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\u2009years, 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 (\u3b2 -\u20090.04; 95% CI -0.06, -\u20090.01; \u3b2 -\u20090.02; 95% CI -0.05, -\u20090.001; \u3b2 -\u20090.02 95% CI -0.05, -\u20090.003) 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 (\u3b2 2.2; 95% CI 0.3, 3.9) and the reaction time of stop signal task (\u3b2 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 (\u3b2 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 (\u3b2 -\u20094.0; 95% CI -6.9, -\u20091.1). 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

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 ferromanga-nese 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, 0:08 lg=g; hair Cu, 9:6 lg=g; hair Cr, 0:05 lg=g; and blood Pb, 1:3 lg=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, 5:4 lg=g), higher concentrations (90th percentiles) of the mixture of Mn, Pb, and Cr (0:3 lg=g, 2:6 lg=dL, and 0:1 lg=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 fur-ther investigation into Cu as both beneficial and toxic for neurobehavioral outcomes

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

Neurofunctional dopaminergic impairment in elderly after lifetime exposure to manganese.

BACKGROUND: Manganese (Mn) is an essential element that can become neurotoxic through various exposure windows over the lifespan. While there is clear evidence of Mn neurotoxicity in pediatric and adult occupational populations, little is known about effects in the elderly who may exhibit enhanced susceptibilities due to compromised physiology compared to younger adults. In the province of Brescia, Italy, the Valcamonica area has been the site of three ferroalloy plants operating from 1902 to 2001. Metal emissions of Mn and to a lesser extent lead (Pb) have impacted the surrounding environment, where a high prevalence of Parkinsonism was previously observed. This study aimed to assess neurocognitive and motor functions in healthy elderly subjects residing for most of their lifetime in Valcamonica or in a reference area unimpacted by ferroalloy plant activity. METHODS: Subjects were enrolled for extensive neurobehavioral assessment of motor, cognitive and sensory functions. Exposure was assessed with 24h personal air sampling for PM10 airborne particles, surface soil and tap water measurement at individual households, Mn levels in blood and urine and Pb in blood. Dose-response relationships between exposure indicators and biomarkers and health outcomes were analyzed with generalized (linear and logistic) additive models (GAM). RESULTS: A total of 255 subjects (55% women) were examined; most (52.9%) were within the 65-70 years age class. Average airborne Mn was 26.41 ng/m(3) (median 18.42) in Valcamonica and 20.96 ng/m(3) (median 17.62) in the reference area. Average Mn in surface soil was 1026 ppm (median 923) in Valcamonica and 421 ppm (median 410) in the reference area. Manganese in drinking water was below the LDL of 1 μg/L. The GAM analysis showed significant association between airborne Mn (p=0.0237) and the motor coordination tests of the Luria Nebraska Neuropsychological Battery. The calculation of the Benchmark Dose using this dose-response relationship yielded a lower level confidence interval of 22.7 ng/m(3) (median 26.4). For the odor identification score of the Sniffin Stick test, an association was observed with soil Mn (p=0.0006) and with a significant interaction with blood Pb (p=0.0856). Significant dose-responses resulted also for the Raven's Colored Progressive Matrices with the distance from exposure point source (p=0.0025) and Mn in soil (p=0.09), and for the Trail Making test, with urinary Mn (p=0.0074). Serum prolactin (PRL) levels were associated with air (p=0.061) and urinary (p=0.003) Mn, and with blood Pb (p=0.0303). In most of these associations age played a significant role as an effect modifier. CONCLUSION: Lifelong exposure to Mn was significantly associated with changes in odor discrimination, motor coordination, cognitive abilities and serum PRL levels. These effects are consistent with the hypothesis of a specific mechanism of toxicity of Mn on the dopaminergic system. Lead co-exposure, even at very low levels, can further enhance Mn toxicity

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

Manganese (Mn) is an essential element required for growth and development, but higher body burdens have been associated with neurobehavioral decrements in children

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

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

19siIntroduction: 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: 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. 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.reservedmixedBauer J.A.; White R.F.; Coull B.A.; Austin C.; Oppini M.; Zoni S.; Fedrighi C.; Cagna G.; Placidi D.; Guazzetti S.; Yang Q.; Bellinger D.C.; Webster T.F.; Wright R.O.; Smith D.; Horton M.; Lucchini R.G.; Arora M.; Claus Henn B.Bauer, J. A.; White, R. F.; Coull, B. A.; Austin, C.; Oppini, M.; Zoni, S.; Fedrighi, C.; Cagna, G.; Placidi, D.; Guazzetti, S.; Yang, Q.; Bellinger, D. C.; Webster, T. F.; Wright, R. O.; Smith, D.; Horton, M.; Lucchini, R. G.; Arora, M.; Claus Henn, B