manganese exposure assessment, the potential for bias due
to difference in exposure is unlikely. The correlation between BMn
and depression scores was very small (Spearman 0.05) and not
statistically significant, so it is unlikely that depression could have
a direct association with maternal levels of Mn. Another possible
explanation for the difference in Mn blood concentrations might be
due to Mn regulation resulting from microbiome composition
(Dunlop et al., 2015)or other inherent characteristics (genetic or
epigenetic (Maccani et al., 2015)), which could result in a different
biliary excretion and GI absorption; these were unmeasured in our
study and if these mechanisms were also related to the neuro-
developmental processes, this could be a potential source of
confounding in our study.
Gestational depression often persists after childbirth, impairing
mother-child bonding and interfering with the role that mothers
normally perform in raising their children (Field, 2010). Depressive
symptoms in mothers can obstruct the establishment of an
affective connection with their newborns, which is a major
contributing factor to child neurodevelopment (Koutra et al.,
2013). Although we did not explore postnatal depression in this
study, when looking at the receptive and expressive language
scores separately, we saw a difference in the association depending
on depressive symptoms only for receptive scores. A depressed
mother likely speaks less to her child, providing less support for the
Please cite this article in press as: T.V. Muñoz-Rocha, et al., Prenatal co-exposure to manganese and depression and 24-months
neurodevelopment, Neurotoxicology (2017), http://dx.doi.org/10.1016/j.neuro.2017.07.007
Language Motor
p b (SE) p
0.48 (.20) 0.01 0.36 (.19) 0.06
0.004 (.00) 0.01 0.003 (0.0) 0.08
.781 (.28) <0.01 .28 (.31) 0.38
0.007 (.00) <0.01 0.003 (0.0) 0.45
<0.01 0.38
<0.01 0.45
child’s development of language skills. Less verbal input and
interaction might have less impact on a child’s motor and cognitive
development (Stein et al., 2008; Tse et al., 2010).
The results from our secondary analysis using quartiles of EDS
in adjusted models, supported the associations found with the 13
point cut-off. In fact, when comparing the 4th to the 1st quartile of
EDS, the associations with the different cognitive, language and
motor scores the associations increased in magnitude and
improved statistical significance. All other associations were not
statistically significant with exception of the CMn associations for
cognitive and motor scores comparing the 2nd to the 1st EDS
quartiles which also showed a decrease in the scores.
Our study has several strengths: it is longitudinal in design,
with data from the PROGRESS birth cohort which includes
biomarkers as well as psychosocial measures from prenatal stages
and follow-up of mother-infant pairs. Another strength of our work
was the use of multivariate multiple regression models, which
allowed analysis of the three neurodevelopment scores simulta-
neously.
The reduced analytic sample due to missing data on cord
blood is a limitation of our study. Missing information on the
HOME evaluation also limited our ability to adjust for this
covariate, however our results remained without its inclusion in
analyses.
5. Conclusions
More in-depth research is now required to determine whether
Mn toxicity increases among children of depressed mothers. Our
findings highlight the importance of understanding the effects of
co-exposure to these conditions, particularly during sensitive
development stages.
Prenatal care is important because of its basic contribution to
adequate neurodevelopment in the offspring. Over a quarter of our
study participants had depressive symptoms in pregnancy; this
highlights a need for special attention must be paid to the
emotional state of the expectant mother, alongside the nutrients
she requires to ensure a stable pregnancy without complications or
deficiencies.
It is important for decision makers to promote strategies aimed
specifically at preventing, detecting and treating maternal
depression across perinatal public health services in Mexico.
Public policy also needs to address the growing evidence of
environmental Mn toxicity and the irreversible short- and long-
term effects of intrauterine exposure, particularly on neuro
development.
Funding sources
This work was supported by NIH grants R01ES013744,
R01ES014930, R01ES021357 and P30ES023515. It was also
supported and partially funded by the National Institute of Public
Health/Ministry of Health of Mexico.
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Competing financial interest’s declaration
All authors have no actual or potential competing interests
regarding the submitted article and the nature of those interests.
Acknowledgements
We thank the Centro Médico ABC and the National Institute of
Perinatology, México for their support with this research. Authors
from INSP are members of the Mexican Network for Children’s
Environmental Health.
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