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Early-Life Critical Windows of Susceptibility to Manganese Exposure and Sex-Specific Changes in Brain Connectivity in Late Adolescence

Open AccessPublished:April 19, 2022DOI:https://doi.org/10.1016/j.bpsgos.2022.03.016

      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.

      Keywords

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      ). While CWs to Mn have been identified during gestation, infancy, early childhood, and adolescence (
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      Uncovering neurodevelopmental windows of susceptibility to manganese exposure using dentine microspatial analyses.
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      Dentine biomarkers of prenatal and early childhood exposure to manganese, zinc and lead and childhood behavior.
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      ), the brain mechanism underlying its neurotoxicity remains largely unknown. Further, animal and human studies demonstrate sex-specific associations between Mn exposure and behavioral outcomes (
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      In this study, we used rs-fMRI to investigate sex-specific associations between prenatal, early postnatal, and childhood Mn exposure, measured in deciduous teeth, and brain intrinsic functional connectivity (iFC) in older adolescents. Notably, sex differences in associations between Mn and neurocognition have been previously reported in this cohort (
      • Rechtman E.
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      Sex-specific associations between co-exposure to multiple metals and visuospatial learning in early adolescence.
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      ). Based on previous studies suggesting associations between early-life Mn exposure and changes in brain areas implicated in motor and cognitive control (
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      Early-life dentine manganese concentrations and intrinsic functional brain connectivity in adolescents: A pilot study.
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      Prenatal manganese exposure and intrinsic functional connectivity of emotional brain areas in children.
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      Neuroimaging identifies increased manganese deposition in infants receiving parenteral nutrition.
      ), we hypothesized that early-life exposure to Mn will have downstream impacts on brain functional connectivity in the basal ganglia, prefrontal cortex, parietal cortex, and motor cortex and that these effects will be different in females compared with males.

      Methods and Materials

      Participants

      Participants were part of the ongoing Public Health Impact of Metal Exposure (PHIME) cohort based in the province of Brescia in Northern Italy. Details of the study recruitment and enrollment have been described previously (
      • Lucchini R.G.
      • Guazzetti S.
      • Zoni S.
      • Donna F.
      • Peter S.
      • Zacco A.
      • et al.
      Tremor, olfactory and motor changes in Italian adolescents exposed to historical ferro-manganese emission.
      ). Briefly, participants were enrolled in the study using a community-based participatory approach from schools throughout the local public school system in Northern Italy. Schools are located in 3 geographically different but demographically similar communities in the province of Brescia, characterized by the presence of ferroalloy plants causing Mn exposure through airborne emission. All participants completed baseline questionnaires to evaluate inclusion and exclusion criteria. Inclusion criteria included birth in the study area of interest, residence in the study area since birth, and family residence in the study area since the 1970s. Exclusion criteria included known neurologic, hepatic, metabolic, endocrine, or major psychiatric disorder; medication usage with known neuropsychological side effects; clinically diagnosed motor deficits or cognitive impairment; and visual deficits that are not adequately corrected. A total of 720 adolescents were enrolled in the Public Health Impact of Metal Exposure cohort between 2007 and 2014. At the time of enrollment, participants were asked to provide a naturally shed deciduous tooth. Between 2015 and 2020, 207 subjects (age 16–23 years) participated in a multimodal MRI follow-up study and completed baseline questionnaires, including information on parental educational and occupational levels, and neuropsychological tests, including IQ using the Wechsler Intelligence Scale for Children-III assessment (
      • Woolger C.
      Wechsler Intelligence Scale for Children-Third Edition (WISC-III).
      ). Between 2015 and 2016, a convenience sample of teeth from 195 (27%) participants were analyzed for early-life Mn. From this sample, MRI scans were acquired for 73 subjects. Complete exposure data (i.e., dentine Mn), outcome (MRI data), and covariate data were available for the 73 adolescents (38 females) included in this analysis. After excluding 2 participants due to movement in the scanner, Mn uptake, MRI scans, and covariate data were available for 71 adolescents (38 females). This study was approved by the Institutional Review Board of the Icahn School of Medicine at Mount Sinai and the Public Health Agency of Brescia. Written informed consent was obtained from all participants.

      Dentine Mn Biomarker

      To identify early-life CWs of vulnerability to Mn, we used deciduous teeth as a biomarker of retrospective exposure. Because deciduous teeth accumulate metals in a pattern similar to the growth rings of a tree, they can provide estimates of both the timing and intensity of exposure, allowing us to detect when exposure is most hazardous (
      • Arora M.
      • Austin C.
      Teeth as a biomarker of past chemical exposure.
      ). Only incisors, canines, and molars that were free of defects such as caries and extensive tooth wear, were analyzed. Detailed analytic methods have been described previously (
      • Arora M.
      • Austin C.
      Teeth as a biomarker of past chemical exposure.
      ,
      • Arora M.
      • Hare D.
      • Austin C.
      • Smith D.R.
      • Doble P.
      Spatial distribution of manganese in enamel and coronal dentine of human primary teeth.
      ,
      • Arora M.
      • Bradman A.
      • Austin C.
      • Vedar M.
      • Holland N.
      • Eskenazi B.
      • Smith D.R.
      Determining fetal manganese exposure from mantle dentine of deciduous teeth.
      ). Briefly, teeth were washed in an ultrasonic bath of ultrapure Milli-Q water (18.2 MΩ/cm) and sectioned on a vertical, labial-lingual, or buccal-lingual plane using a diamond-encrusted blade. The neonatal line, which histologically distinguishes pre- and postnatally formed regions of dentine, was identified using light microscopy. With the neonatal line as a reference point, the concentrations and spatial distribution of Mn in different developmental windows were determined using laser ablation–inductively coupled plasma–mass spectrometry. Dentine Mn concentrations were normalized to dentine calcium levels (55Mn:43Ca ratio) to account for variations in mineral density within and between teeth. A total of 30 sampling points were ablated parallel to the enamel-dentine junction and assigned to pre- or postnatal zones after identifying the neonatal line. Area under the curve was used to account for the different number of sampling points in each zone per tooth. Childhood cumulative Mn concentrations (1 to ∼6 years of age) were determined by averaging across 10 sampling locations within secondary dentine, the formation of which starts after the completion of the tooth root and proceeds at a slower rate. The limit of detection was 0.02 μg/g. Only one dentine measurement fell below the detection limit (n = 1) and was assigned half the lowest value among the samples above the detection limit.

      Covariates

      Given that age and socioeconomic status (SES) may impact iFC (
      • Solé-Padullés C.
      • Castro-Fornieles J.
      • de la Serna E.
      • Calvo R.
      • Baeza I.
      • Moya J.
      • et al.
      Intrinsic connectivity networks from childhood to late adolescence: Effects of age and sex.
      ,
      • Tooley U.A.
      • Mackey A.P.
      • Ciric R.
      • Ruparel K.
      • Moore T.M.
      • Gur R.C.
      • et al.
      Associations between neighborhood SES and functional brain network development [published correction appears in Cereb Cortex 2021; 31:2307].
      ) and associations between Mn exposure and neurodevelopment (
      • Lucchini R.
      • Placidi D.
      • Cagna G.
      • Fedrighi C.
      • Oppini M.
      • Peli M.
      • Zoni S.
      Manganese and developmental neurotoxicity.
      ), we included these variables as covariates in the analyses. SES index (low, medium, high) was determined using parental educational and occupational levels (
      • Cesana G.C.
      • Ferrario M.
      • De Vito G.
      • Sega R.
      • Grieco A.
      [Evaluation of the socioeconomic status in epidemiological surveys: Hypotheses of research in the Brianza area MONICA project].
      ).

      MRI Data Acquisition

      The MRI scan was performed on a 3T MR unit (Skyra, Siemens) equipped with a 64-channel phased array head coil at the Neuroimaging Division at the ASST Spedali Civili Hospital of Brescia. The 10-minute rs-fMRI scans were acquired using a T2∗-weighted echo-planar imaging sequence (repetition time = 1000 ms, echo time = 27 ms, 70 axial slices, 2.1-mm thickness, matrix size 108 × 108, covering the brain from vertex to cerebellum). During this acquisition, lights were turned off and subjects were instructed to keep their eyes open and stare at a night skyline picture projected on the monitor, to not think of anything specific, and to not fall asleep. For registration purposes, we acquired a high-resolution anatomical T1-weighted scan using three-dimensional magnetization-prepared rapid gradient echo (repetition time = 2400 ms, echo time = 2.06 ms, 230 mm field of view, matrix size 256 × 256, 224 sagittal slices, 0.9 mm3 voxel size).

      rs-fMRI Data Preprocessing

      rs-fMRI data were preprocessed using the Functional Connectivity (CONN) toolbox (http://web.mit.edu/swg/software.htm) following the standard CONN preprocessing pipeline (
      • Nieto-Castanon A.
      Handbook of Functional Connectivity Magnetic Resonance Imaging Methods in CONN.
      ): functional realignment and unwarp (
      • Andersson J.L.
      • Hutton C.
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      • Turner R.
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      Modeling geometric deformations in EPI time series.
      ), slice-timing correction (
      • Henson R.
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      • Josephs O.
      • Friston K.J.
      The slice-timing problem in event-related fMRI.
      ), outlier identification (volumes exceeding >0.9 mm framewise displacement or global blood oxygen level–dependent signal changes above 5 SD), direct segmentation and normalization [images were normalized into standard Montreal Neurological Institute space and segmented into gray matter, white matter, and cerebral spinal fluid tissue classes using SPM12 unified segmentation and normalization procedure (
      • Ashburner J.
      • Friston K.J.
      Unified segmentation.
      )], and functional smoothing (images were smoothed using spatial convolution with a Gaussian kernel of 8 mm full width at half maximum). After preprocessing, we applied CONN’s default denoising pipeline composed of linear regression of confounding effects and temporal bandpass filtering. White matter and cerebral spinal fluid noise were estimated and regressed out using an anatomical component-based noise correction procedure (
      • Behzadi Y.
      • Restom K.
      • Liau J.
      • Liu T.T.
      A component based noise correction method (CompCor) for BOLD and perfusion based fMRI.
      ). To reduce motion artifacts, we included 12 noise parameters as nuisance regressors (3 translation and 3 rotation parameters and their associated first-order derivatives) at the single-subject level. Temporal frequencies were filtered to 0.01 to ∼0.09 Hz to focus on low-frequency fluctuations while minimizing the influence of physiological, head motion, and other noise sources. These noise and motion confounders were regressed out in the lower-level multiple regression analyses for each participant before any group-level analyses were carried out.

      Seed-Based Correlation Analyses

      Seed-based analyses were performed using the CONN toolbox by computing the temporal correlation between the blood oxygen level–dependent signals from regions of interest to all other voxels in the brain. Based on previous pilot results by our group (
      • de Water E.
      • Papazaharias D.M.
      • Ambrosi C.
      • Mascaro L.
      • Iannilli E.
      • Gasparotti R.
      • et al.
      Early-life dentine manganese concentrations and intrinsic functional brain connectivity in adolescents: A pilot study.
      ), we selected 7 seeds from the probabilistic Harvard-Oxford Subcortical Structural Atlas (
      • Kennedy D.N.
      • Lange N.
      • Makris N.
      • Bates J.
      • Meyer J.
      • Caviness Jr., V.S.
      Gyri of the human neocortex: An MRI-based analysis of volume and variance.
      ): left and right putamen, left and right caudate, left and right pallidum, and bilateral middle frontal gyrus. Group-level analyses were performed using the general linear model implemented in the CONN toolbox with natural log-transformed Mn concentrations at each time point as predictors and iFC as the outcome. Given that Mn concentrations were moderately correlated across 2 of the 3 time points (r values = 0.03–0.42), we performed separate analyses for each of the 3 time points. To investigate the moderating effect of sex on the associations between dentine Mn and iFC, we examined interactions between sex and Mn adjusting for age and SES. Statistical images were thresholded using a cluster-corrected threshold of p < .05 false discovery rate correction (
      • de Water E.
      • Proal E.
      • Wang V.
      • Medina S.M.
      • Schnaas L.
      • Téllez-Rojo M.M.
      • et al.
      Prenatal manganese exposure and intrinsic functional connectivity of emotional brain areas in children.
      ,
      • Worsley K.J.
      Statistical analysis of activation images.
      ,
      • Shehzad Z.
      • Kelly A.M.C.
      • Reiss P.T.
      • Gee D.G.
      • Gotimer K.
      • Uddin L.Q.
      • et al.
      The resting brain: Unconstrained yet reliable.
      ,
      • van Duijvenvoorde A.C.K.
      • Achterberg M.
      • Braams B.R.
      • Peters S.
      • Crone E.A.
      Testing a dual-systems model of adolescent brain development using resting-state connectivity analyses.
      ). To control for the number of comparisons (n = 21; 7 seed regions × 3 Mn time points), we applied a secondary false discovery rate correction and only report findings surviving both false discovery rate corrections. Finally, in a sensitivity analysis, we investigated sex-stratified associations between dentine Mn and iFC in regions found to have a significant interaction term. Stratified models were implemented in R (version 3.5.1) with the glm package.

      Results

      Descriptive Statistics

      Participant demographics are presented in Table 1. Among the 71 participants (38 [54%] female), the mean age of participants was 19.4 years (SD = 2.2 years). The average IQ score of participants was 104 (SD = 10.1). The majority of participants were from families reporting medium SES (66%). Dentine Mn was log-transformed to reduce skewness and approximate a normal distribution. There were no statistically significant differences found in dentine Mn, age at scan, IQ, and SES between male and female participants. Dentine Mn concentrations in each time point, stratified by sex, are presented in Figure 1.
      Table 1Sex-Stratified Sociodemographic Characteristics of 71 Adolescents From Northern Italy
      Sociodemographic CharacteristicsFemale, n = 38Male, n = 33Total, 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 (%)
       Low5 (13.2%)2 (6.1%)7 (9.9%)
       Medium25 (65.8%)23 (69.7%)48 (67.6%)
       High8 (21.1%)8 (24.2%)16 (22.5%)
      Site, n (%)
       BM13 (34.2%)18 (54.5%)31 (43.7%)
       GL13 (34.2%)6 (18.2%)19 (26.8%)
       VC12 (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 (
      • Woolger C.
      Wechsler Intelligence Scale for Children-Third Edition (WISC-III).
      ). 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.
      Figure thumbnail gr1
      Figure 1Prenatal, postnatal, and early childhood manganese (Mn) concentrations (log) measured in naturally shed deciduous teeth of 71 study participants by sex. The density curve represents the relative frequency of all observations, such that the area underneath it is exactly 1. Dentine Mn did not differ between males and females (logistic regression adjusted for socioeconomic status and age, p > .05). Ca, calcium.

      Seed-Based Correlation Analyses of Sex-Specific Associations

      For all time points, the seed-based correlation analyses revealed sex-specific associations between dentine Mn and iFC (Table 2, Figure 2). Seed-to-region connectivity and peak coordinates in Montreal Neurological Institute space for models showing significant interactions between dentine Mn and sex are reported in Table 2. We observed sex-specific associations between prenatal dentine Mn and iFC in the following connections: 1) left caudate and left occipital pole, 2) left putamen and left middle frontal gyrus, 3) left putamen and left occipital fusiform gyrus, and 4) middle frontal gyrus and right occipital pole. Sex-stratified analyses showed that in connections 1 and 3, prenatal Mn exposure was associated with increased iFC in females and decreased iFC in males, whereas connections 2 and 4 show an inverse pattern (Table S1). Mn uptake during the early postnatal period (<1 year of age) showed sex-specific effects on iFC between the right putamen and the right cerebellum, with decreased iFC in females and increased iFC in males. Exposure to Mn during the early childhood period (1 to ∼6 years) showed sex-specific effects on iFC between 1) the left putamen and the right superior division of the lateral occipital cortex and 2) the middle frontal gyrus and the left posterior division of the middle temporal gyrus. In both connections, increased Mn exposure was associated with increased iFC in females and decreased iFC in males.
      Table 2Results 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 PointSeed-to-Region ConnectivityCluster (x, y, z)Cluster Sizeβp-FDR
      PrenatalLeft caudate—left occipital pole(−04, −90, +08)2230.67<.001
      Left putamen—left middle frontal gyrus(−30, +26, +42)64−0.71.014
      Left putamen—left occipital fusiform gyrus(−28, −78, −16)600.67.014
      Middle frontal gyrus—right occipital pole(+14, −98, +12)99−0.92.003
      PostnatalRight putamen—right cerebellum(+42, −68, −54)74−0.70.009
      Early ChildhoodLeft putamen—lateral occipital cortex, right superior division(+12, −52, +58)900.64.003
      Middle frontal gyrus—middle temporal gyrus, left posterior division(−50, −22, −04)1380.74.002
      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.
      Figure thumbnail gr2
      Figure 2Sex-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 .

      Discussion

      In this study, we sought to test our Developmental Origins of Health and Disease–based hypothesis that Mn uptake during early-life CWs of development is associated with changes in functional connectivity in adolescence, and that environmentally associated brain changes are sex specific. Using an objective, retrospective biomarker of Mn uptake during prenatal, early postnatal, and childhood periods and rs-fMRI in adolescence, we found significant sex-specific associations between dentine Mn at all time points and iFC in adolescents. Moreover, we report associations in different networks depending on the timing of exposure, suggesting that different brain networks may present distinctive CWs of vulnerability to Mn. During the prenatal period, we observed sex-specific associations between dentine Mn and functional connectivity between the dorsal striatum (caudate and putamen) and regions in the occipital and frontal lobes and between the middle frontal gyrus and the occipital lobe. During the early postnatal period (<1 year), dentine Mn was associated with sex-specific changes in the right putamen and the cerebellum. Finally, during the early childhood period (1 to ∼6 years), exposure to Mn showed sex-specific effects on iFC between the putamen and the occipital lobe and between the frontal and temporal lobes. Our results highlight that the effect of Mn on iFC differs 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 (
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      ). This study contributes to the growing literature suggesting that early-life Mn uptake impacts neurodevelopmental 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 effect 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 (
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      ). Numerous structural basal ganglia abnormalities have been reported in workers exposed to Mn, including T1 hyperintensities (
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      Editor’s highlight: Lower fractional anisotropy in the globus pallidus of asymptomatic welders, a marker for long-term welding exposure.
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      ). Only 2 occupational MRI studies have investigated functional brain changes related to Mn exposure (
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      ). Chang et al. (
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      Altered working memory process in the manganese-exposed brain.
      ) showed Mn-induced alterations in brain activity during a working memory task, with higher activation in the basal ganglia (i.e., including the putamen) in exposed welders. Seo et al. (
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      ) showed decreased activation of the frontal, parietal, and insular cortices in welders during an executive function task. Our findings are consistent with prior structural and functional MRI studies, because we detect effects in the caudate and putamen, which are central components of the basal ganglia. This study builds on the previous literature by adding 1) a focus on lower nonoccupational exposures in children, 2) longitudinal retrospective measures of Mn uptake allowing the detection CWs of susceptibility, 3) direct and objective measurement of Mn concentrations instead of self-reported exposure history, and 4) analyses of sex-specific effects.
      Substantial research demonstrates associations between early-life Mn exposure and adverse neurodevelopmental outcomes (
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      ). In a recent pilot study, de Water et al. (
      • de Water E.
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      • Mascaro L.
      • Iannilli E.
      • Gasparotti R.
      • et al.
      Early-life dentine manganese concentrations and intrinsic functional brain connectivity in adolescents: A pilot study.
      ) reported associations between postnatal Mn dentine concentrations and iFC in areas of the brain implicated in cognitive control and motor function. In this study, we built on this pilot work to explore sex-specific vulnerabilities to the effect of early-life Mn exposure on iFC. Our findings indicate that Mn exposure is differently associated with functional connectivity in males and females in brain regions involved in cognitive control and motor function. Mn concentrations were associated with sex-specific effects on iFC between regions of the basal ganglia (striatum or caudate–putamen) and cortical regions (occipital and frontal).
      The cortical–subcortical connections impacted by Mn exposure in our study are known to be associated with neurologic health outcomes in adults. According to the current model of basal ganglia function in adults, the striatum is the main entry point of cortical information to the basal ganglia; it receives afferents from widespread areas of the cerebral cortex through the thalamus (i.e., corticobasal ganglia–thalamocortical loops) (
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      ). These circuits are crucial for emotional, cognitive, and motor functions (
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      ). The caudate and putamen are involved in the planning and execution of movement, learning, memory, and reward (
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      ). Mn dyshomeostasis may disrupt the corticobasal ganglia circuitry, because Mn is known to accumulate in basal ganglia structures (
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      Elevated caudate connectivity in cognitively normal Parkinson’s disease patients.
      ), putamen dysfunction (
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      Altered putamen and cerebellum connectivity among different subtypes of Parkinson’s disease.
      ) have been observed among adults diagnosed with Parkinsonism. Mn-exposed occupational workers demonstrate clinical symptoms mirroring Parkinson disease (
      • Racette B.A.
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      ). Middle frontal gyrus and middle temporal gyrus connectivity have also been associated with cognitive and executive function, specifically literacy and numeracy abilities (
      • Koyama M.S.
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      Differential contributions of the middle frontal gyrus functional connectivity to literacy and numeracy.
      ,
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      ), with increased connectivity in the middle frontal gyrus within the occipital pole network reported among children with autism spectrum disorder (
      • Xu S.
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      Altered functional connectivity in children with low-function autism spectrum disorders.
      ). Little is known about the dynamic development of these circuits during childhood. Given the known vulnerability of these circuits to perturbation during development, our study adds to the literature by relating Mn exposure to alterations in typical neurodevelopment of subcortical–cortical connections.
      Our novel approach combining neuroimaging in late adolescence with the use of deciduous teeth as a retrospective biomarker of early-life Mn uptake allows us to test our Developmental Origins of Health and Disease–based hypothesis. Traditional biomarkers of Mn exposure (e.g., urine, blood, hair) used in prior studies are unable to directly measure exposure in fetal life. Further, traditional biomarkers fail to provide longitudinal exposure spanning several potential CWs of development including the fetal, postnatal, and childhood periods. There is a lack of consensus regarding the appropriate biomarker to assess Mn-associated impacts on the developing brain because each biomarker reflects differences in pharmacokinetics, and therefore, associated health effects may be matrix dependent. Instead, dentine Mn is a validated biomarker providing a direct measure of Mn across prenatal and postnatal periods, which enabled us to detect CWs for effects of Mn exposure on iFC of the brain. Results from a recent study in the same cohort, using the dentine biomarker to study associations between Mn and neurocognition, suggest a subtle shift over time from a beneficial role of Mn during the prenatal period to a more detrimental role in childhood (
      • Bauer J.A.
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      Critical windows of susceptibility in the association between manganese and neurocognition in Italian adolescents living near ferro-manganese industry.
      ). Our unique study design is able to provide detailed insights into the neural mechanisms that may underpin these associations between early-life Mn exposure and cognitive and motor control reported in prior studies (
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      Sex differences in sensitivity to prenatal and early childhood manganese exposure on neuromotor function in adolescents.
      ,
      • Mora A.M.
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      • Parra K.
      • Hernández-Bonilla D.
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      Prenatal and postnatal manganese teeth levels and neurodevelopment at 7, 9, and 10.5 years in the CHAMACOS cohort.
      ,
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      Sex-specific associations between co-exposure to multiple metals and visuospatial learning in early adolescence.
      ,
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      • Zoni S.
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      ,
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      ).
      Very few previous investigations have explored sex-specific effects of early-life Mn on neurodevelopmental outcomes, and although most of them detect a difference in vulnerabilities by sex, the direction of reported associations is inconsistent. Early-life Mn has been positively associated with improved cognition and motor outcomes among females compared with males (
      • Chiu Y.H.M.
      • Claus Henn B.
      • Hsu H.H.L.
      • Pendo M.P.
      • Coull B.A.
      • Austin C.
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      Sex differences in sensitivity to prenatal and early childhood manganese exposure on neuromotor function in adolescents.
      ,
      • Irizar A.
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      • San Román A.
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      Prenatal manganese serum levels and neurodevelopment at 4 years of age.
      ). Contrastingly, other groups have found a negative association between Mn concentrations and nonverbal performance, motor outcomes, visuospatial learning, and IQ scores among females (
      • Mora A.M.
      • Arora M.
      • Harley K.G.
      • Kogut K.
      • Parra K.
      • Hernández-Bonilla D.
      • et al.
      Prenatal and postnatal manganese teeth levels and neurodevelopment at 7, 9, and 10.5 years in the CHAMACOS cohort.
      ,
      • Rechtman E.
      • Curtin P.
      • Papazaharias D.M.
      • Renzetti S.
      • Cagna G.
      • Peli M.
      • et al.
      Sex-specific associations between co-exposure to multiple metals and visuospatial learning in early adolescence.
      ,
      • Gunier R.B.
      • Mora A.M.
      • Smith D.
      • Arora M.
      • Austin C.
      • Eskenazi B.
      • Bradman A.
      Biomarkers of manganese exposure in pregnant women and children living in an agricultural community in California.
      ,
      • Riojas-Rodríguez H.
      • Solís-Vivanco R.
      • Schilmann A.
      • Montes S.
      • Rodríguez S.
      • Ríos C.
      • Rodríguez-Agudelo Y.
      Intellectual function in Mexican children living in a mining area and environmentally exposed to manganese.
      ). Discrepancies in direction of association may be due to differences in the task used to assess behavior, type of biomarker used to assess exposure, and timing of exposure and/or outcome assessment. Our results are in line with previous studies, suggesting that male and female neurodevelopment is not equally vulnerable to the effect of Mn exposure, and the direction of effect varies not only in magnitude but also in direction. Notably, unlike assessments of cognition and motor function, interpretation of directional changes in iFC is challenging. Increased functional connectivity does not necessarily indicate better performance, as it has been associated with memory and cognitive impairments (
      • Hafkemeijer A.
      • Altmann-Schneider I.
      • Oleksik A.M.
      • van de Wiel L.
      • Middelkoop H.A.M.
      • van Buchem M.A.
      • et al.
      Increased functional connectivity and brain atrophy in elderly with subjective memory complaints.
      ,
      • Hawellek D.J.
      • Hipp J.F.
      • Lewis C.M.
      • Corbetta M.
      • Engel A.K.
      Increased functional connectivity indicates the severity of cognitive impairment in multiple sclerosis.
      ), anxiety (
      • Qin S.
      • Young C.B.
      • Duan X.
      • Chen T.
      • Supekar K.
      • Menon V.
      Amygdala subregional structure and intrinsic functional connectivity predicts individual differences in anxiety during early childhood.
      ), and epilepsy (
      • Hsiao F.J.
      • Yu H.Y.
      • Chen W.T.
      • Kwan S.Y.
      • Chen C.
      • Yen D.J.
      • et al.
      Increased intrinsic connectivity of the default mode network in temporal lobe epilepsy: Evidence from resting-state MEG recordings.
      ), or may reflect a compensatory mechanism. Despite this limitation, our results add to the growing literature relating early-life Mn exposure with alterations in typical neurodevelopment and suggest that males and females are not equally vulnerable to Mn exposure, with effects persistent throughout extended adolescence.
      To our knowledge, this is the first study to use a neuroimaging approach to examine sex-specific effects of early-life Mn exposure on neurodevelopmental outcomes in adolescence. We acknowledge several limitations to our research. The modest sample size of this study limits the generalization of our findings. Exclusion criteria such as diagnosis of neurologic or psychiatric disorders could potentially exclude participants with the highest levels of Mn exposure. The exact age at which teeth were shed was not documented in this study. However, because the age of shedding is not expected to be related to MRI data, any resulting bias would likely be toward the null. Pubertal stage data were not collected, which could potentially be considered as a covariate. Moreover, because the interpretation of the directionality of our observed associations is challenging, future studies with a larger sample size should include cognitive and motor outcomes to test whether Mn-associated changes in iFC are associated with increased or decreased performance. Finally, children and adolescents are rarely exposed to Mn alone and, in most cases, are exposed to low levels of several metals simultaneously. Coexposure to multiple metals may influence Mn toxicity (
      • Sanders A.P.
      • Claus Henn B.
      • Wright R.O.
      Perinatal and childhood exposure to cadmium, manganese, and metal mixtures and effects on cognition and behavior: A review of recent literature.
      ,
      • Merced-Nieves F.M.
      • Arora M.
      • Wright R.O.
      • Curtin P.
      Metal mixtures and neurodevelopment: Recent findings and emerging principles.
      ). Thus, future studies should explore associations between early-life exposure to mixtures of metals and iFC later in life.
      In conclusion, we identified sex-specific CWs of susceptibility to Mn exposure on iFC in areas of the brain implicated in cognitive and motor function. These findings suggest that the developing brain is especially vulnerable to Mn exposure, with effects lasting at least through late adolescence and possibly later. More research into identifying CWs of development that are sensitive to environmental insults will improve public health and risk management and may help identify especially susceptible subgroups for interventions and methods to optimize Mn exposure. Future research is needed to link sex-specific neural correlates with their behavioral and cognitive outcomes.

      Acknowledgments and Disclosures

      Funding was provided by the National Institute of Environmental Health Sciences (Grant Nos. R01 ES019222 and P30ES023515).
      The authors report no biomedical financial interests or potential conflicts of interest.

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