Prenatal Mn Research Articles

Prenatal manganese biomarkers and operant test battery performance in Mexican children: Effect modification by child sex

BackgroundManganese (Mn) is essential to healthy neurodevelopment, but both Mn deficiency and over-exposure have been linked to prefrontal cortex (PFC) impairments, the brain region that regulates cognitive and neurobehavioral processes responsible for spatial memory, learning, motivation, and time perception. These processes facilitated by attention, inhibitory control, working memory, and cognitive flexibility are often sexually dimorphic and complex, driven by multiple interconnected neurologic and cognitive domains. ObjectiveWe investigated the role of child sex as an effect modifier of the association between prenatal Mn exposure and performance in an operant testing battery (OTB) that assessed multiple cognitive and behavioral functional domains. MethodsChildren (N = 575) aged 6–8 years completed five OTB tasks. Blood and urinary Mn measurements were collected from mothers in the 2nd and 3rd trimesters. Multiple regression models estimated the association between Mn biomarkers at each trimester with OTB performance while adjusting for socio-demographic covariates. Covariate-adjusted weighted quantile sum (WQS) regression models were used to estimate the association of a Mn multi-media biomarker (MMB) mixture with OTB performance. Interaction terms were used to estimate modification effect by child sex. ResultsHigher blood Mn exposure was associated with better response rates (more motivation) on the progressive ratio task and higher overall accuracy on the delayed matching-to-sample task. In the WQS models, the MMB mixture was associated with better response rates (more motivation) on the progressive ratio task. Additionally, for the linear and WQS models, we observed a modification effect by child sex in the progressive ratio and delayed matching-to-sample tasks. Higher prenatal Mn biomarker levels were associated with improved task performance for girls and reduced performance in boys. ConclusionHigher prenatal blood Mn concentrations and the MMB mixture predicted improved performance on two of five operant tasks. Higher prenatal Mn concentrations regulated executive functions in children in a sexually dimorphic manner. Higher prenatal Mn exposure is associated with improved performance on spatial memory and motivation tasks in girls, suggesting that Mn's nutritional role is sexually dimorphic, and should be considered when making dietary and/or environmental intervention recommendations.

Sex-specific association between prenatal manganese exposure and working memory in school-aged children in Mexico city: An exploratory multi-media approach

It remains unclear whether manganese (Mn) exposure affects working memory (WM) in a sexually dimorphic manner. Further, no gold standard media exists to measure Mn, suggesting a combined blood and urinary Mn index may better capture the totality of exposure. We investigated the modification effect of child sex on the influence of prenatal Mn exposure on WM in school-age children, exploring two methodological frameworks to integrate exposure estimates across multiple exposure biomarkers. Leveraging the PROGRESS birth cohort in Mexico City, children (N = 559) ages 6–8 completed the between errors and strategy measures of the CANTAB Spatial Working Memory (SWM) task. Mn levels were assayed in blood and urine of mothers during the 2nd and 3rd trimesters and in umbilical cord blood from mothers and children at delivery. Weighted quantile sum regression estimated the association of a multi-media biomarker (MMB) mixture with SWM. We applied a confirmatory factor analysis to similarly quantify a latent blood Mn burden index. We then used an adjusted linear regression to estimate the Mn burden index with SWM measures. Interaction terms were used to estimate the modification effect by child sex for all models. Results showed that the between-errors-specific MMB mixture (i.e., this model demonstrates the impact of the MMB mixture on the between-error scores.) was associated (β = 6.50, 95% CI: 0.91, 12.08) with fewer between errors for boys and more between errors for girls. The strategy-specific MMB mixture (i.e., this model demonstrates the impact of the MMB mixture on the strategy scores) was associated (β = −1.36, 95% CI: 2.55, - 0.18) with less efficient strategy performance for boys and more efficient strategy performance for girls. A higher Mn burden index was associated (β = 0.86, 95% CI: 0.00, 1.72) with more between errors in the overall sample. The vulnerability to prenatal Mn biomarkers on SWM differs in the directionality by child sex. An MMB mixture and composite index of body burden are stronger predictors than a single biomarker for Mn exposure on WM performance.

The association of prenatal manganese exposure with problem-solving skills and its mediation by the building blocks of executive function

BackgroundProblem-solving skills build upon three core executive functions: inhibition, working memory, and cognitive flexibility. There is evidence of adverse associations of prenatal exposure to manganese (Mn) with core executive functions, but less is known about Mn associations with problem-solving or potential mediators of this association. ObjectivesThis study aimed to investigate the association of prenatal Mn exposure with problem-solving and to identify potential neuropsychological mechanisms through which this association may be mediated. MethodsStudy participants were 410 adolescents from the New Bedford Cohort (NBC) who have undergone periodic evaluations since their birth (1993–1998) to mothers residing near a Massachusetts Superfund site. We investigated the association of cord blood Mn with problem-solving measured by the Delis-Kaplan Executive Function System (D-KEFS) Sorting and Tower subtests (scores scaled to a mean ± SD of 10 ± 3) using multivariable linear regression. Inhibition and cognitive flexibility were also measured by the D-KEFS; working memory was measured with the Wide Range Assessment of Memory and Learning, 2nd edition. Regression-based causal mediation analysis was used to assess the proportion of the Mn-problem-solving association mediated by inhibition, working memory, and cognitive flexibility individually and jointly. ResultsNBC adolescents (mean age 15.5 years) were socio-demographically diverse with 31 % in a low-income household at birth and had cord blood Mn concentrations similar to other general population samples. Mn was associated with Sorting but not Tower scores. Specifically, a doubling of cord blood Mn concentrations was associated with − 0.59 points lower (95 % CI: −1.16, −0.03) Sort Recognition score. In mediation analyses, there was suggestive evidence that inhibition, working memory, and cognitive flexibility combined mediated 30 % of the total effect of Mn on Sorting. When analyzed individually, working memory mediated a larger proportion (24 %) of the effect than inhibition or cognitive flexibility. DiscussionWe observed adverse associations of cord blood Mn with problem-solving among adolescents. There was suggestive evidence that the building blocks of executive function jointly, and working memory individually, were potentially important mediators of this association.

Cord Blood Manganese Concentrations in Relation to Birth Outcomes and Childhood Physical Growth: A Prospective Birth Cohort Study.

Gestational exposure to manganese (Mn), an essential trace element, is associated with fetal and childhood physical growth. However, it is unclear which period of growth is more significantly affected by prenatal Mn exposure. The current study was conducted to assess the associations of umbilical cord-blood Mn levels with birth outcomes and childhood continuous physical development. The umbilical cord-blood Mn concentrations of 1179 mother–infant pairs in the Sheyang mini birth cohort were measured by graphite furnace atomic absorption spectrometry (GFAAS). The association of cord-blood Mn concentrations with birth outcomes, and the BMI z-score at 1, 2, 3, 6, 7 and 8 years old, were estimated separately using generalized linear models. The relationship between prenatal Mn exposure and BMI z-score trajectory was assessed with generalized estimating equation models. The median of cord-blood Mn concentration was 29.25 μg/L. Significantly positive associations were observed between Mn exposure and ponderal index (β, regression coefficient = 0.065, 95% CI, confidence interval: 0.021, 0.109; p = 0.004). Mn exposure was negatively associated with the BMI z-score of children aged 1, 2, and 3 years (β = −0.383 to −0.249, p < 0.05), while no significant relationships were found between Mn exposure and the BMI z-score of children at the age of 6, 7, and 8 years. Prenatal Mn exposure was related to the childhood BMI z-score trajectory (β = −0.218, 95% CI: −0.416, −0.021; p = 0.030). These results indicated that prenatal Mn exposure was positively related to the ponderal index (PI), and negatively related to physical growth in childhood, which seemed most significant at an early stage.

Critical windows of susceptibility in the association between manganese and neurocognition in Italian adolescents living near ferro-manganese industry

IntroductionUnderstanding the neurodevelopmental effects of manganese (Mn) is complicated due to its essentiality for growth and development. While evidence exists for the harmful effects of excess Mn, pediatric epidemiologic studies have observed inconsistent associations between Mn and child cognition. ObjectiveWe sought to estimate prospective associations between Mn measured in three different early-life time windows with adolescent cognition using deciduous teeth biomarkers. MethodsDeciduous teeth were collected from 195 participants (ages 10–14 years) of the Public Health Impact of Manganese Exposure (PHIME) study in Brescia, Italy. Measurements of tooth Mn represented prenatal (∼14 weeks gestation – birth), early postnatal (birth – 1.5 years) and childhood (∼1.5 – 6 years) time windows. Neuropsychologists administered the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), to obtain composite IQ and subtest scores. Associations between tooth Mn at each time window and adolescent WISC-III scores were estimated using multivariable linear regression. We tested differences in associations between Mn and outcomes across time windows using multiple informant models. Sex-specific associations were explored in stratified models. ResultsAdjusted associations between tooth Mn and composite IQ scores were positive in the prenatal period and negative in the childhood period. Associations were strongest for subtest scores that reflect working memory, problem solving, visuospatial ability and attention: prenatal Mn was positively associated with Digits backward [SD change in score per interquartile range increase in Mn: β = 0.20 (95 % CI: 0.02, 0.38)] and Block design [β = 0.21 (0.01, 0.41)] and early postnatal Mn was positively associated with Digits forward [β = 0.24 (0.09, 0.40)], while childhood Mn was negatively associated with Coding [β = -0.14 (-0.28, -0.001)]. Sex-stratified analyses suggested different Mn-cognition associations for boys and girls and was also dependent on the time window of exposure. ConclusionOur results suggest that exposure timing is critical when evaluating Mn associations between Mn and cognition. Higher prenatal Mn was beneficial for adolescent cognition; however, these beneficial associations shifted towards harmful effects in later time windows. Cognitive domains most sensitive to Mn across time windows included visuospatial ability, working memory, attention and problem-solving.

Associations between early life exposure to manganese and developmental trajectories of executive functions

BACKGROUND AND AIM: Manganese (Mn) is an essential nutrient at low doses, yet high levels can be neurotoxic. Executive functions (EF) are a set of cognitive abilities critical for goal directed behavior, which develop throughout childhood and adolescence. Only few studies examined the influence of early life exposures to Mn and developmental trajectories of EF. In this study, we investigated associations between early-life Mn exposure and changes in EF throughout adolescence. METHODS: Participants (N=154. 53% females) from the Public Health Impact of Metals Exposure (PHIME) study were included in this analysis. EF were measured using the Conners ADHD Scales (ages 11-14) and Brown ADD scales (ages 17-22). Prenatal, early postnatal and childhood Mn concentrations were measured in naturally shed deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. We used general linear models to examine associations between prenatal, postnatal, and childhood dentine Mn with the change in attention (z-scored changes over time), adjusted for sex, and age. RESULTS:Childhood dentine Mn was significantly associated with developmental changes in attention (i.e., a negative slope; β = -0.98, p = 0.0008). No significant associations with prenatal and postnatal Mn were detected. CONCLUSIONS:These results indicate that Mn exposure during childhood may protect against increased attention problems, consistent with its nutrient properties. The flatter slope for postnatal and prenatal Mn and attention suggests an absence of protection. These finding support our hypotheses that trajectories are key to understanding the role of early-life metal exposures on EF development. KEYWORDS: Heavy metals, Children's environmental health, Neurodevelopmental outcomes,

Building blocks of executive function as mediators of the association of prenatal manganese exposure with problem-solving skills among adolescents

BACKGROUND AND AIM: Problem-solving skills build upon three core executive functions: inhibition, working memory, and cognitive flexibility. There is evidence of adverse associations of prenatal exposure to manganese (Mn) with core executive functions, but less is known about Mn associations with problem-solving. This study aimed to investigate the association of prenatal Mn exposure with problem-solving and to identify potential neuropsychological mechanisms through which this association may be mediated. METHODS: Study participants were 379 adolescents from the New Bedford Cohort (NBC) who have undergone periodic evaluations since their birth (1993-1998) to mothers residing near a Massachusetts Superfund site. We assessed the association of cord blood Mn with problem-solving measured by the Delis-Kaplan Executive Function System (D-KEFS) Sorting and Tower subtests [scores scaled to a mean (SD) of 10 (3)] using multivariable linear regression. Inhibition and cognitive flexibility were also measured with the D-KEFS; working memory was measured with the Wide Range Assessment of Memory and Learning, 2nd edition. Regression-based causal mediation was used to assess the proportion of the Mn-problem-solving association mediated by inhibition, working memory, and cognitive flexibility. RESULTS:NBC adolescents (age 13-17 years) were diverse with 29% non-white and 31% in a low-income household at birth. Their cord blood Mn concentrations were similar to other general population samples. Mn was associated with Sorting but not Tower scores. Specifically, a doubling of cord blood Mn concentrations was associated with a -0.66 points lower (95% CI: -1.26, -0.06) Sort Recognition score. In mediation analyses, inhibition, working memory, and cognitive flexibility combined mediated 44% of the total effect of Mn on Sort Recognition. When analyzed individually, working memory mediated a larger proportion (37%) of the effect than inhibition (14%) or cognitive flexibility (23%). CONCLUSIONS:We observed adverse associations of cord blood Mn with problem-solving among adolescents. Working memory was an important mediator of this association. KEYWORDS: Neurodevelopment outcomes, children's environmental health, environmental epidemiology, chemical exposures

Prenatal manganese serum levels and neurodevelopment at 4 years of age

BackgroundThe excess of manganese (Mn) causes severe deleterious effects in the central nervous system, and the developing brain is especially sensitive to Mn overload. However, results of prospective studies regarding Mn neurodevelopmental effects remain inconclusive. The present study aims at studying the association of prenatal Mn exposure and neurodevelopment at 4–5 years of age. Methods: Mn serum concentration was measured in 1465 pregnant women from the INMA (INfancia y MedioAmbiente, Environment and Childhood) Project. Neurodevelopment was assessed using a standardized version of the McCarthy Scales of Children's Abilities (MSCA). Multivariate regression models were used for data analysis. Results: No association was found between Mn levels in serum and any of the McCarthy scales. However, the stratification by sex showed a positive and beneficial association of prenatal Mn levels and the verbal, quantitative and general-cognitive scales in girls (β (95%CI): 4 (0.03, 7.96), 4.5 (0.43, 8.57) and 4.32 (0.6, 8.05), respectively). Conclusions: A beneficial association was found for the first time between prenatal Mn levels measured in serum and neurodevelopment of female offspring at 4 years of age, which could have implications on public health policies, specifically on the establishment of policies promoting prenatal health related to dietary deficits of micronutrients such as Mn.

A Nonlinear Relation Between Maternal Red Blood Cell Manganese Concentrations and Child Blood Pressure at Age 6–12 y: A Prospective Birth Cohort Study

BackgroundAlthough manganese (Mn) is an essential trace element and a common component of most multivitamins on the market, an adverse effect on blood pressure (BP) has been reported in adults. In addition, the longitudinal relation between prenatal Mn status and childhood BP is still unknown. ObjectiveThis study investigated the association between prenatal Mn concentrations and risk of elevated BP at ages 3–12 y. MethodThe analyses included 1268 mother-child dyads who were enrolled at birth and followed prospectively at the Boston Medical Center. Maternal RBC Mn concentrations were measured by inductively coupled plasma mass spectrometry, using RBCs collected within 1–3 d after delivery (reflecting late-pregnancy Mn exposure). Child elevated BP was defined as systolic or diastolic BP ≥90th percentile for a given age, sex and height. Multivariate logistic regression models were conducted. Path analysis was applied to mediation estimation. ResultsThe median (IQR) maternal RBC Mn concentration was 37.5 (29.2–48.5) μg/L. The rate of child elevated BP at ages 3–12 y was 25%. Both the lowest and highest quartiles of maternal RBC Mn concentrations were associated with higher risk of elevated BP among children aged 6–12 y (OR: 1.52; 95% CI: 1.04, 2.21 and OR: 1.65; 95% CI: 1.13, 2.40, respectively) compared with those in the second and third quartiles. Gestational age and fetal growth mediated the association between low maternal RBC Mn (first quartile) and child elevated BP, explaining 25% of the association, but not for high (fourth quartile) maternal RBC Mn concentrations. No association was found between maternal RBC Mn concentrations and BP among children aged 3–5 y. ConclusionWe found a nonlinear association between maternal RBC Mn concentrations and elevated BP among children aged 6–12 y from a high-risk, predominantly minority population. Our findings warrant further investigation.

Prenatal Manganese Exposure and Long-Term Neuropsychological Development at 4 Years of Age in a Population-Based Birth Cohort.

Background: Manganese (Mn) is an essential micronutrient for humans, the diet being the main source of exposure. Some epidemiological studies describe a negative association between prenatal Mn and later neuropsychological development, but results are inconsistent. The aim of this study was to explore the association between prenatal Mn exposure and neuropsychological development assessed at 4 years of age. Methods: Study subjects were 304 mother-child pairs from the Gipuzkoa cohort of the INMA (Environment and Childhood) Project. Mn was measured in newborns’ hair. Children’s neuropsychological development was assessed at 4 years of age using the McCarthy Scales of Children’s Abilities. Multivariate linear regression models were built. Stratified analysis by sex was performed. Generalized additive models were used to assess the shape of the relation. Results: The median Mn concentration in newborns’ hair was 0.42 μg/g (95% CI = 0.38, 0.46). The association between Mn levels and the neuropsychological development was not statistically significant for the general cognitive scale (β [95% CI] = 0.36 [−5.23, 5.95]), motor scale (β [95% CI] = 1.9 [−3.74, 7.55]) or any of the other outcomes. No sex-specific pattern was found. The best shape describing the relationship was linear for all the scales. Conclusion: Our results suggest that prenatal Mn concentrations measured in newborns’ hair do not affect cognitive or motor development at 4 years of age in boys or in girls at the observed Mn levels.

Modification of the effects of prenatal manganese exposure on child neurodevelopment by maternal anemia and iron deficiency.

BackgroundWe evaluated: 1) associations of prenatal manganese (Mn) levels with child neurodevelopment at 4 – 6 years; 2) effect modification by maternal anemia and iron deficiency; and 3) sex-specific effects.MethodsWe measured blood Mn, hemoglobin, and serum ferritin in mothers at the 2nd trimester, 3rd trimester, and at birth, and in cord blood from a prospective birth cohort in Mexico City (n=571). McCarthy Scales of Children’s Abilities were measured at 4 – 6 years. Using linear regression, we estimated associations between prenatal Mn and neurodevelopment, examined anemia and iron deficiency as effect modifiers, and analyzed associations by child sex.ResultsNo direct associations were observed between Mn, anemia, or iron deficiency and McCarthy scales. Second trimester iron deficiency and 3rd trimester anemia modified the effect of Mn on child neurodevelopment. For instance, 2nd trimester Mn was positively associated child memory scores in mother’s with normal ferritin (1.85 (0.02, 3.45), but negatively associated in mother’s with low ferritin (−2.41 (−5.28, 0.47), interaction p value = 0.01), a pattern observed across scales. No effect modification at birth or in cord blood was observed.ConclusionsAnemia/iron deficiency during pregnancy may modify Mn impacts on child neurodevelopment, particularly in boys.

Prenatal manganese and cord blood mitochondrial DNA copy number: Effect modification by maternal anemic status

IntroductionManganese (Mn) is an essential nutrient but also a toxicant at high exposures, when it can induce oxidative stress (OS). Mn uptake is inversely correlated with iron status, therefore anemic individuals may be more susceptible to Mn overload induced-OS, which can manifest as changes in mitochondrial DNA copy number (mtDNA CN). Our objectives were to: 1) determine stage-specific associations of prenatal Mn exposure with cord blood MtDNA CN; and 2) investigate effect modification by maternal anemia, ferritin, and mean corpuscular volume (MCV). Materials and methodsWe measured whole blood Mn, hemoglobin, serum ferritin, and MCV in the 2nd and 3rd trimester, in maternal blood at birth, and in cord blood from a prospective birth cohort in Mexico City, Mexico (n = 485). We then extracted DNA from cord blood leukocytes to determine mtDNA CN. We used robust regression to measure associations between Mn and mtDNA CN at each trimester and at birth. Anemia (hemoglobin ≤11 g/dL), iron deficiency (ferritin ≤15 ng/mL) and MCV (stratified at median), were examined as effect modifiers. ResultsMn levels increased throughout pregnancy, and Mn was inversely correlated with ferritin. We observed a positive association between Mn in the 3rd trimester and Mn in cord blood and mtDNA CN (β = 0.04–0.05; 95% CI = 0.01, 0.08). Anemia significantly modified the association between mtDNA CN and Mn in the 2nd trimester. We found a positive association between 2nd trimester Mn and mtDNA CN in mothers with normal hemoglobin, and a negative association in those with low hemoglobin. (βhigh = 0.06; 95% CI = 0.01, 0.11; p = 0.01 and βlow = −0.06; 95% CI = 0.03, −0.13; p = 0.06). No associations were detected between anemia, iron deficiency and MCV and mtDNA CN. ConclusionsMaternal blood Mn in the 3rd trimester and in cord blood was positively associated with mtDNA CN, suggesting that higher late pregnancy prenatal Mn exposures can impact newborn mitochondria by promoting OS. Furthermore, 2nd trimester Mn was positively associated with mtDNA in non-anemic mother-child pairs but inversely associated in anemic individuals, indicating potential interactions between Mn and chronic anemia.

Prenatal and Early Postnatal Dentine Mn, Zn and Pb and Childhood Behavior

Prenatal and Early Postnatal Dentine Mn, Zn and Pb and Childhood Behavior

Congenital Malformations and Trace Metals: A Case-Control Study from Lubumbashi, DR Congo

As part of the African &amp;#8216;Copperbelt&amp;#8217;, Southern Katanga (DR Congo) has been an area of intensive mining, resulting in widespread environmental contamination. This study was initiated to address concerns about the possible causation of birth defects by toxic metals.Neonates born with a visible birth defect (cases) were recruited by systematic reporting in Lubumbashi for 2 years; controls were normal neonates from the same maternity. Within 1 day after delivery, mothers were interviewed about medical/obstetrical history, socio-economic variables, personal habits, residence and occupation. Trace metals were measured by ICP-MS in maternal urine and venous blood, umbilical cord blood and placental tissue. Congenital malformations were characterized clinically and photographs. Associations between congenital malformations and metal concentrations and variables obtained from the questionnaire are being analysed by multivariate analysis.Overall, 138 cases and 108 controls were included. The two groups were well-matched with regard to potential confounders (maternal age, parity, socio-economic status). Mining-related jobs were more prevalent (p&amp;lt;0.05) among fathers of cases (17%) than controls (8%). In both cases and controls, trace metals in urine and blood were substantially higher than reference values from industrially developed countries. In preliminary analyses, manganese (Mn) appeared significantly higher in cord blood and placental tissue (fetal side) from cases.This is the first study to investigate the association between environmental pollution by mining-related activities and birth defects in sub-Saharan Africa. Preliminary analyses suggest father&amp;#8217;s work in mining and prenatal Mn exposure are associated with the occurrence of congenital malformations. Limitations of our study include a possible over-matching of cases and controls (controls were born in the same maternity as cases) and that biomonitoring data were obtained at delivery and not early in pregnancy.

Manganese in teeth and neurobehavior: Sex-specific windows of susceptibility

BackgroundManganese (Mn) is an essential element required for growth and development, but higher body burdens have been associated with neurobehavioral decrements in children. ObjectivesWe examined whether prenatal or postnatal Mn measured in deciduous teeth was associated with scores on a test of visuospatial learning and memory. MethodsDeciduous teeth were collected from 142 participants (ages 10–14years) residing near varied ferro‑manganese industry in Italy. Mn concentrations were measured in prenatal and postnatal tooth regions by laser ablation inductively coupled plasma mass spectrometry (ICP-MS). The Virtual Radial Arm Maze (VRAM), an animal-human analogue task, was used to assess visuospatial learning and memory. We used generalized additive, linear and zero-inflated Poisson mixed regression models to estimate associations between prenatal or postnatal Mn concentrations and repeated measures of all four VRAM outcomes: time, distance, working and reference memory errors. Effect measure modification by sex was examined in stratified models. ResultsU-shaped associations between prenatal Mn and VRAM outcomes were observed among girls only (pGAMM=0.001 to 0.02 in stratified models). Compared to the mid-tertile of prenatal Mn, girls in the highest tertile took 7.7s [95% CI: −6.1, 21.5] longer to complete the task, traveled 2.3 maze units [0.1, 4.4] farther, and committed more working and reference memory errors (β for count ratio=1.33 [1.01, 1.83]; 1.10 [0.98, 1.24], respectively). This association was not observed among boys. In contrast, for postnatal Mn, no significant associations were found, and patterns were similar for boys and girls. ConclusionsThe prenatal period may be a critical window for the impact of environmental Mn on visuospatial ability and executive function, especially for females.

Sex differences in sensitivity to prenatal and early childhood manganese exposure on neuromotor function in adolescents

IntroductionWhile studies have suggested that exposure to manganese (Mn) may be associated with neurodevelopment in school-age children, there is limited information on prenatal and postnatal Mn exposures and tremor or motor function in children. MethodsWe measured Mn levels in dentine of shed teeth, representing prenatal, early postnatal, and cumulative childhood exposure windows, from 195 children (predominantly right-handed, 92%) in Italy. Pursuit Aiming, Luria Nebraska Motor Battery, as well as Tremor and Sway system from Computerized Adaptive Testing System (CATSYS) were administered at 11–14 years old. We examined the relationships of tooth Mn (ln-transformed) with motor function using multivariable linear regressions and generalized additive models, adjusting for age, sex, and socioeconomic status index. Effect modification by sex was also examined. ResultsWe found that higher prenatal Mn was associated with better body stability in boys in a number of sway tests (including mean sway, transversal sway, sagittal sway, sway area, and sway intensity), while Mn was associated with poorer performance in girls on all of these metrics (all p for Mn × sex interaction < 0.05). Higher prenatal Mn was also modestly associated with better hand/finger and eye-hand coordination in boys compared to girls in sex-stratified analyses, although interaction models did not reach statistical significance. For tremor, on the other hand, higher early postnatal Mn was associated with increased right-hand center frequency in girls (p for interaction < 0.01), but increased Mn level at the later postnatal period was associated with increased center frequency in boys (p for interaction = 0.01). ConclusionsThis study, which used a direct measure of prenatal and childhood Mn exposure, suggested sex-specific critical windows of early life Mn exposure in relation to neuromotor function in adolescents. The sex-specific associations might be strongest with measures of whole body stability, for which the critical exposure window was during the prenatal period.

Prenatal manganese exposure and intrinsic functional connectivity of emotional brain areas in children

Manganese (Mn) is an essential trace metal that is neurotoxic at high levels of exposure. Disruption of brain maturation processes during the prenatal period may have lasting consequences. During this critical period, the developing human brain is uniquely vulnerable to exposure to environmental toxicants such as Mn, and prenatal Mn exposure has been associated with changes in brain areas involved in emotion processing and regulation. The goal of the present pilot study was to examine whether prenatal Mn exposure is associated with changes in the intrinsic functional connectivity (iFC) of the brain in childhood, focusing on changes in emotional brain areas. We selected 15 subjects (age 6–7 years) from an ongoing longitudinal birth cohort study to participate in a resting state functional magnetic resonance imaging (fMRI) study. Prenatal Mn exposure was determined from maternal blood collected during the 2nd and 3rd trimesters of pregnancy. We used seed-based correlation analyses and independent component analyses to examine whether prenatal Mn exposure was associated with the iFC of the brain in children. We found that the right globus pallidus showed reduced iFC with the dorsal anterior cingulate cortex and lateral prefrontal cortex in children who were exposed to higher prenatal Mn levels, after controlling for sociodemographic confounders (SES, maternal education, child sex, home environment support) and environmental confounders (prenatal lead exposure and air pollution). These findings suggest that prenatal Mn exposure is associated with reduced iFC of brain areas involved in emotion processing and regulation in children. Future studies should investigate whether this reduced iFC mediates the association between prenatal Mn exposure and emotional dysfunction in childhood.

The role of cord blood BDNF in infant cognitive impairment induced by low-level prenatal manganese exposure: LW birth cohort, China

This study aimed to examine the potential association between low-level prenatal manganese (Mn) exposure and 1-year-old children's neurodevelopment quotient (DQ) by using the Gesell Developmental Inventory (GDI) (motor, adaptive, language, and social domains) and explored the role of brain-derived neurotrophic factor (BDNF) in Mn-induced cognitive impairments. A total of 377 mothers were recruited from a prospective birth cohort in rural northern China. Cord serum concentrations of Mn and BDNF were measured and children's DQ was evaluated. The median serum Mn concentration was 3.4 μg/L. After adjusting for confounding factors, Mn level was significantly associated with gross motor scores (β = −6.0, 95% CI: −11.8 to −0.2, p < 0.05) and personal–social scores (β = −4.2, 95% CI: −8.4 to 0.1, p < 0.05). BDNF level was positively correlated with personal–social score (β = 0.7, 95% CI: 0–1.4, p < 0.05). A significant correlation was found between Mn and BDNF (r = −0.13, 95% CI: −0.23 to −0.03, p < 0.01). Furthermore, the interaction between cord serum Mn and BDNF was significant (p < 0.001). In conclusion, elevated low-level prenatal Mn exposure impaired infant's neurodevelopment, and BDNF plays an important role in cognitive impairment, especially in the personal–social ability.

Tooth manganese and neurobehavior in Italian children: sex-specific windows of susceptibility

Introduction: Manganese (Mn) exposure can now be quantified using teeth, which can determine dose and exposure timing. Translation of epidemiologic research can be further facilitated by employing behavioral tasks that parallel animal studies, which in turn have access to neurologic tissue for mechanistic research. We examined associations of Mn exposure among Italian adolescents living near a ferromanganese plant with visuospatial learning assessed using the virtual radial arm maze (VRAM). Methods: We analyzed deciduous teeth from 137 children ages 10-15 years by laser ablation inductively coupled plasma mass spectrometry. Mn levels were measured in prenatal and postnatal exposure periods. We assessed performance on the VRAM, a computerized version of the rodent task, estimating latency, distance, working and reference memory errors. Linear mixed regression and generalized additive mixed regression were used to model associations between tooth Mn and VRAM performance and to assess interactions with sex. Results are compared to rodent research. Results: Adjusting for age, socioeconomic status, video game use, childhood blood lead, and tooth type, we observed sex-specific associations of tooth Mn with VRAM performance: among girls, there was a U-shaped association between prenatal Mn and latency, distance and working memory errors (pGAM=0.009-0.02). This result suggest both lower and higher prenatal tooth Mn predict worse performance among girls. Among boys, no association was observed in the prenatal period, but postnatal Mn was associated with latency, distance and reference memory in a non-linear manner (pGAM=0.004-0.08), which is consistent with a rodent study of Mn that also used a radial arm maze. Conclusions: Our sex specific results parallel a rodent study of postnatal Mn exposure demonstrating the utility of employing parallel phenotyping methods for translational research. Sensitive exposure windows appeared to be sex-specific.

Tooth Matrix Biomarkers of Pre- and Postnatal Manganese Exposure and Motor Function in Adolescents

INTRODUCTION: While studies have suggested that exposure to manganese (Mn) may be associated with neurodevelopment in school-age children, there is limited information on prenatal and postnatal Mn exposures and tremor or motor function in children. METHODS: We measured Mn levels in dentine of shed teeth, representing prenatal, early postnatal, and cumulative childhood exposure windows, from 192 children in Italy. Pursuit Aiming, Luria Nebraska Motor Battery, as well as Tremor and Sway system from Computerized Adaptive Testing System (CATSYS) were measured at 11-14 years old. We examined the relationships of tooth Mn (log-transformed) with motor function using generalized linear models and generalized additive models, adjusting for age, sex, and socioeconomic status index. Effect modification by sex was also examined. RESULTS: We found that higher prenatal Mn was associated with increased number of correct aiming dots (β=10.8, p=0.02) on the Pursuit Aiming test, particularly in boys (p for Mn × sex interaction=0.04). In contrast, higher cumulative childhood Mn was associated with poorer accuracy as indicated by the ratio of correct-to-total number of aiming dots (β=−0.04, p=0.04), particularly in girls (p for interaction=0.05). Higher prenatal Mn was also associated with lower tremor intensity of non-dominant hand (β=−1.16, p=0.048). We did not observe significant effect estimates of prenatal or postnatal Mn on Luria battery or Sway test. Conclusions: Our findings suggest that higher prenatal Mn levels measured in tooth dentine, a novel biomarker that provides reliable information on the timing of exposures to Mn, may be associated with better eye-hand coordination, particularly in boys. On the other hand, higher postnatal Mn was inversely associated with eye-hand coordination in girls. These data potentially support the existence of two distinct critical windows (prenatal vs. postnatal) of Mn exposure in relation to motor function.