Caregiving and infants' neurodevelopment in rural Costa Rica: Results from the Infants' Environmental Health Study (ISA).

Early caregiving is one of the strongest influences on children's development, and among the most significant modifiable environmental factor. The aim of this study was to explore the association between quality of caregiver-infant interactions and neurodevelopment of infants living in banana-growing communities in rural Costa Rica characterized as having environmental toxic exposures. Home visits were conducted with 94 caregiver-infant dyads from the Infants' Environmental Health Study (ISA), living within Matina county, Limón province. One-year infant neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development®, Third Edition (Bayley-III). Quality of caregiver-infant interaction was assessed with a standardized observational task: Nursing Child Assessment Satellite Training Teaching scale (NCATS) at around two years of age. Multiple regression analyses examined associations between components of caregiver-infant interactions and neurodevelopmental outcomes, adjusting for mancozeb and manganese exposure and other potential confounders. Compared to NCATS normative data for U.S. Hispanic mothers, 35% of the sample had overall caregiving interaction scores ≤10th percentile cut-off, indicating less than optimal interactions. Higher quality of caregiver-infant interaction was associated with higher expressive communication ability in infants [ß = 0.03 (95% CI: 0.01, 0.06)], controlling for pesticide exposure and confounders. Aspects of caregiving such as stimulation and growth-fostering of infants were most strongly associated with language outcomes. Results suggest an association between positive caregiving on language development for infants living in a rural agricultural area in Costa Rica, and highlight aspects of caregiving that could be targeted to improve resilience of these children who live in vulnerable conditions.

Latent subgroups of cognitive performance in lead- and manganese-exposed Uruguayan children: Examining behavioral signatures.

OBJECTIVES: Lead (Pb) and manganese (Mn) are confirmed neurotoxins but it is unclear to what extent low-level exposure produces a unique behavioral signature. The objective of this study was to investigate latent cognitive profiles among children (6-8 years) from Montevideo, Uruguay co-exposed to these metals. METHOD: Among 345 children, blood Pb and hair Mn were measured using atomic absorption spectroscopy and ICP-MS, respectively. Sixteen measures, reflecting multiple domains of cognitive functioning were gathered: (1) three tests from Cambridge Neuropsychological Test Automated Battery (CANTAB): Intra-Extra Dimensional Shift (IED), Spatial Span (SSP) and Stockings of Cambridge (SOC), (2) ten tasks from Woodcock-Muñoz Achievement Battery, Revised (WM): Visual-Motor Integration, Verbal Comprehension (Vocabulary, Synonyms, Antonyms, Analogies), Visual-Auditory Comprehension, Concept Formation, Visual Spatial Thinking, Number Inversion and Spatial Relations, (3) Bender Gestalt task, and (4) Weschler block design task. Scores were modeled using latent profile analysis (LPA). Association between blood Pb and hair Mn on performance profiles was assessed using ordinal regression, controlling for confounders. An interaction between Pb and Mn was tested. RESULTS: Mean ± SD of blood Pb was 4.1 ± 2.1 µg/dL and 35% of children had blood Pb ≥ 5 µg/dL. Median [5%, 95%] hair Mn level was 0.8 [0.3, 4.1] ppb. Three latent cognitive performance profiles were identified: high (n = 46, 13%), average (n = 209, 61%) and low (n = 90, 26%). Each one-unit increase in blood Pb was associated with a 28% greater likelihood of belonging to a poorer-performing profile. The association was non-linear, with the effect of Pb on profile membership strongest at lower levels of exposure. There was no meaningful interaction between Pb and Mn. CONCLUSIONS: A behavioral signature for low-level Pb & Mn exposure was not identified, but the likelihood of membership in low-performing profile was higher at lowest levels of blood Pb. There was no effect measure modification between Pb and Mn. Future research should address how complex environments created by chemical exposures and the social context relate to cognitive performance in young children.

Elevated airborne manganese and low executive function in school-aged children in Brazil.

Exposure to airborne manganese (Mn) has been associated with neurotoxic effects, including motor and cognitive deficits. The main deficits related to excessive exposure to Mn are predominantly the dysfunction of fronto-striatal and dopaminergic circuits observed in animal experimental studies, which are involved in attention, working memory and motor function. The present study aims to assess the association between elevated Mn exposure and performance on executive function and attention neuropsychological tests in children living in two communities near a ferro-manganese alloy plant. Seventy children aged between 7 and 12 years with no history of neurologic disease and an estimated IQ >68 (Vocabulary and Block Design subtests) that had lived near the iron-Mn production alloy plant for at least 1.5 years were included. Participants were assessed for cognitive functioning with neuropsychological measures for sustained attention (Test of Visual Attention - TAVIS-3R), cognitive flexibility (WCST), and verbal and visual working memory (WISC-III Digit Span subtest and Corsi Block). Manganese hair (MnH) levels were used as a biomarker of exposure. Mean scores among study participants were lower than general population norms/averages for block design, digit span, reaction time and commission errors. The median MnH level was 11.48 (range 0.52-55.74) µg/g, and no difference between sexes was observed. Spearman's correlation analysis showed a significant inverse correlation between MnH levels and estimated IQ (rho=-0.448, p=0.0001), Vocabulary (rho=-0.272, p=0.02), Block Design (rho=-0.485, p=0.00002) and Digit Span (rho=-0.410, p=0.0004). Multiple regression analyses detected inverse associations between log MnH and scores on estimated IQ (ß=-9.67; 95%CI=-16.97 to -2.37), Block Design (ß=-2.50; 95%CI=-3.91 to -1.10) and Digit Span Total (ß=-2.59; 95%CI=-4.13 to -1.05) standardized scores and the number of correct answers in forward and backward Digit Span methods, after adjusting for covariates (ß=-1.32=95%CI=-2.23 to -0.40; ß=-1.09 95%CI=-2.02 to -0.16, respectively). The results suggest that airborne Mn exposure may be associated with lower IQ and neuropsychological performance in tests of executive function of inhibition responses, strategic visual formation and verbal working memory. Executive function is dependent on the fronto-striatal circuit, which may be disrupted by Mn accumulation in the brain.

Elevated manganese exposure and school-aged children's behavior: a gender-stratified analysis.

High levels of waterborne manganese have been associated with problematic behavior in school-aged children, however to date this has not been reported for children exposed to airborne manganese. The objective of the present study was to examine behavioral traits among children with exposure to airborne manganese from a ferro-manganese alloy plant, located in the metropolitan region of Salvador, Brazil. The study included 34 boys and 36 girls, aged 7-12 years, living in two communities within a 3-km radius from the plant. For each child, hair manganese levels (MnH) and blood lead (PbB) levels were analyzed by graphite furnace atomic absorption spectrometry. The Children's Behavior Check List (CBCL) (Portuguese version validated in Brazil) was administered to parents or caregivers, providing scale scores of internalizing (withdrawn, somatic complaints, and anxious/depressed scales), externalizing (disruptive and aggressive) behaviors and a separate scale for attention problems. Median and range for MnH and PbB were 11.48 µg/g (range: 0.52-55.74); 1.1 µg/dL (range: 0.5-6.1), respectively. Spearman correlation analyses showed that several behavioral indices were significantly correlated with MnH levels for girls, but not for boys: total externalizing behavior (rho=0.484 vs rho=0.041) and attention problem scores (rho=0.542 vs rho=0.003) coefficients were significantly at p<0.001 level, respectively for girls and boys. No significant correlation was observed with any of the internalizing sub-scales. A linear regression model was fitted with the total externalizing behavior, inattention and total CBCL scores as dependent variables, with log transformed MnH stratified by sex, adjusting for age and maternal IQ. Total externalizing behaviors and attention problem scores were significantly associated with girls' MnH levels but not with boys'. Adjusting for maternal IQ, the ß-coefficients for LogMnH associations with total externalizing and attention problems are 8.85 (95%CI 2.44-15.24) and 4.03 (95%CI 1.50-6.56) for girls. For boys, after adjusting for age, the ß-coefficients are 0.08 (95%CI 11.51-11.66) and -0.05 (95%CI 4.34-4.25), respectively. The findings of this study suggest a positive association between elevated Mn exposure and externalizing behavioral problems and inattention, with girls presenting more pronounced effects. Future studies on Mn exposure in children should attempt to further elucidate sex and/or gender differences in Mn exposed populations.

Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox.

While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive Mn exposure may lead to neurotoxicity. Mn preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson's disease-like disorder. Compared to adults, younger individuals accumulate greater Mn levels in the CNS and are more vulnerable to its toxicity. Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood. The present study investigated the developmental neurotoxicity elicited by Mn exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 to PN27 in rats. Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, Akt and DARPP-32), oxidative stress generation and cell death. Motor alterations were evaluated later in life at 3, 4 or 5 weeks of age. Mn exposure (20 mg/kg) increased p38(MAPK) and Akt phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation. Mn (10 and 20 mg/kg) increased caspase activity and F2-isoprostane production (a biological marker of lipid peroxidation). Paralleling the changes in striatal biochemical parameters, Mn (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test. Notably, the antioxidant Trolox™ reversed the Mn (20 mg/kg)-dependent augmentation in p38(MAPK) phosphorylation and reduced the Mn (20 mg/kg)-induced caspase activity and F2-isoprostane production. Trolox™ also reversed the Mn-induced motor coordination deficits. These findings are the first to show that long-term exposure to Mn during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, p38(MAPK) phosphorylation and caspase activity in the striatum. Moreover, we establish Trolox™ as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects.

Elevated manganese and cognitive performance in school-aged children and their mothers.

BACKGROUND: Growing evidence suggests that excess manganese (Mn) in children is associated with neurobehavioral impairments. In Brazil, elevated hair Mn concentrations were reported in children living near a ferro-manganese alloy plant. OBJECTIVES: We investigated these children's and caregivers' cognitive function in relation to bioindicators of Mn exposure. METHODS: In this cross-sectional study, the WISC-III was administered to 83 children aged between 6 and 12 years; the Raven Progressive Matrix was administered to the primary caregivers (94% mothers), who likewise responded to a questionnaire on socio demographics and birth history. Mn in hair (MnH) and blood (MnB) and blood lead (PbB) were measured by graphite furnace atomic absorption spectrometry (GFAAS). RESULTS: Children's mean MnB and MnH were 8.2 µg/L (2.7-23.4) and 5.83 µg/g (0.1-86.68), respectively. Mean maternal MnH was 3.50 µg/g (0.10-77.45) and correlated to children's MnH (rho=0.294, p=0.010). Children's MnH was negatively related to Full-Scale Intelligence Quotient (IQ) and Verbal IQ; ß coefficients for MnH were -5.78 (95% CI -10.71 to -0.21) and -6.72 (-11.81 to -0.63), adjusted for maternal education and nutritional status. Maternal MnH was negatively associated with performance on the Raven's (ß=-2.69, 95% CI -5.43 to 0.05), adjusted for education years, family income and age. CONCLUSIONS: These findings confirm that high MnH in children is associated with poorer cognitive performance, especially in the verbal domain. Primary caregiver's IQ is likewise associated to Mn exposure, suggesting that, in this situation, children's cognition may be affected directly and indirectly by Mn exposure.