Exposure to manganese, fetal growth, and neurodevelopment in children living in agricultural communities in Costa Rica and California

There is a growing concern about excess manganese (Mn) exposure in pregnant women and children. Recent studies have reported adverse health effects in children living near Mn mining and/or transformation plants or drinking water contaminated with Mn. This dissertation focuses on environmental exposures to Mn in pregnant women and children living near agricultural fields treated with Mn-containing fungicides in Costa Rica and California, and their effects on fetal growth, length of gestation, and children's neurodevelopment.Chapter 1 provides a general introduction to human exposure to Mn and highlights the background, significance and specific aims for each study/chapter.Chapter 2 focuses on the environmental and lifestyle factors associated with Mn concentrations in pregnant women living near banana plantations with extensive aerial spraying of Mn-containing fungicide mancozeb in Costa Rica. For these analyses, Mn concentrations were measured in repeated blood and hair samples collected from 449 pregnant women enrolled in the Infants' Environmental Health Study (ISA). Mean blood Mn and geometric mean hair Mn concentrations were 24.4 mg/L (8.9-56.3) and 1.8 mg/g (0.05-53.3), respectively. Blood Mn concentrations were positively associated with gestational age at sampling (b = 0.2; 95% CI: 0.1, 0.2), number of household members (b = 0.4; 95% CI: 0.1, 0.6), and living in a house made of permeable and difficult-to-clean materials (b = 2.6; 95% CI: 1.3, 4.0); and inversely related to smoking (b = -3.1; 95% CI: -5.8, -0.3). Hair Mn concentrations were inversely associated with gestational age at sampling (% change = 0.8; 95% CI: -1.6, 0.0); and positively associated with living within 50 meters of a plantation (% change = 42.1; 95% CI: 14.2, 76.9) and Mn concentrations in drinking water (% change = 17.5; 95% CI: 12.2, 22.8). Findings from these analyses suggest that pregnant women living near banana plantations aerially sprayed with mancozeb may be environmentally exposed to Mn.In Chapter 3 the association of prenatal blood and hair Mn concentrations with fetal growth and length of gestation in pregnant women and children living near banana plantations sprayed with mancozeb in Costa Rica was examined. Data on blood or hair Mn concentrations and birth outcomes were collected from 380 mother-infant pairs from the ISA study. Linear regression and generalized additive models were used in these analyses to test for linear and nonlinear associations. Mean (p SD) blood Mn concentration was 24.4 p 6.6 mg/L and geometric mean (geometric SD) hair Mn concentration was 1.8 (3.2) mg/g. Hair Mn concentrations during the 2nd trimester and averaged over pregnancy were positively related to infant chest circumference (b for 10-fold increase = 0.6 cm; 95%CI: 0.2, 1.1; and b = 0.7 cm; 95%CI: 0.2, 1.2). Similarly, mean maternal hair Mn concentrations during pregnancy were associated with increased chest circumference (b for 10-fold increase = 1.32 cm; 95% CI: 0.54, 2.09) in infants whose mothers did not have gestational anemia but not in infants of mothers who had gestational anemia (b = 0.24 cm; 95% CI: -0.57, 1.05; pINT = 0.09). Mean maternal blood Mn concentrations during pregnancy were associated with decreased chest circumference in infants whose mothers were living below the poverty line (b for one-unit increase = -0.06 cm; 95% CI: -0.12, -0.01), but not in those living above poverty (b = 0.02 cm; 95% CI: -0.06, 0.09; pINT = 0.08). Mean maternal hair Mn concentrations were positively associated with length of gestation in infants born to women living below the poverty line (b for 10-fold increase = 4.11 days; 95% CI: 0.47, 7.75) but negatively associated in those living above poverty (b = -3.17 days; 95% CI: -7.93, 1.58; pINT = 0.03). In contrast to findings from previous studies, no linear or nonlinear associations of Mn concentrations with lowered birth weight or head circumference were observed. Nevertheless, hair Mn concentrations were related to larger chest circumference in infants born to women without gestational anemia and longer gestational durations in women living below the poverty line, while blood Mn concentrations were associated with smaller chest circumferences. The clinical significance of larger chest circumference, in the absence of an association between hair Mn concentrations and other measures of fetal growth in this study, is unknown. Inconsistencies between studies could be due to differences in the study population, sample size, time of biological sampling, and sources of Mn exposure.In Chapter 4 the neurodevelopmental effects of early life exposure to Mn, indicated by prenatal and postnatal dentine Mn levels in children's deciduous teeth, were examined in school-age children living near agricultural fields treated with Mn-containing fungicides in California. Participants in these analyses included 247 children enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a prospective cohort study in an agricultural area of California. Data on attention, cognition, memory, and motor functioning were collected from children at ages 7, 9, and 10.5 years. Generalized linear models and generalized additive models were used to test for linear and nonlinear associations, and generalized estimating equation models to assess longitudinal effects. Higher prenatal and postnatal dentine Mn levels were associated with improved cognitive abilities and fine motor coordination at 7, 9, and 10.5 years. Higher prenatal dentine Mn levels were associated with poorer attention at ages 7, 9, and 10.5 but only in boys and children born to mothers with higher lead exposure during pregnancy or gestational anemia. Higher postnatal dentine Mn levels were associated with better immediate and delayed memory at 9 and 10.5 years. Longitudinal models showed a weak association between postnatal dentine Mn levels and better cognitive outcomes at 7 and 10.5 years. These associations were all linear, and no threshold was observed. Previous studies have reported associations between childhood Mn exposure and negative neurodevelopmental effects, but in this study, small and positive relationships between postnatal dentine Mn and fine motor coordination, memory, and cognition were observed in children aged 7, 9, and 10.5 years. Disparities in findings between studies could be due to differences in the study design, timing of Mn measurements, exposure pathways, and/or exposure matrix.Finally, Chapter 5 highlights the major findings for each chapter/study, conclusion, and future directions.