Biological

Psychiatry:
GOS Archival Report

Early-Life Critical Windows of Susceptibility to

Manganese Exposure and Sex-Specific Changes
in Brain Connectivity in Late Adolescence
Elza Rechtman, Esmeralda Navarro, Erik de Water, Cheuk Y. Tang, Paul Curtin,
Demetrios M. Papazaharias, Claudia Ambrosi, Lorella Mascaro, Giuseppa Cagna,
Roberto Gasparotti, Azzurra Invernizzi, Abraham Reichenberg, Christine Austin, Manish Arora,
Donald R. Smith, Roberto G. Lucchini, Robert O. Wright, Donatella Placidi, and
Megan K. Horton

ABSTRACT
BACKGROUND: Early-life environmental exposures during critical windows (CWs) of development can impact life
course health. Exposure to neuroactive metals such as manganese (Mn) during prenatal and early postnatal CWs may
disrupt typical brain development, leading to persistent behavioral changes. Males and females may be differentially
vulnerable to Mn, presenting distinctive CWs to Mn exposure.
METHODS: We used magnetic resonance imaging to investigate sex-specific associations between early-life Mn
uptake and intrinsic functional connectivity in adolescence. A total of 71 participants (15–23 years old; 53%
female) from the Public Health Impact of Manganese Exposure study completed a resting-state functional
magnetic resonance imaging scan. We estimated dentine Mn concentrations at prenatal, postnatal, and early
childhood periods using laser ablation–inductively coupled plasma–mass spectrometry. We performed seed-based
correlation analyses to investigate the moderating effect of sex on the associations between Mn and intrinsic
functional connectivity adjusting for age and socioeconomic status.
RESULTS: We identified significant sex-specific associations between dentine Mn at all time points and intrinsic
functional connectivity in brain regions involved in cognitive and motor function: 1) prenatal: dorsal striatum,
occipital/frontal lobes, and middle frontal gyrus; 2) postnatal: right putamen and cerebellum; and 3) early
childhood: putamen and occipital, frontal, and temporal lobes. Network associations differed depending on
exposure timing, suggesting that different brain networks may present distinctive CWs to Mn.
CONCLUSIONS: These findings suggest that the developing brain is vulnerable to Mn exposure, with effects lasting
through late adolescence, and that females and males are not equally vulnerable to these effects. Future studies
should investigate cognitive and motor outcomes related to these associations.
https://doi.org/10.1016/j.bpsgos.2022.03.016

The Developmental Origins of Health and Disease theory in which the phenotype/outcome is measured plays an
postulates that early-life environmental influences can result important role in estimating the impact of exposure (1,6). The
in long-lasting effects on health (1). Indeed, exposure to extended period of brain development, spanning the third
toxicants during critical windows (CWs) of development has gestational week through late adolescence, gives rise to
been shown to alter tissue-specific plasticity by interfering many CWs of vulnerability to toxic chemicals across devel-
with maturational processes, leading to functional changes in opment (e.g., prenatal, early postnatal, and childhood pe-
various organ systems throughout the life course (2). Such riods) (7). Extensive evidence suggests that the effects of
CWs result from gene-environment interactions, giving rise environmental exposure on neurodevelopment may depend
to sensitive periods during development in which the for- as much on the exposure timing as on the concentration
mation of a phenotype is responsive to external factors (3). (8,9). A better understanding of CWs of vulnerability to
These changes may increase susceptibility to disease and developmental neurotoxicants and the biological mecha-
dysfunction later in life (4,5). This reprogramming process nisms underlying these associations would inform our un-
depends on 1) the sensitivity of a specific tissue to the derstanding of typically developmental trajectories as well as
chemical and 2) a temporal overlap between exposure and inform prevention and treatment strategies for reducing
the tissue’s CW of development. In addition, the time window adverse environmentally associated brain outcomes.

460 ª 2022 THE AUTHORS. Published by Elsevier Inc on behalf of the Society of Biological Psychiatry. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Biological Psychiatry: Global Open Science July 2023; 3:460–469 www.sobp.org/GOS ISSN: 2667-1743
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Manganese Exposure and Adolescence Brain Connectivity GOS

Magnetic resonance imaging (MRI) provides insight into neurocognition have been previously reported in this cohort
biological mechanisms underlying human cognition and (32,41). Based on previous studies suggesting associations
behavior. Applied to studies of environmental epidemiology, between early-life Mn exposure and changes in brain areas
MRI offers the possibility of linking exposure with changes in implicated in motor and cognitive control (42–46), we hy-
the brain. Specifically, resting-state functional MRI (rs-fMRI) pothesized that early-life exposure to Mn will have down-
can be used to map large-scale functional networks in the stream impacts on brain functional connectivity in the basal
human brain by examining slow (,1 Hz) oscillatory intrinsic ganglia, prefrontal cortex, parietal cortex, and motor cortex
fluctuations in hemodynamics (10), with the assumption that and that these effects will be different in females compared
regions with correlated activity form functional networks. with males.
Changes in brain functional connectivity have been reported in
various neurodevelopmental disorders (11). rs-fMRI is partic-
METHODS AND MATERIALS
ularly suited to benefit pediatric research because it is inher-
ently noninvasive and does not require cooperation or Participants
motivation, minimizing many confounders related to task per-
Participants were part of the ongoing Public Health Impact of
formance and increasing consistency across participants and
datasets (12). Incorporating rs-fMRI into children’s environ- Metal Exposure (PHIME) cohort based in the province of
Brescia in Northern Italy. Details of the study recruitment and
mental health studies allows us to examine the in vivo impacts
of environmental exposures on the developing brain’s func- enrollment have been described previously (19). Briefly, par-
ticipants were enrolled in the study using a community-based
tional organization (13).
Throughout development, the brain undergoes a complex participatory approach from schools throughout the local
public school system in Northern Italy. Schools are located in 3
series of dynamic processes in which few cells develop into a
highly interconnected brain (7,14). Environmental exposure to geographically different but demographically similar commu-
nities in the province of Brescia, characterized by the presence
neuroactive metals such as manganese (Mn) during specific
CWs of brain development may disrupt typical development of ferroalloy plants causing Mn exposure through airborne
emission. All participants completed baseline questionnaires
and functioning, leading to persistent behavioral and cognitive
changes (14,15). The general population can be exposed to Mn to evaluate inclusion and exclusion criteria. Inclusion criteria
included birth in the study area of interest, residence in the
through inhalation, dietary intake, and drinking of contami-
nated water (16–18). Human activities such as ferroalloy in- study area since birth, and family residence in the study area
since the 1970s. Exclusion criteria included known neurologic,
dustries may expose children and pregnant women residing in
adjacent areas to higher levels of Mn (19). Mn can cross the hepatic, metabolic, endocrine, or major psychiatric disorder;
medication usage with known neuropsychological side effects;
placental and blood-brain barriers and lead to changes in the
brain (20). Mn levels outside of the homeostatic range (i.e., clinically diagnosed motor deficits or cognitive impairment;
and visual deficits that are not adequately corrected. A total of
deficiency or intoxication) alter neuron function (21,22), in-
crease oxidative stress (23), accumulate in the basal ganglia 720 adolescents were enrolled in the Public Health Impact of
Metal Exposure cohort between 2007 and 2014. At the time of
(21–23), and adversely affect cognitive and behavioral out-
enrollment, participants were asked to provide a naturally shed
comes including IQ (24,25), motor function (19,26,27), and
hyperactivity (28,29). While CWs to Mn have been identified deciduous tooth. Between 2015 and 2020, 207 subjects (age
16–23 years) participated in a multimodal MRI follow-up study
during gestation, infancy, early childhood, and adolescence
(8,9,30,31), the brain mechanism underlying its neurotoxicity and completed baseline questionnaires, including information
on parental educational and occupational levels, and neuro-
remains largely unknown. Further, animal and human studies
demonstrate sex-specific associations between Mn exposure psychological tests, including IQ using the Wechsler Intelli-
gence Scale for Children-III assessment (47). Between 2015
and behavioral outcomes (26,32–34), suggesting that males
and females may present distinctive CWs to Mn exposure and and 2016, a convenience sample of teeth from 195 (27%)
participants were analyzed for early-life Mn. From this sample,
may be differentially vulnerable to its effects. Sex-specific
vulnerability may relate to the brain’s sexually dimorphic MRI scans were acquired for 73 subjects. Complete exposure
data (i.e., dentine Mn), outcome (MRI data), and covariate data
developmental trajectory, beginning in utero (35–37). Sex dif-
ferences in developmental trajectories may emerge from were available for the 73 adolescents (38 females) included in
this analysis. After excluding 2 participants due to movement
endogenous developmental programming, developmental
experience, or other environmental exposures (38–40). Sex- in the scanner, Mn uptake, MRI scans, and covariate data were
available for 71 adolescents (38 females). This study was
specific CWs may explain sex differences in the prevalence,
severity, and progression of neurodevelopmental disorders. approved by the Institutional Review Board of the Icahn School
of Medicine at Mount Sinai and the Public Health Agency of
Understanding the impact of both timing and concentration of
Mn exposure on brain functional connectivity may provide Brescia. Written informed consent was obtained from all
participants.
mechanistic insights into sex differences in Mn-associated
neurotoxicity.
In this study, we used rs-fMRI to investigate sex-specific Dentine Mn Biomarker
associations between prenatal, early postnatal, and child- To identify early-life CWs of vulnerability to Mn, we used de-
hood Mn exposure, measured in deciduous teeth, and brain ciduous teeth as a biomarker of retrospective exposure.
intrinsic functional connectivity (iFC) in older adolescents. Because deciduous teeth accumulate metals in a pattern
Notably, sex differences in associations between Mn and similar to the growth rings of a tree, they can provide estimates

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of both the timing and intensity of exposure, allowing us to correction (57), outlier identification (volumes exceeding .0.9
detect when exposure is most hazardous (48). Only incisors, mm framewise displacement or global blood oxygen level–
canines, and molars that were free of defects such as caries dependent signal changes above 5 SD), direct segmentation
and extensive tooth wear, were analyzed. Detailed analytic and normalization [images were normalized into standard
methods have been described previously (48–50). Briefly, teeth Montreal Neurological Institute space and segmented into gray
were washed in an ultrasonic bath of ultrapure Milli-Q water matter, white matter, and cerebral spinal fluid tissue classes
(18.2 MU/cm) and sectioned on a vertical, labial-lingual, or using SPM12 unified segmentation and normalization pro-
buccal-lingual plane using a diamond-encrusted blade. The cedure (58)], and functional smoothing (images were smoothed
neonatal line, which histologically distinguishes pre- and using spatial convolution with a Gaussian kernel of 8 mm full
postnatally formed regions of dentine, was identified using width at half maximum). After preprocessing, we applied
light microscopy. With the neonatal line as a reference point, CONN’s default denoising pipeline composed of linear
the concentrations and spatial distribution of Mn in different regression of confounding effects and temporal bandpass
developmental windows were determined using laser ablation– filtering. White matter and cerebral spinal fluid noise were
inductively coupled plasma–mass spectrometry. Dentine Mn estimated and regressed out using an anatomical component-
concentrations were normalized to dentine calcium levels based noise correction procedure (59). To reduce motion ar-
(55Mn:43Ca ratio) to account for variations in mineral density tifacts, we included 12 noise parameters as nuisance re-
within and between teeth. A total of 30 sampling points were gressors (3 translation and 3 rotation parameters and their
ablated parallel to the enamel-dentine junction and assigned to associated first-order derivatives) at the single-subject level.
pre- or postnatal zones after identifying the neonatal line. Area Temporal frequencies were filtered to 0.01 to w0.09 Hz to
under the curve was used to account for the different number focus on low-frequency fluctuations while minimizing the in-
of sampling points in each zone per tooth. Childhood cumu- fluence of physiological, head motion, and other noise sour-
lative Mn concentrations (1 to w6 years of age) were deter- ces. These noise and motion confounders were regressed out
mined by averaging across 10 sampling locations within in the lower-level multiple regression analyses for each
secondary dentine, the formation of which starts after the participant before any group-level analyses were carried out.
completion of the tooth root and proceeds at a slower rate. The
limit of detection was 0.02 mg/g. Only one dentine measure- Seed-Based Correlation Analyses
ment fell below the detection limit (n = 1) and was assigned half
Seed-based analyses were performed using the CONN
the lowest value among the samples above the detection limit.
toolbox by computing the temporal correlation between the
blood oxygen level–dependent signals from regions of interest
Covariates to all other voxels in the brain. Based on previous pilot results
Given that age and socioeconomic status (SES) may impact by our group (43), we selected 7 seeds from the probabilistic
iFC (51,52) and associations between Mn exposure and neu- Harvard-Oxford Subcortical Structural Atlas (60): left and right
rodevelopment (53), we included these variables as covariates putamen, left and right caudate, left and right pallidum, and
in the analyses. SES index (low, medium, high) was determined bilateral middle frontal gyrus. Group-level analyses were per-
using parental educational and occupational levels (54). formed using the general linear model implemented in the
CONN toolbox with natural log-transformed Mn concentra-
MRI Data Acquisition tions at each time point as predictors and iFC as the outcome.
The MRI scan was performed on a 3T MR unit (Skyra, Siemens) Given that Mn concentrations were moderately correlated
equipped with a 64-channel phased array head coil at the across 2 of the 3 time points (r values = 0.03–0.42), we per-
Neuroimaging Division at the ASST Spedali Civili Hospital of formed separate analyses for each of the 3 time points. To
Brescia. The 10-minute rs-fMRI scans were acquired using a investigate the moderating effect of sex on the associations
T2*-weighted echo-planar imaging sequence (repetition time = between dentine Mn and iFC, we examined interactions be-
1000 ms, echo time = 27 ms, 70 axial slices, 2.1-mm thickness, tween sex and Mn adjusting for age and SES. Statistical im-
matrix size 108 3 108, covering the brain from vertex to cer- ages were thresholded using a cluster-corrected threshold of p
ebellum). During this acquisition, lights were turned off and , .05 false discovery rate correction (44,61–63). To control for
subjects were instructed to keep their eyes open and stare at a the number of comparisons (n = 21; 7 seed regions 3 3 Mn
night skyline picture projected on the monitor, to not think of time points), we applied a secondary false discovery rate
anything specific, and to not fall asleep. For registration pur- correction and only report findings surviving both false dis-
poses, we acquired a high-resolution anatomical T1-weighted covery rate corrections. Finally, in a sensitivity analysis, we
scan using three-dimensional magnetization-prepared rapid investigated sex-stratified associations between dentine Mn
gradient echo (repetition time = 2400 ms, echo time = 2.06 ms, and iFC in regions found to have a significant interaction term.
230 mm field of view, matrix size 256 3 256, 224 sagittal slices, Stratified models were implemented in R (version 3.5.1) with
0.9 mm3 voxel size). the glm package.

rs-fMRI Data Preprocessing RESULTS

rs-fMRI data were preprocessed using the Functional Con-
nectivity (CONN) toolbox (http://web.mit.edu/swg/software. Descriptive Statistics
htm) following the standard CONN preprocessing pipeline Participant demographics are presented in Table 1. Among the
(55): functional realignment and unwarp (56), slice-timing 71 participants (38 [54%] female), the mean age of participants

462 Biological Psychiatry: Global Open Science July 2023; 3:460–469 www.sobp.org/GOS
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Table 1. Sex-Stratified Sociodemographic Characteristics of 71 Adolescents From Northern Italy

Sociodemographic Characteristics Female, n = 38 Male, n = 33 Total, N = 71
Age, Years
Mean (SD) 19.7 (2.08) 19.1 (2.36) 19.4 (2.22)
Median [min, max] 19.7 [15.9, 23.1] 19.1 [15.9, 23.4] 19.4 [15.9, 23.4]
IQ
Mean (SD) 103 (10.7) 106 (9.25) 104 (10.1)
Median [min, max] 105 [78, 117] 105 [77, 121] 105 [77, 121]
SES, n (%)
Low 5 (13.2%) 2 (6.1%) 7 (9.9%)
Medium 25 (65.8%) 23 (69.7%) 48 (67.6%)
High 8 (21.1%) 8 (24.2%) 16 (22.5%)
Site, n (%)
BM 13 (34.2%) 18 (54.5%) 31 (43.7%)
GL 13 (34.2%) 6 (18.2%) 19 (26.8%)
VC 12 (31.6%) 9 (27.3%) 21 (29.6%)
Prenatal Mn
Mean (SD) 0.433 (0.165) 0.471 (0.192) 0.451 (0.178)
Median [min, max] 0.417 [0.168, 1.14] 0.470 [0.148, 0.869] 0.427 [0.148, 1.14]
Postnatal Mn
Mean (SD) 0.137 (0.0477) 0.119 (0.0555) 0.129 (0.0519)
Median [min, max] 0.125 [0.0486, 0.256] 0.121 [0, 0.238] 0.124 [0, 0.256]
Childhood Mn
Mean (SD) 0.000821 (0.000422) 0.000818 (0.000447) 0.000820 (0.000431)
Median [min, max] 0.000720 [0.000328, 0.00267] 0.000757 [0, 0.00208] 0.000727 [0, 0.00267]
IQ was measured using the Wechsler Intelligence Scale for Children, 3rd edition (47). Sociodemographic characteristics did not differ between
males and females (p . .05).
BM, Bagnolo Mella; GL, Garde Lake; max, maximum; min, minimum; Mn, manganese; SES, socioeconomic status; VC, Valcamonica.

was 19.4 years (SD = 2.2 years). The average IQ score of right putamen and the right cerebellum, with decreased iFC in
participants was 104 (SD = 10.1). The majority of participants females and increased iFC in males. Exposure to Mn during the
were from families reporting medium SES (66%). Dentine Mn early childhood period (1 to w6 years) showed sex-specific
was log-transformed to reduce skewness and approximate a effects on iFC between 1) the left putamen and the right su-
normal distribution. There were no statistically significant dif- perior division of the lateral occipital cortex and 2) the middle
ferences found in dentine Mn, age at scan, IQ, and SES be- frontal gyrus and the left posterior division of the middle tem-
tween male and female participants. Dentine Mn poral gyrus. In both connections, increased Mn exposure was
concentrations in each time point, stratified by sex, are pre- associated with increased iFC in females and decreased iFC in
sented in Figure 1. males.

Seed-Based Correlation Analyses of Sex-Specific DISCUSSION

Associations In this study, we sought to test our Developmental Origins of
For all time points, the seed-based correlation analyses Health and Disease–based hypothesis that Mn uptake during
revealed sex-specific associations between dentine Mn and early-life CWs of development is associated with changes in
iFC (Table 2, Figure 2). Seed-to-region connectivity and peak functional connectivity in adolescence, and that environmen-
coordinates in Montreal Neurological Institute space for tally associated brain changes are sex specific. Using an
models showing significant interactions between dentine Mn objective, retrospective biomarker of Mn uptake during pre-
and sex are reported in Table 2. We observed sex-specific natal, early postnatal, and childhood periods and rs-fMRI in
associations between prenatal dentine Mn and iFC in the adolescence, we found significant sex-specific associations
following connections: 1) left caudate and left occipital pole, 2) between dentine Mn at all time points and iFC in adolescents.
left putamen and left middle frontal gyrus, 3) left putamen and Moreover, we report associations in different networks
left occipital fusiform gyrus, and 4) middle frontal gyrus and depending on the timing of exposure, suggesting that different
right occipital pole. Sex-stratified analyses showed that in brain networks may present distinctive CWs of vulnerability to
connections 1 and 3, prenatal Mn exposure was associated Mn. During the prenatal period, we observed sex-specific as-
with increased iFC in females and decreased iFC in males, sociations between dentine Mn and functional connectivity
whereas connections 2 and 4 show an inverse pattern between the dorsal striatum (caudate and putamen) and re-
(Table S1). Mn uptake during the early postnatal period (,1 gions in the occipital and frontal lobes and between the middle
year of age) showed sex-specific effects on iFC between the frontal gyrus and the occipital lobe. During the early postnatal

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in magnitude and directionality between females and males.

Four connections showed increased iFC in females and
decrease in males, whereas 3 connections showed a reverse
pattern. These sex-specific effects may not be attributed to
sex differences in exposure or absorption of Mn, because we
report similar Mn uptake levels between males and females.
Despite the proximity of study participants to active ferroalloy
smelting activity, dentine Mn levels measured in this study are
comparable to previously reported levels in other populations
and are not suggestive of exceptionally heightened exposure
(28,43,64,65). This study contributes to the growing literature
suggesting that early-life Mn uptake impacts neuro-
developmental outcomes by providing mechanistic insights
into the brain regions underlying these associations. Using our
dentine biomarker to provide a retrospective marker of Mn
uptake in 3 developmental stages, we identified 3 CWs of
vulnerability to this neuroactive metal. Finally, our findings of
sex-specific associations support our hypothesis that the ef-
fect of early-life exposure to Mn differs by sex.
MRI allows in vivo visualization of the brain. It is noninvasive
and free of ionizing radiation, making it suitable for research in
children. In the field of environmental epidemiology, MRI plays
a critical role in elucidating biological mechanisms underlying
Mn neurotoxicity. Until recently, the use of brain imaging in
environmental health studies of Mn neurotoxicity has focused
on structural brain abnormalities, primarily in the basal ganglia,
and mostly targeted highly exposed workers (66,67).
Numerous structural basal ganglia abnormalities have been
reported in workers exposed to Mn, including T1 hyper-
intensities (68–71), lower apparent diffusion coefficient (68),
higher pallidal index (72,73), and lower fractional anisotropy
Figure 1. Prenatal, postnatal, and early childhood manganese (Mn) (74–76). Only 2 occupational MRI studies have investigated
concentrations (log) measured in naturally shed deciduous teeth of 71 study functional brain changes related to Mn exposure (77,78).
participants by sex. The density curve represents the relative frequency of all Chang et al. (77) showed Mn-induced alterations in brain ac-
observations, such that the area underneath it is exactly 1. Dentine Mn did tivity during a working memory task, with higher activation in
not differ between males and females (logistic regression adjusted for so-
cioeconomic status and age, p . .05). Ca, calcium.
the basal ganglia (i.e., including the putamen) in exposed
welders. Seo et al. (78) showed decreased activation of the
frontal, parietal, and insular cortices in welders during an ex-
period (,1 year), dentine Mn was associated with sex-specific ecutive function task. Our findings are consistent with prior
changes in the right putamen and the cerebellum. Finally, structural and functional MRI studies, because we detect ef-
during the early childhood period (1 to w6 years), exposure to fects in the caudate and putamen, which are central compo-
Mn showed sex-specific effects on iFC between the putamen nents of the basal ganglia. This study builds on the previous
and the occipital lobe and between the frontal and temporal literature by adding 1) a focus on lower nonoccupational ex-
lobes. Our results highlight that the effect of Mn on iFC differs posures in children, 2) longitudinal retrospective measures of

Table 2. Results From Seed-Based Correlation Analysis Demonstrating Significant Sex-Specific Associations Between
Dentine Mn at Three Time Points and Intrinsic Functional Connectivity in Adolescents
Exposure Time Point Seed-to-Region Connectivity Cluster (x, y, z) Cluster Size b p-FDR
Prenatal Left caudate—left occipital pole (204, 290, 108) 223 0.67 ,.001
Left putamen—left middle frontal gyrus (230, 126, 142) 64 20.71 .014
Left putamen—left occipital fusiform gyrus (228, 278, 216) 60 0.67 .014
Middle frontal gyrus—right occipital pole (114, 298, 112) 99 20.92 .003
Postnatal Right putamen—right cerebellum (142, 268, 254) 74 20.70 .009
Early Childhood Left putamen—lateral occipital cortex, right superior division (112, 252, 158) 90 0.64 .003
Middle frontal gyrus—middle temporal gyrus, left posterior division (250, 222, 204) 138 0.74 .002
All models controlled for age (years) and SES. Voxel threshold p , .001 (uncorrected); cluster threshold p , .05 (p-FDR corrected). Coordinates
presented are in MNI space. All coefficients refer to sex-Mn interaction term.
FDR, false discovery rate; Mn, manganese; MNI, Montreal Neurological Institute; SES, socioeconomic status.

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Figure 2. Sex-specific correlations between intrinsic functional connectivity (iFC) in adolescents and natural log-transformed dentine manganese (Mn) from
3 time points: (A) prenatal, (B) postnatal, and (C) childhood (N = 71). Brain regions are color-coded: left caudate, red; right putamen, blue; left putamen, pink;
middle frontal gyrus, green; left occipital pole, purple; left middle frontal gyrus left, yellow; left occipital fusiform gyrus, teal; right occipital pole, orange;
cerebellum, black; lateral occipital cortex, light pink; middle temporal gyrus, brown. Graphs plot regression lines and standard errors for females (green) and
males (orange). Only significant interactions (p , .05) between dentine Mn and sex are shown. Regions are color-coded for visualization purposes. Exact
cluster locations in Montreal Neurological Institute coordinates and cluster sizes are reported in Table 2.

Mn uptake allowing the detection CWs of susceptibility, 3) model of basal ganglia function in adults, the striatum is the
direct and objective measurement of Mn concentrations main entry point of cortical information to the basal ganglia; it
instead of self-reported exposure history, and 4) analyses of receives afferents from widespread areas of the cerebral cortex
sex-specific effects. through the thalamus (i.e., corticobasal ganglia–
Substantial research demonstrates associations between thalamocortical loops) (81,82). These circuits are crucial for
early-life Mn exposure and adverse neurodevelopmental out- emotional, cognitive, and motor functions (83–87). The
comes (9,28,79,80). In a recent pilot study, de Water et al. (43) caudate and putamen are involved in the planning and
reported associations between postnatal Mn dentine concen- execution of movement, learning, memory, and reward
trations and iFC in areas of the brain implicated in cognitive (88–90). Mn dyshomeostasis may disrupt the corticobasal
control and motor function. In this study, we built on this pilot ganglia circuitry, because Mn is known to accumulate in basal
work to explore sex-specific vulnerabilities to the effect of ganglia structures (42,91). Increased caudate connectivity (92),
early-life Mn exposure on iFC. Our findings indicate that Mn putamen dysfunction (93), and increased putamen–cerebellum
exposure is differently associated with functional connectivity connectivity (94) have been observed among adults diagnosed
in males and females in brain regions involved in cognitive with Parkinsonism. Mn-exposed occupational workers
control and motor function. Mn concentrations were associ- demonstrate clinical symptoms mirroring Parkinson disease
ated with sex-specific effects on iFC between regions of the (95). Middle frontal gyrus and middle temporal gyrus connec-
basal ganglia (striatum or caudate–putamen) and cortical re- tivity have also been associated with cognitive and executive
gions (occipital and frontal). function, specifically literacy and numeracy abilities (96,97),
The cortical–subcortical connections impacted by Mn with increased connectivity in the middle frontal gyrus within
exposure in our study are known to be associated with the occipital pole network reported among children with autism
neurologic health outcomes in adults. According to the current spectrum disorder (98). Little is known about the dynamic

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development of these circuits during childhood. Given the adolescence. We acknowledge several limitations to our
known vulnerability of these circuits to perturbation during research. The modest sample size of this study limits the
development, our study adds to the literature by relating Mn generalization of our findings. Exclusion criteria such as diag-
exposure to alterations in typical neurodevelopment of nosis of neurologic or psychiatric disorders could potentially
subcortical–cortical connections. exclude participants with the highest levels of Mn exposure.
Our novel approach combining neuroimaging in late The exact age at which teeth were shed was not documented
adolescence with the use of deciduous teeth as a retrospective in this study. However, because the age of shedding is not
biomarker of early-life Mn uptake allows us to test our Devel- expected to be related to MRI data, any resulting bias would
opmental Origins of Health and Disease–based hypothesis. likely be toward the null. Pubertal stage data were not
Traditional biomarkers of Mn exposure (e.g., urine, blood, hair) collected, which could potentially be considered as a covari-
used in prior studies are unable to directly measure exposure ate. Moreover, because the interpretation of the directionality of
in fetal life. Further, traditional biomarkers fail to provide lon- our observed associations is challenging, future studies with a
gitudinal exposure spanning several potential CWs of devel- larger sample size should include cognitive and motor outcomes
opment including the fetal, postnatal, and childhood periods. to test whether Mn-associated changes in iFC are associated with
There is a lack of consensus regarding the appropriate increased or decreased performance. Finally, children and ado-
biomarker to assess Mn-associated impacts on the developing lescents are rarely exposed to Mn alone and, in most cases, are
brain because each biomarker reflects differences in pharma- exposed to low levels of several metals simultaneously. Coex-
cokinetics, and therefore, associated health effects may be posure to multiple metals may influence Mn toxicity (105,106).
matrix dependent. Instead, dentine Mn is a validated biomarker Thus, future studies should explore associations between early-
providing a direct measure of Mn across prenatal and post- life exposure to mixtures of metals and iFC later in life.
natal periods, which enabled us to detect CWs for effects of In conclusion, we identified sex-specific CWs of suscepti-
Mn exposure on iFC of the brain. Results from a recent study in bility to Mn exposure on iFC in areas of the brain implicated in
the same cohort, using the dentine biomarker to study asso- cognitive and motor function. These findings suggest that the
ciations between Mn and neurocognition, suggest a subtle developing brain is especially vulnerable to Mn exposure, with
shift over time from a beneficial role of Mn during the prenatal effects lasting at least through late adolescence and possibly
period to a more detrimental role in childhood (41). Our unique later. More research into identifying CWs of development that
study design is able to provide detailed insights into the neural are sensitive to environmental insults will improve public health
mechanisms that may underpin these associations between and risk management and may help identify especially sus-
early-life Mn exposure and cognitive and motor control re- ceptible subgroups for interventions and methods to optimize
ported in prior studies (26,28,32,41,99). Mn exposure. Future research is needed to link sex-specific
Very few previous investigations have explored sex-specific neural correlates with their behavioral and cognitive outcomes.
effects of early-life Mn on neurodevelopmental outcomes, and
although most of them detect a difference in vulnerabilities by
ACKNOWLEDGMENTS AND DISCLOSURES
sex, the direction of reported associations is inconsistent. Early-
Funding was provided by the National Institute of Environmental Health
life Mn has been positively associated with improved cognition
Sciences (Grant Nos. R01 ES019222 and P30ES023515).
and motor outcomes among females compared with males The authors report no biomedical financial interests or potential conflicts
(26,100). Contrastingly, other groups have found a negative as- of interest.
sociation between Mn concentrations and nonverbal perfor-
mance, motor outcomes, visuospatial learning, and IQ scores
among females (28,32,79,99). Discrepancies in direction of as- ARTICLE INFORMATION
sociation may be due to differences in the task used to assess From the Departments of Environmental Medicine and Public Health (ER,
behavior, type of biomarker used to assess exposure, and timing EN, PC, DMP, AI, AR, CA, MA, RGL, ROW, MKH), Diagnostic, Molecular,
and Interventional Radiology (CYT), and Psychiatry (AR), Icahn School of
of exposure and/or outcome assessment. Our results are in line Medicine at Mount Sinai, New York, New York; Department of Psychiatry &
with previous studies, suggesting that male and female neuro- Behavioral Sciences (EdW), University of Minnesota, Minneapolis, Minne-
development is not equally vulnerable to the effect of Mn sota; ASST Spedali Civili Hospital (CA, LM); Department of Medical and
exposure, and the direction of effect varies not only in magnitude Surgical Specialties (GC, RG, RGL, DP), Radiological Sciences and Public
but also in direction. Notably, unlike assessments of cognition Health, University of Brescia, Brescia, Italy; Department of Microbiology and
and motor function, interpretation of directional changes in iFC is Environmental Toxicology (DRS), University of California Santa Cruz, Santa
Cruz, California; and the Department of Environmental Health Sciences
challenging. Increased functional connectivity does not neces- (RGL), Robert Stempel College of Public Health and Social Work, Florida
sarily indicate better performance, as it has been associated with International University, Miami, Florida.
memory and cognitive impairments (101,102), anxiety (103), and ER and EN contributed equally to this work.
epilepsy (104), or may reflect a compensatory mechanism. Address correspondence to Elza Rechtman, Ph.D., at elza.rechtman@
Despite this limitation, our results add to the growing literature mssm.edu.
relating early-life Mn exposure with alterations in typical neuro- Received Oct 21, 2021; revised Mar 16, 2022; accepted Mar 20, 2022.
Supplementary material cited in this article is available online at https://
development and suggest that males and females are not doi.org/10.1016/j.bpsgos.2022.03.016.
equally vulnerable to Mn exposure, with effects persistent
throughout extended adolescence.
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