Sex-specific associations between co-exposure to multiple metals and externalizing symptoms in adolescence and young adulthood.

Externalizing disorders, such as attention-deficit/hyperactivity disorder (ADHD), account for the majority of the child/adolescent referrals to mental health services and increase risk for later-life psychopathology. Although the expression of externalizing disorders is more common among males, few studies have addressed how sex modifies associations between metal exposure and adolescent externalizing symptoms. This study aimed to examine sex-specific associations between co-exposure to multiple metals and externalizing symptoms in adolescence and young adulthood. Among 150 adolescents and young adults (55% female, ages: 15-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study in Brescia, Italy, we measured five metals (manganese (Mn), lead (Pb), copper (Cu), chromium (Cr), nickel (Ni)) in four biological matrices (blood, urine, hair, and saliva). Externalizing symptoms were assessed using the Achenbach System of Empirically Based Assessment (ASEBA) Youth Self-Report (YSR) or Adult Self Report (ASR). Using generalized weighted quantile sum (WQS) regression, we investigated the moderating effect of sex (i.e., assigned at birth) on associations between the joint effect of exposure to the metal mixture and externalizing symptoms, adjusting for age and socioeconomic status. We observed that metal mixture exposure was differentially associated with aggressive behavior in males compared to females (ß = -0.058, 95% CI [-0.126, -0.009]). In males, exposure was significantly associated with more externalizing problems, and aggressive and intrusive behaviors, driven by Pb, Cu and Cr. In females, exposure was not significantly associated with any externalizing symptoms. These findings suggest that the effect of metal exposure on externalizing symptoms differs in magnitude between the sexes, with males being more vulnerable to increased externalizing symptoms following metal exposure. Furthermore, our findings support the hypothesis that sex-specific vulnerabilities to mixed metal exposure during adolescence/young adulthood may play a role in sex disparities observed in mental health disorders, particularly those characterized by externalizing symptoms.

Associations of an industry-relevant metal mixture with verbal learning and memory in Italian adolescents: The modifying role of iron status.

BACKGROUND: Biomarker concentrations of metals are associated with neurodevelopment, and these associations may be modified by nutritional status (e.g., iron deficiency). No prior study on associations of metal mixtures with neurodevelopment has assessed effect modification by iron status. OBJECTIVES: We aimed to quantify associations of an industry-relevant metal mixture with verbal learning and memory among adolescents, and to investigate the modifying role of iron status on those associations. METHODS: We used cross-sectional data from 383 Italian adolescents (10-14 years) living in proximity to ferroalloy industry. Verbal learning and memory was assessed using the California Verbal Learning Test for Children (CVLT-C), and metals were quantified in hair (manganese, copper, chromium) or blood (lead) using inductively coupled plasma mass spectrometry. Serum ferritin, a proxy for iron status, was measured using immunoassays. Covariate-adjusted associations of the metal mixture with CVLT subtests were estimated using Bayesian Kernel Machine Regression, and modification of the mixture associations by ferritin was examined. RESULTS: Compared to the 50th percentile of the metal mixture, the 90th percentile was associated with a 0.12 standard deviation [SD] (95% CI = -0.27, 0.50), 0.16 SD (95% CI = -0.11, 0.44), and 0.11 SD (95% CI = -0.20, 0.43) increase in the number of words recalled for trial 5, long delay free, and long delay cued recall, respectively. For an increase from its 25th to 75th percentiles, copper was beneficially associated the recall trials when other metals were fixed at their 50th percentiles (for example, trial 5 recall: ß = 0.31, 95% CI = 0.14, 0.48). The association between copper and trial 5 recall was stronger at the 75th percentile of ferritin, compared to the 25th or 50th percentiles. CONCLUSIONS: In this metal mixture, copper was beneficially associated with neurodevelopment, which was more apparent at higher ferritin concentrations. These findings suggest that metal associations with neurodevelopment may depend on iron status, which has important public health implications.

Neurocognitive impact of metal exposure and social stressors among schoolchildren in Taranto, Italy.

BACKGROUND: Metal exposure is a public health hazard due to neurocognitive effects starting in early life. Poor socio-economic status, adverse home and family environment can enhance the neurodevelopmental toxicity due to chemical exposure. Disadvantaged socio-economic conditions are generally higher in environmentally impacted areas although the combined effect of these two factors has not been sufficiently studied. METHODS: The effect of co-exposure to neurotoxic metals including arsenic, cadmium, manganese, mercury, lead, selenium, and to socio-economic stressors was assessed in a group of 299 children aged 6-12 years, residing at incremental distance from industrial emissions in Taranto, Italy. Exposure was assessed with biological monitoring and the distance between the home address and the exposure point source. Children's cognitive functions were examined using the Wechsler Intelligence Scale for Children (WISC) and the Cambridge Neuropsychological Test Automated Battery (CANTAB). Linear mixed models were chosen to assess the association between metal exposure, socio-economic status and neurocognitive outcomes. RESULTS: Urinary arsenic, cadmium and hair manganese resulted inversely related to the distance from the industrial emission source (ß - 0.04; 95% CI -0.06, - 0.01; ß - 0.02; 95% CI -0.05, - 0.001; ß - 0.02 95% CI -0.05, - 0.003) while the WISC intellectual quotient and its sub-scores (except processing speed index) showed a positive association with distance. Blood lead and urinary cadmium were negatively associated with the IQ total score and all sub-scores, although not reaching the significance level. Hair manganese and blood lead was positively associated with the CANTAB between errors of spatial working memory (ß 2.2; 95% CI 0.3, 3.9) and the reaction time of stop signal task (ß 0.05; 95% CI 0.02, 0.1) respectively. All the other CANTAB neurocognitive tests did not show to be significantly influenced by metal exposure. The highest socio-economic status showed about five points intellectual quotient more than the lowest level on average (ß 4.8; 95% CI 0.3, 9.6); the interaction term between blood lead and the socio-economic status showed a significant negative impact of lead on working memory at the lowest socio-economic status level (ß - 4.0; 95% CI -6.9, - 1.1). CONCLUSIONS: Metal exposure and the distance from industrial emission was associated with negative cognitive impacts in these children. Lead exposure had neurocognitive effect even at very low levels of blood lead concentration when socio-economic status is low, and this should further address the importance and prioritize preventive and regulatory interventions.

Sex differences in sensitivity to prenatal and early childhood manganese exposure on neuromotor 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 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. RESULTS: We 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). CONCLUSIONS: This 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.

A multi-environmental source approach to explore associations between metals exposure and olfactory identification among school-age children residing in northern Italy.

BACKGROUND: Metal exposures can adversely impact olfactory function. Few studies have examined this association in children. Further, metal exposure occurs as a mixture, yet previous studies of metal-associated olfactory dysfunction only examined individual metals. Preventing olfactory dysfunctions can improve quality of life and prevent neurodegenerative diseases with long-term health implications. OBJECTIVE: We aimed to test the association between exposure to a mixture of 12 metals measured in environmental sources and olfactory function among children and adolescents residing in the industrialized province of Brescia, Italy. METHODS: We enrolled 130 children between 6 and 13 years old (51.5% females) and used the "Sniffin' Sticks" test to measure olfactory performance in identifying smells. We used a portable X-ray fluorescence instrument to determine concentrations of metals (arsenic (As), calcium, cadmium (Cd), chromium, copper, iron, manganese, lead (Pb), antimony, titanium, vanadium and zinc) in outdoor and indoor deposited dust and soil samples collected from participants' households. We used an extension of weighted quantile sum (WQS) regression to test the association between exposure to metal mixtures in multiple environmental media and olfactory function adjusting for age, sex, socio-economic status, intelligence quotient and parents' smoking status. RESULTS: A higher multi-source mixture was significantly associated with a reduced Sniffin' Sticks identification score (ß = -0.228; 95% CI -0.433, -0.020). Indoor dust concentrations of Pb, Cd and As provided the strongest contributions to this association (13.8%, 13.3% and 10.1%, respectively). The metal mixture in indoor dust contributed more (for 8 metals out of 12) to the association between metals and olfactory function compared to soil or outdoor dust. IMPACT STATEMENT: Among a mixture of 12 metals measured in three different environmental sources (soil, outdoor and indoor dust), we identified Pb, Cd and As measured in indoor dust as the main contributors to reduced olfactory function in children and adolescents residing in an industrialized area. Exposure to indoor pollution can be effectively reduced through individual and public health interventions allowing to prevent the deterioration of olfactory functions. Moreover, the identification of the factors that can deteriorate olfactory functions can be a helpful instrument to improve quality of life and prevent neurodegenerative diseases as long-term health implications.

Covid-19 related cognitive, structural and functional brain changes among Italian adolescents and young adults: a multimodal longitudinal case-control study.

Coronavirus disease 2019 (COVID-19) has been associated with brain functional, structural, and cognitive changes that persist months after infection. Most studies of the neurologic outcomes related to COVID-19 focus on severe infection and aging populations. Here, we investigated the neural activities underlying COVID-19 related outcomes in a case-control study of mildly infected youth enrolled in a longitudinal study in Lombardy, Italy, a global hotspot of COVID-19. All participants (13 cases, 27 controls, mean age 24 years) completed resting state functional (fMRI), structural MRI, cognitive assessments (CANTAB spatial working memory) at baseline (pre-COVID) and follow-up (post-COVID). Using graph theory eigenvector centrality (EC) and data-driven statistical methods, we examined differences in ECdelta (i.e., the difference in EC values pre- and post-COVID-19) and volumetricdelta (i.e., the difference in cortical volume of cortical and subcortical areas pre- and post-COVID) between COVID-19 cases and controls. We found that ECdeltasignificantly between COVID-19 and healthy participants in five brain regions; right intracalcarine cortex, right lingual gyrus, left hippocampus, left amygdala, left frontal orbital cortex. The left hippocampus showed a significant decrease in volumetricdelta between groups (p=0.041). The reduced ECdelta in the right amygdala associated with COVID-19 status mediated the association between COVID-19 and disrupted spatial working memory. Our results show persistent structural, functional and cognitive brain changes in key brain areas associated with olfaction and cognition. These results may guide treatment efforts to assess the longevity, reversibility and impact of the observed brain and cognitive changes following COVID-19.

Topological network properties of resting-state functional connectivity patterns are associated with metal mixture exposure in adolescents.

Introduction: Adolescent exposure to neurotoxic metals adversely impacts cognitive, motor, and behavioral development. Few studies have addressed the underlying brain mechanisms of these metal-associated developmental outcomes. Furthermore, metal exposure occurs as a mixture, yet previous studies most often consider impacts of each metal individually. In this cross-sectional study, we investigated the relationship between exposure to neurotoxic metals and topological brain metrics in adolescents. Methods: In 193 participants (53% females, ages: 15-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study, we measured concentrations of four metals (manganese, lead, copper, and chromium) in multiple biological media (blood, urine, hair, and saliva) and acquired resting-state functional magnetic resonance imaging scans. Using graph theory metrics, we computed global and local efficiency (global:GE; local:LE) in 111 brain areas (Harvard Oxford Atlas). We used weighted quantile sum (WQS) regression models to examine association between metal mixtures and each graph metric (GE or LE), adjusted for sex and age. Results: We observed significant negative associations between the metal mixture and GE and LE [ßGE = -0.076, 95% CI (-0.122, -0.031); ßLE= -0.051, 95% CI (-0.095, -0.006)]. Lead and chromium measured in blood contributed most to this association for GE, while chromium measured in hair contributed the most for LE. Discussion: Our results suggest that exposure to this metal mixture during adolescence reduces the efficiency of integrating information in brain networks at both local and global levels, informing potential neural mechanisms underlying the developmental toxicity of metals. Results further suggest these associations are due to combined joint effects to different metals, rather than to a single metal.

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

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.

Early-life manganese exposure during multiple developmental periods and adolescent verbal learning and memory.

BACKGROUND: Manganese (Mn) is both an essential and toxic metal, and associations with neurodevelopment depend on exposure timing. Prospective data examining early life Mn with adolescent cognition are sparse. METHODS: We enrolled 140 Italian adolescents (10-14 years old) from the Public Health Impact of Metals Exposure study. Mn in deciduous teeth was measured using laser ablation-mass spectrometry to represent prenatal, postnatal and early childhood exposure. The California Verbal Learning Test for Children (CVLT-C) was administered to assess adolescent verbal learning and memory. Multivariable regression models estimated changes in CVLT-C scores and the odds of making an error per doubling in dentine Mn in each exposure period. Multiple informant models tested for differences in associations across exposure periods. RESULTS: A doubling in prenatal dentine Mn levels was associated with lower odds of making an intrusion error (OR = 0.23 [95% CI: 0.09, 0.61]). This beneficial association was not observed in other exposure periods. A doubling in childhood Mn was beneficially associated with short delay free recall: (ß = 0.47 [95% CI: -0.02, 0.97]), which was stronger in males (ß = 0.94 [95% CI: 0.05, 1.82]). Associations were null in the postnatal period. CONCLUSION: Exposure timing is critical for understanding Mn-associated changes in cognitive function.

COVID-19 Aftermath: Exploring the Mental Health Emergency among Students at a Northern Italian University.

In this study, we investigated the symptoms of physical and mental health associated with lifestyle changes due to a lockdown among the students of a university in Northern Italy, one of the most affected areas in Europe during the first wave of COVID-19. We examined the psychopathological variations in relation to mental health problems in a young population. The goal was to develop interventions to resolve these new psychosocial problems. From June to July 2020, students participated in an anonymous survey asking about habits and symptoms that emerged during the lockdown and the COVID-19 pandemic. Five health outcomes were assessed: digestive disorders; headaches; fear of COVID-19; panic and anxiety crises; and depression/sadness. The conditions and duration of the social isolation, lifestyle, SARS-CoV-2 infection in the household, financial situation, and productivity were considered in the analysis. A total of 3533 students completed the survey. The participants experienced headaches, depression and sadness, digestive disorders, a fear of COVID-19, and anxiety/panic crises. The duration of isolation was associated with an increased risk of digestive disorders, headaches, and COVID-19 fear. The female gender, medium-intense telephone usage, sleep quality, memory difficulties, and performance reduction were associated with an increased risk of the health outcomes. Future interventions should focus on promoting and implementing different habits with the support of health and university organizations.

Impact of COVID-19-Related Social Isolation on Behavioral Outcomes in Young Adults Residing in Northern Italy.

Social isolation affects our emotions, behavior and interactions. Worldwide, individuals experienced prolonged periods of isolation during the first wave of the COVID-19 pandemic when authorities-imposed restrictions to reduce the spread of the virus. In this study, we investigated the effects of social isolation on emotional and behavioral outcomes in young adults from Lombardy, Italy, a global hotspot of COVID-19. We leveraged baseline (pre-social isolation) and follow-up (mid- or post-isolation) data collected from young adults enrolled in the ongoing, longitudinal Public Health Impact of Metals Exposure (PHIME) study. At baseline, 167 participants completed the ASEBA questionnaires (ASR/YSR) by web link or in person; 65 completed the ASR 12-18 weeks after the onset of restrictions. Using the sign test and multiple linear regression models, we examined differences in ASR scores between baseline and follow-up adjusting for sex, age, pre-pandemic IQ and time with social restrictions (weeks). Further, we examined interactions between sex and time in social isolation. Participants completed the ASR after spending an average of 14 weeks in social isolation (range 12-18 weeks). Thought problems increased between baseline and follow-up (median difference 1.0; 1st, 3rd quartile: -1.0, 4.0; p = 0.049). Among males, a longer time in social isolation (≥14 weeks) was associated with increased rule-breaking behaviors of 2.8 points. These results suggest the social isolation related to COVID-19 adversely impacted mental health. In particular, males seem to externalize their condition. These findings might help future interventions and treatment to minimize the consequences of social isolation experience in young adults.

The effects of the exposure to neurotoxic elements on Italian schoolchildren behavior.

Neurodevelopmental disorders are constantly increasing on a global scale. Some elements like heavy metals are known to be neurotoxic. In this cross-sectional study we assessed the neurobehavioral effect of the exposure to trace elements including lead, mercury, cadmium, manganese, arsenic and selenium and their interactions among 299 schoolchildren residing in the heavily polluted Taranto area in Italy. Whole blood, urine and hair were collected for metal analyses, while the Child Behavior Checklist and the Social Responsiveness Scale, administered to the main teacher and the mothers were considered to identify behavioral problems in children. Blood lead mainly influenced social problems, aggressive behavior, externalizing and total problems. Urinary arsenic showed an impact on anxiety and depression, somatic problems, attention problems and rule breaking behavior. A significant interaction between lead and arsenic was observed, with a synergistic effect of the two metals increasing the risk of attention problems, aggressive behavior, externalizing problems and total problems. Overall, we were able to test that higher blood lead, urinary arsenic concentrations and their interaction increase the risk of neurobehavioral problems. This is in line with the U.S. Environmental Protection Agency's priority list of hazardous substances where arsenic and lead are ranked as first and second respectively.

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

INTRODUCTION: Understanding 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. OBJECTIVE: We sought to estimate prospective associations between Mn measured in three different early-life time windows with adolescent cognition using deciduous teeth biomarkers. METHODS: Deciduous 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. RESULTS: Adjusted 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: ß = 0.20 (95 % CI: 0.02, 0.38)] and Block design [ß = 0.21 (0.01, 0.41)] and early postnatal Mn was positively associated with Digits forward [ß = 0.24 (0.09, 0.40)], while childhood Mn was negatively associated with Coding [ß = -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. CONCLUSION: Our 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.

Sex-specific associations between co-exposure to multiple metals and visuospatial learning in early adolescence.

The predisposition, severity, and progression of many diseases differ between males and females. Sex-related differences in susceptibility to neurotoxicant exposures may provide insight into the cause of the observed discrepancy. Early adolescence, a period of substantial structural and functional brain changes, may present a critical window of vulnerability to environmental exposures. This study aimed to examine sex-specific associations between co-exposure to multiple metals and visuospatial memory in early adolescence. Manganese (Mn), lead (Pb), chromium (Cr), and copper (Cu) were measured in blood, urine, hair, nails, and saliva of 188 participants (88 girls; 10-14 years of age). Visuospatial memory skills were assessed using a computerized maze task, the virtual radial arm maze (VRAM). Using generalized weighted quantile sum regression, we investigated sex-specific associations between the combined effect of exposure to the metal mixture and visuospatial working memory and determined the contribution of each component to the outcome. The results suggest that sex moderates the association between the metal mixture and visuospatial learning for all outcomes measured. In girls, exposure was associated with slower visuospatial learning and driven by Mn and Cu. In boys, exposure was associated with faster visuospatial learning, and driven by Cr. These results suggest that (a) the effect of metal co-exposure on learning differs in magnitude, and in the direction between sexes, and (b) early adolescence may be a sensitive developmental period for metal exposure.

Associations of a Metal Mixture Measured in Multiple Biomarkers with IQ: Evidence from Italian Adolescents Living near Ferroalloy Industry.

BACKGROUND: Research on the health effects of chemical mixtures has focused mainly on early life rather than adolescence, a potentially important developmental life stage. OBJECTIVES: We examined associations of a metal mixture with general cognition in a cross-sectional study of adolescents residing near ferromanganese industry, a source of airborne metals emissions. METHODS: We measured manganese (Mn), lead (Pb), copper (Cu), and chromium (Cr) in hair, blood, urine, nails, and saliva from 635 Italian adolescents 10-14 years of age. Full-scale, verbal, and performance intelligence quotient (FSIQ, VIQ, PIQ) scores were assessed using the Wechsler Intelligence Scale for Children-III. Multivariable linear regression and Bayesian kernel machine regression (BKMR) were used to estimate associations of the metal mixture with IQ. In secondary analyses, we used BKMR's hierarchical variable selection option to inform biomarker selection for Mn, Cu, and Cr. RESULTS: Median metal concentrations were as follows: hair Mn, 0.08µg/g; hair Cu, 9.6µg/g; hair Cr, 0.05µg/g; and blood Pb, 1.3µg/dL. Adjusted models revealed an inverted U-shaped association between hair Cu and VIQ, consistent with Cu as an essential nutrient that is neurotoxic in excess. At low levels of hair Cu (10th percentile, 5.4µg/g), higher concentrations (90th percentiles) of the mixture of Mn, Pb, and Cr (0.3µg/g, 2.6µg/dL, and 0.1µg/g, respectively) were associated with a 2.9 (95% CI: -5.2, -0.5)-point decrease in VIQ score, compared with median concentrations of the mixture. There was suggestive evidence of interaction between Mn and Cu. In secondary analyses, saliva Mn, hair Cu, and saliva Cr were selected as the biomarkers most strongly associated with VIQ score. DISCUSSION: Higher adolescent levels of Mn, Pb, and Cr were associated with lower IQ scores, especially at low Cu levels. Findings also support further investigation into Cu as both beneficial and toxic for neurobehavioral outcomes. https://doi.org/10.1289/EHP6803.

Manganese transporter genetics and sex modify the association between environmental manganese exposure and neurobehavioral outcomes in children.

There is increasing evidence that environmental manganese (Mn) exposure early in life can have negative effects on children's neurodevelopment and increase the risk of behavioral problems, including attention deficit hyperactivity disorder (ADHD). Factors that may contribute to differences in sensitivity to Mn exposure are sex and genetic variation of proteins involved in the regulation of Mn concentrations. Here we investigate if sex and polymorphisms in Mn transporter genes SLC30A10 and SLC39A8 influence the association between Mn exposure and ADHD-related behavioral problems in children. The SNPs rs1776029 and rs12064812 in SLC30A10, and rs13107325 in SLC39A8 were genotyped by TaqMan PCR or pyrosequencing in a population of Italian children (aged 11-14 years; n = 645) with a wide range of environmental Mn exposure. Mn in surface soil was measured in situ using XRF technology or modeled by geospatial analysis. Linear regression models or generalized additive models (GAM) were used for analyzing associations between soil Mn and neurobehavioral problems assessed by the Conners' behavior rating scales (self-, and parent-reported). Gene-environment interactions (Mn transporter genotype x soil Mn) were evaluated using a genetic score in which genotypes for the three SNPs were combined based on their association with blood Mn, as an indication of their influence on Mn regulation. We observed differences in associations between soil Mn and neurobehavior between sexes. For several self-reported Conners' scales, girls showed U-shaped relationships with higher (worse) Conners' scoring at higher soil Mn levels, and several parent-reported scales showed positive linear relationships between increasing soil Mn and higher Conner's scores. For boys, we observed a positive linear relationship with soil Mn for one Conner's outcome only (hyperactivity, parent-reported). We also observed some interactions between soil Mn and the genetic score on Conner's scales in girls and girls with genotypes linked to high blood Mn showed particularly strong positive associations between soil Mn and parent-reported Conners' scales. Our results indicate that sex and polymorphisms in Mn transporter genes contribute to differences in sensitivity to Mn exposure from the environment and that girls that are genetically less efficient at regulating Mn, may be a particularly vulnerable group.

Metabolic Outcomes in Southern Italian Preadolescents Residing Near an Industrial Complex: The Role of Residential Location and Socioeconomic Status.

Evidence suggests that environmental exposures and socioeconomic factors may interact to produce metabolic changes in children. We assessed the influence of residential location and socioeconomic status (SES) on pediatric body mass index (BMI) Z-score and fasting blood glucose (FBG) concentration. Participants included 214 children aged 6-11 years who live near a large industrial complex in Taranto, Italy. Participants were grouped into residential zones based on the distance between their home address and the complex periphery (Zone 1: 0.000-4.999 km, Zone 2: 5.000-9.999 km, Zone 3: 10.000-15.000 km). BMI Z-scores were calculated via World Health Organization (WHO) pediatric reference curves. FBG was obtained via venous blood sampling. Closer residential location to the industrial complex on the order of 5.000 km was significantly associated with worsened metabolic outcomes, particularly in female children. Zone 1 participants had higher BMI-adjusted FBG than Zone 2 and 3 participants (p < 0.05 versus Zone 2; p < 0.01 versus Zone 3). SES did not significantly influence BMI-adjusted FBG. Moreover, BMI Z-scores indicated high rates of overweight (22.0%) and obesity (22.9%) in the cohort. BMI Z-score was not significantly associated with SES or residential zone but was negatively associated with maternal education level (p < 0.05). These results offer new evidence that residing near industrial activity may predict adverse effects on child metabolic health.

Polymorphisms in Manganese Transporters SLC30A10 and SLC39A8 Are Associated With Children's Neurodevelopment by Influencing Manganese Homeostasis.

Background: Manganese (Mn) is an essential element but at excessive levels, it is neurotoxic. Even a moderate increase in Mn has been suggested to interfere with neurodevelopment in children. Genetics influencing Mn concentrations and toxicity is unclear. Objective: We assessed, in a cross-sectional study, whether common single-nucleotide polymorphisms in the Mn transporters SLC39A8 (influx) and SLC30A10 (efflux) are associated with neurodevelopment in children. Design: We genotyped SLC39A8 (rs13107325 C/T) and SLC30A10 (rs1776029 G/A and rs12064812 T/C) in Italian children (n = 686, ages 11-14). We then used linear regression models to analyze associations between genotype, blood Mn concentrations, and neurodevelopmental outcomes including intelligence, behavior, motor function, and sway. Inferred causal relationships were evaluated using instrumental variables (IV) analysis. Results: For SLC30A10 rs1776029, the minor allele (A) was associated with increased average blood Mn of 41% (p < 0.001), whereas minor alleles for rs12064812 (C) and rs13107325 (T) were associated with reduced blood Mn of 7% (p = 0.002) and 15% (p < 0.001), respectively. For children carrying genotypes associated with high blood Mn, we observed lower performance for certain IQ subtests, increased sway, and increased scores for behavioral problems. High Mn genotypes showed odds ratios of 2-4 (p ≤ 0.01) for high scores in tests assessing ADHD-related behavior. IV analyses suggested that several of the associations were mediated by blood Mn. Conclusions: Our results suggest that common polymorphisms in SLC39A8 and SLC30A10 influence neurodevelopmental outcomes in children via differences in Mn homeostasis.

Manganese and Developmental Neurotoxicity.

Manganese (Mn) is an essential metal that plays a fundamental role for brain development and functioning. Environmental exposure to Mn may lead to accumulation in the basal ganglia and development of Parkinson-like disorders. The most recent research is focusing on early-life overexposure to Mn and the potential vulnerability of younger individuals to Mn toxicity also in regard to cognitive and executive functions through the involvement of the frontal cortex.Neurodevelopmental disturbances are increasing in the society, and understanding the potential role of environmental determinants is a key for prevention. Therefore, assessing the environmental sources of Mn exposure and the mechanisms of developmental neurotoxicity and defining appropriate biomarkers of exposure and early functional alterations represent key issues to improve and address preventive strategies. These themes will be reviewed in this chapter.

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

BACKGROUND: Manganese (Mn) is an essential element required for growth and development, but higher body burdens have been associated with neurobehavioral decrements in children. OBJECTIVES: We examined whether prenatal or postnatal Mn measured in deciduous teeth was associated with scores on a test of visuospatial learning and memory. METHODS: Deciduous teeth were collected from 142 participants (ages 10-14years) residing near varied ferro­manganese 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. RESULTS: U-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 (ß 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. CONCLUSIONS: The prenatal period may be a critical window for the impact of environmental Mn on visuospatial ability and executive function, especially for females.