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BACKGROUND: Manganese (Mn) plays a significant role in both human health and global industries. Epidemiological studies of exposed populations demonstrate a dose-dependent association between Mn and neuromotor effects ranging from subclinical effects to a clinically defined syndrome. However, little is known about the relationship between early life Mn biomarkers and adolescent postural balance. OBJECTIVES: This study investigated the associations between childhood and adolescent Mn biomarkers and adolescent postural balance in participants from the longitudinal Marietta Communities Actively Researching Exposures Study (CARES) cohort. METHODS: Participants were recruited into CARES when they were 7-9 y old, and reenrolled at 13-18 years of age. At both time points, participants provided samples of blood, hair, and toenails that were analyzed for blood Mn and lead (Pb), serum cotinine, hair Mn, and toenail Mn. In adolescence, participants completed a postural balance assessment. Greater sway indicates postural instability (harmful effect), whereas lesser sway indicates postural stability (beneficial effect). Multivariable linear regression models were conducted to investigate the associations between childhood and adolescent Mn biomarkers and adolescent postural balance adjusted for age, sex, height--weight ratio, parent/caregiver intelligence quotient, socioeconomic status, blood Pb, and serum cotinine. RESULTS: CARES participants who completed the adolescent postural balance assessment (n=123) were 98% White and 54% female and had a mean age of 16 y (range: 13-18 y). In both childhood and adolescence, higher Mn biomarker concentrations were significantly associated with greater adolescent sway measures. Supplemental analyses revealed sex-specific associations; higher childhood Mn biomarker concentrations were significantly associated with greater sway in females compared with males. DISCUSSION: This study found childhood and adolescent Mn biomarkers were associated with subclinical neuromotor effects in adolescence. This study demonstrates postural balance as a sensitive measure to assess the association between Mn biomarkers and neuromotor function. https://doi.org/10.1289/EHP13381, Introduction Manganese (Mn) is an element that exists ubiquitously in the environment, often in combination with other elements. (1) Mn plays a significant role in both human health and global [...]

Behavioral disorders involving attention and impulse control dysfunction, such as ADHD, are among the most prevalent disorders in children and adolescents, with significant impact on their lives. The etiology of these disorders is not well understood, but is recognized to be multifactorial, with studies reporting associations with polygenic and environmental risk factors, including toxicant exposure. Environmental epidemiological studies, while good at establishing associations with a variety of environmental and genetic risk factors, cannot establish causality. Animal models of behavioral disorders, when properly designed, can play an essential role in establishing causal relationships between environmental risk factors and a disorder, as well as provide model systems for elucidating underlying neural mechanisms and testing therapies. Here, we review how animal model studies of developmental lead or manganese exposure have been pivotal in (1) establishing a causal relationship between developmental exposure and lasting dysfunction in the domains of attention, impulse control, and affect regulation, and (2) testing the efficacy of specific therapeutic approaches for alleviating the lasting deficits. The lead and manganese case studies illustrate how animal models can advance knowledge in ways that are not possible in human studies. For example, in contrast to the Treatment of Lead Poisoned Children (TLC) human clinical trial evaluating succimer chelation efficacy to improve cognitive functioning in lead-exposed children, our developmental lead exposure animal model showed that succimer chelation can produce lasting cognitive benefits if chelation sufficiently reduces brain lead levels. In addition, this study revealed that succimer treatment in the absence of lead exposure produces lasting cognitive dysfunction, highlighting potential risks of chelation in off-label uses, such as the treatment of autistic children without a history of lead exposure. Our animal model of developmental manganese exposure has demonstrated that manganese can cause lasting attentional and sensorimotor deficits, akin to an ADHD-inattentive behavioral phenotype, thereby providing insights into the role of environmental exposures as contributors to ADHD. These studies have also shown that oral methylphenidate (Ritalin) can fully alleviate the deficits produced by early developmental Mn exposure. Future work should continue to focus on the development and use of animal models that appropriately recapitulate the complex behavioral phenotypes of behavioral disorders, in order to determine the mechanistic basis for the behavioral deficits caused by developmental exposure to environmental toxicants, and the efficacy of existing and emerging therapies.

BackgroundPesticides and metals may disrupt thyroid function, which is key to fetal brain development.ObjectivesTo evaluate if current-use pesticide exposures, lead and excess manganese alter free thyroxine (FT4), free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) concentrations in pregnant women from the Infants' Environmental Health Study (ISA).MethodsAt enrollment, we determined women's (n = 400) specific-gravity corrected urinary pesticide (μg/L) metabolite concentrations of mancozeb (ethylene thiourea (ETU)), pyrimethanil, thiabendazole, chlorpyrifos, synthetic pyrethroids, and 2,4-D. We also measured manganese hair (MnH) (μg/g) and blood (MnB) (μg/L), and blood lead (PbB) (μg/L) concentrations. To detect an immediate and late effect on thyroid homeostasis, we determined TSH, FT4 and FT3 in serum obtained at the same visit (n = 400), and about ten weeks afterwards (n = 245). We assessed associations between exposures and outcomes with linear regression and general additive models, Bayesian multivariate linear regression, and Bayesian kernel machine regression.ResultsAbout 80%, 94%, and 100% of the women had TSH, FT4, and FT3 within clinical reference ranges, respectively. Women with higher urinary ETU, and pyrimethanil-metabolites, had lower FT4: β = -0.79 (95%CI = -1.51, -0.08) and β = -0.29 (95%CI = -0.62, -0.03), respectively, for each tenfold increase in exposure. MnB was positively associated with FT4 (β = 0.04 (95%CI = 0.00, 0.07 per 1 μg/L increase), and women with high urinary pyrethroid-metabolite concentrations had decreased TSH (non-linear effects). For the late-effect analysis, metabolites of pyrethroids and chlorpyrifos, as well as MnH, and PbB were associated decreased TSH, or increased FT4 and/or FT3.DiscussionMancozeb (ETU) and pyrimethanil may inhibit FT4 secretion (hypothyroidism-like effect), while chlorpyrifos, pyrethroids, MnB, MnH, PbB and Mn showed hyperthyroidism-like effects. Some effects on thyroid homeostasis seemed to be immediate (mancozeb (ETU), pyrimethanil, MnB), others delayed (chlorpyrifos, MnH, PbB), or both (pyrethroids), possibly reflecting different mechanisms of action.

Background: Sensorimotor difficulties significantly interfere with daily activities, and when undiagnosed in early life, they may increase the risk of later life cognitive and mental health disorders. Subtests from the Luria-Nebraska Neuropsychological Battery (LNNB) discriminate sensorimotor impairments predictive of sensorimotor dysfunction. However, scoring the LNNB sensorimotor assessment is highly subjective and time consuming, impeding the use of this task in epidemiologic studies. Aim: To train and validate a novel automated and image-derived scoring approach to the LNNB neuro-motor tasks for use in adolescents and young adults. Methods: We selected 46 adolescents (19.6 +/− 2.3 years, 48% male) enrolled in the prospective Public Health Impact of Metal Exposure (PHIME) study. We visually recorded the administration of five conventional sensorimotor LNNB tasks and developed automated scoring alternatives using a novel mathematical approach combining optic flow fields from recorded image sequences on a frame-by-frame basis. We then compared the conventional and image-derived LNNB task scores using Pearson’s correlations. Finally, we provided the accuracy of the novel scoring approach with Receiver Operating Characteristic (ROC) curves and the area under the ROC curves (AUC). Results: Image-derived LNNB task scores strongly correlated with conventional scores, which were assessed and confirmed by multiple administrators to limit subjectivity (Pearson’s correlation ≥ 0.70). The novel image-derived scoring approach discriminated participants with low motility (

Studies have reported associations between environmental manganese (Mn) exposure and impaired cognition, attention, impulse control, and fine motor function in children. Our recent rodent studies established that elevated Mn exposure causes these impairments. Here, rats were exposed orally to 0, 25, or 50 mg Mn kg-1  day-1 during early postnatal life (PND 1-21) or lifelong to determine whether early life Mn exposure causes heightened behavioral reactivity in the open field, lasting changes in the catecholaminergic systems in the medial prefrontal cortex (mPFC), altered dendritic spine density, and whether lifelong exposure exacerbates these effects. We also assessed astrocyte reactivity (glial fibrillary acidic protein, GFAP), and astrocyte complement C3 and S100A10 protein levels as markers of A1 proinflammatory or A2 anti-inflammatory reactive astrocytes. Postnatal Mn exposure caused heightened behavioral reactivity during the first 5-10 min intervals of daily open field test sessions, consistent with impairments in arousal regulation. Mn exposure reduced the evoked release of norepinephrine (NE) and caused decreased protein levels of tyrosine hydroxylase (TH), dopamine (DA) and NE transporters, and DA D1 receptors, along with increased DA D2 receptors. Mn also caused a lasting increase in reactive astrocytes (GFAP) exhibiting increased A1 and A2 phenotypes, with a greater induction of the A1 proinflammatory phenotype. These results demonstrate that early life Mn exposure causes broad lasting hypofunctioning of the mPFC catecholaminergic systems, consistent with the impaired arousal regulation, attention, impulse control, and fine motor function reported in these animals, suggesting that mPFC catecholaminergic dysfunction may underlie similar impairments reported in Mn-exposed children.

Prenatal arsenic exposure has been associated with reduced fetal growth and increased risk for preterm birth, but most studies have been conducted in highly exposed populations outside the U.S. or in non-Hispanic populations in the rural U.S. The objectives of the current study were to: 1) examine the impact of early pregnancy exposure to arsenic on birth weight and gestational age at birth in a predominately lower income Hispanic pregnancy cohort in urban Los Angeles and 2) compare multiple biomarkers of arsenic exposure (blood, urine, and hair) assessed in early pregnancy (mean ± SD gestational age at biospecimen collection: 14 ± 4 weeks). Total arsenic (blood, hair) was measured by ICP-MS and speciated arsenic (urine) was measured by HPLC coupled to ICP-MS. Associations between log2-transformed arsenic measures and birth outcomes were evaluated using multivariable linear regression. A doubling in hair arsenic was associated with a 72.2 g (95% CI: -144.3, -0.1, P = 0.05) lower birth weight, after adjusting for potential confounders and gestational age at birth. A similar but non-significant trend was observed for blood arsenic, but not urine arsenic. The inverse association between hair arsenic and birth weight was more pronounced among infants whose mothers gained greater amounts of weight during pregnancy (Pinteraction = 0.02). The association between urinary monomethyl arsenic and GA at birth differed by pre-pregnancy BMI (Pinteraction

Growing evidence from studies with children and animal models suggests that elevated levels of manganese during early development lead to lasting cognitive and fine motor deficits. This study was performed to assess presynaptic biogenic amine function in forebrain of adult Long-Evans rats exposed orally to 0, 25, or 50 mg Mn/kg/day over postnatal day 1-21 or continuously from birth to the end of the study (approximately postnatal day 500). Intracerebral microdialysis in awake rats quantified evoked outflow of biogenic amines in the right medial prefrontal cortex and left striatum. Results indicated that brain manganese levels in the early life exposed groups (postnatal day 24) largely returned to control levels by postnatal day 66, whereas levels in the lifelong exposed groups remained elevated 10%-20% compared with controls at the same ages. Manganese exposure restricted to the early postnatal period caused lasting reductions in cortical potassium-stimulated extracellular norepinephrine, dopamine, and serotonin, and reductions in striatal extracellular dopamine. Lifelong manganese exposure produced similar effects with the addition of significant decreases in cortical dopamine that were not evident in the early postnatal exposed groups. These results indicate that early postnatal manganese exposure produces persistent deficits in cortical and striatal biogenic amine function. Given that these same animals exhibited lasting impairments in attention and fine motor function, these findings suggest that reductions in catecholaminergic activity are a primary factor underlying the behavioral effects caused by manganese, and indicate that children exposed to elevated levels of manganese during early development are at the greatest risk for neuronal deficiencies that persist into adulthood.

Domoic acid (DA) is a neurotoxin produced during harmful algal blooms that accumulates in marine organisms that serve as food resources for humans. While acute DA neurotoxicity can cause seizures and hippocampal lesions, less is known regarding how chronic, subacute DA exposure in adulthood impacts the hippocampus. With more frequent occurrences of harmful algal blooms, it is important to understand the potential impact of repeated, low-level DA exposure on human health. To model repeated, low-dose DA exposure, adult mice received a single low-dose (0.75 ± 0.05 μg/g) of DA or vehicle weekly for 22 consecutive weeks. Quantitative immunohistochemistry was performed to assess the effects of repeated, low-level DA exposure on hippocampal cells and synapses. Vesicular glutamate transporter 1 (VGluT1) immunoreactivity within excitatory boutons in CA1 of DA-exposed mice was increased. Levels of other vesicular transporter proteins (i.e., VGluT2 and the vesicular GABA transporter (VGAT)) within boutons, and corresponding bouton densities, were not significantly altered in CA1, CA3, or dentate gyrus. There were no significant changes in neuron density or glial fibrillary acidic protein (GFAP) immunoreactivity following chronic, low-dose exposure. This suggests that repeated low doses of DA, unlike high doses of DA, do not cause neuronal loss or astrocyte activation in hippocampus in adult mice. Instead, these findings demonstrate that repeated exposure to low levels of DA leads to subtle changes in VGluT1 expression within CA1 excitatory boutons, which may alter glutamatergic transmission in CA1 and disrupt behaviors dependent on spatial memory.

Intracellular sensors detect changes in levels of essential metals to initiate homeostatic responses. But, a mammalian manganese (Mn) sensor is unknown, representing a major gap in understanding of Mn homeostasis. Using human-relevant models, we recently reported that: 1) the primary homeostatic response to elevated Mn is upregulation of hypoxia-inducible factors (HIFs), which increases expression of the Mn efflux transporter SLC30A10; and 2) elevated Mn blocks the prolyl hydroxylation of HIFs by prolyl hydroxylase domain (PHD) enzymes, which otherwise targets HIFs for degradation. Thus, the mammalian mechanism for sensing elevated Mn likely relates to PHD inhibition. Moreover, 1) Mn substitutes for a catalytic iron (Fe) in PHD structures; and 2) exchangeable cellular levels of Fe and Mn are comparable. Therefore, we hypothesized that elevated Mn directly inhibits PHD by replacing its catalytic Fe. In vitro assays using catalytically active PHD2, the primary PHD isoform, revealed that Mn inhibited, and Fe supplementation rescued, PHD2 activity. However, a mutation in PHD2 (D315E) that selectively reduced Mn binding without substantially impacting Fe binding or enzymatic activity resulted in complete insensitivity of PHD2 to Mn in vitro. Additionally, hepatic cells expressing full-length PHD2D315E were less sensitive to Mn-induced HIF activation and SLC30A10 upregulation than PHD2wild-type. These results: 1) define a fundamental Mn sensing mechanism for controlling Mn homeostasis--elevated Mn inhibits PHD2, which functions as a Mn sensor, by outcompeting its catalytic Fe, and PHD2 inhibition activates HIF signaling to up-regulate SLC30A10; and 2) identify a unique mode of metal sensing that may have wide applicability. [ABSTRACT FROM AUTHOR]

BACKGROUND:Although growing evidence suggests that early-life excess manganese (Mn) impairs neurodevelopment, data on the neurodevelopmental effects of mancozeb, a fungicide containing Mn, and its main metabolite ethylenethiourea (ETU) are limited. OBJECTIVE:We examined whether prenatal mancozeb exposure and excess Mn were associated with neurodevelopment in 355 1-y-old infants living near banana plantations with frequent aerial mancozeb spraying in Costa Rica. METHODS:We measured urinary ETU, hair Mn, and blood Mn concentrations in samples collected 1-3 times during pregnancy from mothers enrolled in the Infants' Environmental Health (ISA) study. We then assessed neurodevelopment in their 1-y-old infants using the Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-III). We estimated exposure-outcome associations using linear regression models adjusted for maternal education, parity, gestational age at birth, child age, Home Observation for Measurement of the Environment score, and location of neurodevelopmental assessment. RESULTS:Median (P25-P75) urinary ETU, hair Mn, and blood Mn measured during pregnancy were 3.3 μg/L (2.4-4.9; specific gravity-corrected), 1.7 μg/g (0.9-4.1), and 24.0 μg/L (20.3-28.0), respectively. Among girls, higher ETU was associated with lower social-emotional scores [β per 10-fold increase=-7.4 points (95% CI: -15.2, 0.4)], whereas higher hair Mn was associated with lower cognitive scores [-3.0 (-6.1, 0.1)]. Among boys, higher hair Mn was associated with lower social-emotional scores [-4.6 (-8.5, -0.8)]. We observed null associations for blood Mn, language, and motor outcomes. CONCLUSIONS:Our findings indicate that maternal exposure to mancozeb and excess Mn during pregnancy may have adverse and sex-specific effects on infant neurodevelopment. https://doi.org/10.1289/EHP1955.

Biomarkers of environmental metal exposure in children are important for elucidating exposure and health risk. While exposure biomarkers for As, Cd, and Pb are relatively well defined, there are not yet well-validated biomarkers of Mn exposure. Here, we measured hair Mn, Pb, Cd, and As levels in children from the Mid-Ohio Valley to determine within and between-subject predictors of hair metal levels. Occipital scalp hair was collected in 2009-2010 from 222 children aged 6-12 years (169 female, 53 male) participating in a study of chemical exposure and neurodevelopment in an industrial region of the Mid-Ohio Valley. Hair samples from females were divided into three two centimeter segments, while males provided a single segment. Hair was cleaned and processed in a trace metal clean laboratory, and analyzed for As, Cd, Mn, and Pb by magnetic sector inductively coupled plasma mass spectrometry. Hair Mn and Pb levels were comparable (median 0.11 and 0.15 µg/g, respectively) and were ~10-fold higher than hair Cd and As levels (0.007 and 0.018 µg/g, respectively). Hair metal levels were higher in males compared to females, and varied by ~100-1000-fold between all subjects, and substantially less (10-fold lower than levels reported in other studies in children, most likely because of more rigorous hair cleaning methodology used in the present study, leading to lower levels of unresolved exogenous metal contamination of hair.

Recent studies from our lab have demonstrated that postnatal manganese (Mn) exposure in a rodent model can cause lasting impairments in fine motor control and attention, and that oral methylphenidate (MPH) treatment can effectively treat the dysfunction in fine motor control. However, it is unknown whether MPH treatment can alleviate the impairments in attention produced by Mn exposure. Here we used a rodent model of postnatal Mn exposure to determine whether (1) oral MPH alleviates attention and impulse control deficits caused by postnatal Mn exposure, using attention tasks that are variants of the 5-choice serial reaction time task, and (2) whether these treatments affected neuronal dendritic spine density in the medial prefrontal cortex (mPFC) and dorsal striatum. Male Long-Evans rats were exposed orally to 0 or 50Mn/kg/d throughout life starting on PND 1, and tested as young adults (PND 107-115) on an attention task that specifically tapped selective attention and impulse control. Animals were treated with oral MPH (2.5mg/kg/d) throughout testing on the attention task. Our findings show that lifelong postnatal Mn exposure impaired impulse control and selective attention in young adulthood, and that a therapeutically relevant oral MPH regimen alleviated the Mn-induced dysfunction in impulse control, but not selective attention, and actually impaired focused attention in the Mn group. In addition, the effect of MPH was qualitatively different for the Mn-exposed versus control animals across a range of behavioral measures of inhibitory control and attention, as well as dendritic spine density in the mPFC, suggesting that postnatal Mn exposure alters catecholaminergic systems modulating these behaviors. Collectively these findings suggest that MPH may hold promise for treating the behavioral dysfunction caused by developmental Mn exposure, although further research is needed with multiple MPH doses to determine whether a dose can be identified that ameliorates the dysfunction in both impulse control and selective attention, without impairing focused attention.

The consumption of one meal of seafood containing domoic acid (DA) at levels high enough to induce seizures can cause gross histopathological lesions in hippocampal regions of the brain and permanent memory loss in humans and marine mammals. Seafood regulatory limits have been set at 20mgDA/kg shellfish to protect human consumers from symptomatic acute exposure, but the effects of repetitive low-level asymptomatic exposure remain a critical knowledge gap. Recreational and Tribal-subsistence shellfish harvesters are known to regularly consume low levels of DA. The aim of this study was to determine if chronic low-level DA exposure, at doses below those that cause overt signs of neurotoxicity, has quantifiable impacts on cognitive function. To this end, female C57BL/6NJ mice were exposed to asymptomatic doses of DA (≈0.75mg/kg) or vehicle once a week for several months. Spatial learning and memory were tested in a radial water maze paradigm at one, six and 25 weeks of exposure, after a nine-week recovery period following cessation of exposure, and at three old age time points (18, 24 and 28 months old). Mice from select time points were also tested for activity levels in a novel cage environment using a photobeam activity system. Chronic low-level DA exposure caused significant spatial learning impairment and hyperactivity after 25 weeks of exposure in the absence of visible histopathological lesions in hippocampal regions of the brain. These cognitive effects were reversible after a nine-week recovery period with no toxin exposure and recovery was sustained into old age. These findings identify a new potential health risk of chronic low-level exposure in a mammalian model. Unlike the permanent cognitive impacts of acute exposure, the chronic low-level effects observed in this study were reversible suggesting that these deficits could potentially be managed through cessation of exposure if they also occur in human seafood consumers.

BackgroundStudies in children and adolescents have associated early developmental manganese (Mn) exposure with inattention, impulsivity, hyperactivity, and oppositional behaviors, but causal inferences are precluded by the correlational nature of the data and generally limited control for potential confounders.ObjectivesTo determine whether early postnatal oral Mn exposure causes lasting attentional and impulse control deficits in adulthood, and whether continued lifelong Mn exposure exacerbates these effects, using a rat model of environmental Mn exposure.MethodsNeonates were exposed orally to 0, 25 or 50 mg Mn/kg/day during early postnatal life (PND 1-21) or throughout life from PND 1 until the end of the study. In adulthood, the animals were tested on a series of learning and attention tasks using the five-choice serial reaction time task.ResultsEarly postnatal Mn exposure caused lasting attentional dysfunction due to impairments in attentional preparedness, selective attention, and arousal regulation, whereas associative ability (learning) and impulse control were spared. The presence and severity of these deficits varied with the dose and duration of Mn exposure.ConclusionsThis study is the first to show that developmental Mn exposure can cause lasting impairments in focused and selective attention and arousal regulation, and to identify the specific nature of the impairments. Given the importance of attention and arousal regulation in cognitive functioning, these findings substantiate concerns about the adverse effects of developmental Mn exposure in humans. Citation: Beaudin SA, Strupp BJ, Strawderman M, Smith DR. 2017. Early postnatal manganese exposure causes lasting impairment of selective and focused attention and arousal regulation in adult rats. Environ Health Perspect 125:230-237; http://dx.doi.org/10.1289/EHP258.

BackgroundNumerous cross-sectional studies of school-age children have observed that exposure to manganese (Mn) adversely affects neurodevelopment. However, few prospective studies have looked at the effects of both prenatal and postnatal Mn exposure on child neurodevelopment.MethodsWe measured Mn levels in prenatal and early postnatal dentine of shed teeth and examined their association with behavior, cognition, memory, and motor functioning in 248 children aged 7, 9, and/or 10.5 years living near agricultural fields treated with Mn-containing fungicides in California. We used generalized linear models and generalized additive models to test for linear and nonlinear associations, and generalized estimating equation models to assess longitudinal effects.ResultsWe observed that higher prenatal and early postnatal Mn levels in dentine of deciduous teeth were adversely associated with behavioral outcomes, namely internalizing, externalizing, and hyperactivity problems, in boys and girls at 7 and 10.5 years. In contrast, higher Mn levels in prenatal and postnatal dentine were associated with better memory abilities at ages 9 and 10.5, and better cognitive and motor outcomes at ages 7 and 10.5 years, among boys only. Higher prenatal dentine Mn levels were also associated with poorer visuospatial memory outcomes at 9 years and worse cognitive scores at 7 and 10.5 years in children with higher prenatal lead levels (≥0.8 μg/dL). All these associations were linear and were consistent with findings from longitudinal analyses.ConclusionsWe observed that higher prenatal and early postnatal Mn levels measured in dentine of deciduous teeth, a novel biomarker that provides reliable information on the developmental timing of exposures to Mn, were associated with poorer behavioral outcomes in school-age boys and girls and better motor function, memory, and/or cognitive abilities in school-age boys. Additional research is needed to understand the inconsistencies in the neurodevelopmental findings across studies and the degree to which differences may be associated with different Mn exposure pathways and biomarkers.

BackgroundNumerous cross-sectional studies of school-age children have observed that exposure to manganese (Mn) adversely affects neurodevelopment. However, few prospective studies have looked at the effects of both prenatal and postnatal Mn exposure on child neurodevelopment.MethodsWe measured Mn levels in prenatal and early postnatal dentine of shed teeth and examined their association with behavior, cognition, memory, and motor functioning in 248 children aged 7, 9, and/or 10.5 years living near agricultural fields treated with Mn-containing fungicides in California. We used generalized linear models and generalized additive models to test for linear and nonlinear associations, and generalized estimating equation models to assess longitudinal effects.ResultsWe observed that higher prenatal and early postnatal Mn levels in dentine of deciduous teeth were adversely associated with behavioral outcomes, namely internalizing, externalizing, and hyperactivity problems, in boys and girls at 7 and 10.5 years. In contrast, higher Mn levels in prenatal and postnatal dentine were associated with better memory abilities at ages 9 and 10.5, and better cognitive and motor outcomes at ages 7 and 10.5 years, among boys only. Higher prenatal dentine Mn levels were also associated with poorer visuospatial memory outcomes at 9 years and worse cognitive scores at 7 and 10.5 years in children with higher prenatal lead levels (≥0.8 μg/dL). All these associations were linear and were consistent with findings from longitudinal analyses.ConclusionsWe observed that higher prenatal and early postnatal Mn levels measured in dentine of deciduous teeth, a novel biomarker that provides reliable information on the developmental timing of exposures to Mn, were associated with poorer behavioral outcomes in school-age boys and girls and better motor function, memory, and/or cognitive abilities in school-age boys. Additional research is needed to understand the inconsistencies in the neurodevelopmental findings across studies and the degree to which differences may be associated with different Mn exposure pathways and biomarkers.

BackgroundAnimal studies have shown that both deficiency and excess manganese (Mn) may result in decreased fetal size and weight, but human studies have reported inconsistent results.MethodsWe examined the association of blood and hair Mn concentrations measured at different times during pregnancy with fetal growth among term births and length of gestation in a cohort of 380 mother-infant pairs living near banana plantations aerially sprayed with Mn-containing fungicides in Costa Rica. We used linear regression and generalized additive models to test for linear and nonlinear associationsResultsMean (± SD) blood Mn concentration was 24.4 ± 6.6 μg/L and geometric mean (geometric SD) hair Mn concentration was 1.8 (3.2) μg/g. Hair Mn concentrations during the second and third trimesters of gestation were positively related to infant chest circumference (β for 10-fold increase = 0.62 cm; 95% CI: 0.16, 1.08; and β = 0.55 cm; 95% CI: -0.16, 1.26, respectively). Similarly, average maternal hair Mn concentrations during pregnancy were associated with increased chest circumference (β for 10-fold increase = 1.19 cm; 95% CI: 0.43, 1.95) in infants whose mothers did not have gestational anemia, but not in infants of mothers who had gestational anemia (β = 0.39 cm; 95% CI: -0.32, 1.10; pINT=0.14). All these associations were linear. Blood Mn concentrations did not show consistent linear nor nonlinear relationships with any of the birth outcomesConclusionsMn plays an important role in fetal development, but the extent to which environmental exposures may cause adverse health effects to the developing fetus is not well understood. Among women living near banana plantations in Costa Rica, we did not observe linear or nonlinear associations of Mn concentrations with lowered birth weight or head circumference, as reported in previous studies. However, we did find positive linear associations between maternal hair Mn concentrations during pregnancy and infant chest circumference.

Domoic acid is an algal-derived seafood toxin that functions as a glutamate agonist and exerts excitotoxicity via overstimulation of glutamate receptors (AMPA, NMDA) in the central nervous system (CNS). At high (symptomatic) doses, domoic acid is well-known to cause seizures, brain lesions and memory loss; however, a significant knowledge gap exists regarding the health impacts of repeated low-level (asymptomatic) exposure. Here, we investigated the impacts of low-level repetitive domoic acid exposure on gene transcription and mitochondrial function in the vertebrate CNS using a zebrafish model in order to: (1) identify transcriptional biomarkers of exposure; and (2) examine potential pathophysiology that may occur in the absence of overt excitotoxic symptoms. We found that transcription of genes related to neurological function and development were significantly altered, and that asymptomatic exposure impaired mitochondrial function. Interestingly, the transcriptome response was highly variable across the exposure duration (36 weeks), with little to no overlap of specific genes across the six exposure time points (2, 6, 12, 18, 24, and 36 weeks). Moreover, there were no apparent similarities at any time point with the gene transcriptome profile exhibited by the glud1 mouse model of chronic moderate excess glutamate release. These results suggest that although the fundamental mechanisms of toxicity may be similar, gene transcriptome responses to domoic acid exposure do not extrapolate well between different exposure durations. However, the observed impairment of mitochondrial function based on respiration rates and mitochondrial protein content suggests that repetitive low-level exposure does have fundamental cellular level impacts that could contribute to chronic health consequences.

Manganese (Mn), an essential nutrient, is a neurotoxicant at high concentrations. We measured Mn concentrations in repeated blood and hair samples collected from 449 pregnant women living near banana plantations with extensive aerial spraying of Mn-containing fungicide mancozeb in Costa Rica, and examined environmental and lifestyle factors associated with these biomarkers. Mean blood Mn and geometric mean hair Mn concentrations were 24.4 μg/L (8.9-56.3) and 1.8 μg/g (0.05-53.3), respectively. Blood Mn concentrations were positively associated with gestational age at sampling (β = 0.2; 95% CI: 0.1 to 0.2), number of household members (β = 0.4; 95% CI: 0.1 to 0.6), and living in a house made of permeable and difficult-to-clean materials (β = 2.6; 95% CI: 1.3 to 4.0); and inversely related to smoking (β = -3.1; 95% CI: -5.8 to -0.3). Hair Mn concentrations were inversely associated with gestational age at sampling (% change = 0.8; 95% CI: -1.6 to 0.0); and positively associated with living within 50 m of a plantation (% change = 42.1; 95% CI: 14.2 to 76.9) and Mn concentrations in drinking water (% change = 17.5; 95% CI: 12.2 to 22.8). Our findings suggest that pregnant women living near banana plantations aerially sprayed with mancozeb may be environmentally exposed to Mn.

Manganese (Mn) is an essential nutrient, but overexposure can be neurotoxic. Over 800 000 kg of Mn-containing fungicides are applied each year in California. Manganese levels in teeth are a promising biomarker of perinatal exposure. Participants in our analysis included 207 children enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a longitudinal birth cohort study in an agricultural area of California. Mn was measured in teeth using laser-ablation-inductively coupled plasma-mass spectrometry. Our purpose was to determine environmental and lifestyle factors related to prenatal Mn levels in shed teeth. We found that storage of farmworkers' shoes in the home, maternal farm work, agricultural use of Mn-containing fungicides within 3 km of the residence, residence built on Antioch Loam soil and Mn dust loading (μg/m(2) of floor area) during pregnancy were associated with higher Mn levels in prenatal dentin (p < 0.05). Maternal smoking during pregnancy was inversely related to Mn levels in prenatal dentin (p < 0.01). Multivariable regression models explained 22-29% of the variability of Mn in prenatal dentin. Our results suggest that Mn measured in prenatal dentin provides retrospective and time specific levels of fetal exposure resulting from environmental and occupational sources.

Stable-isotope ratios of carbon (13C/12C; δ13C) and nitrogen (15N/14N; δ15N) in animal tissues are analyzed to estimate animal foraging ecology because these ratios reflect those of an animal's diet. This reflection is generally indirect, as stable-isotope ratios change with trophic level. These differences, called discrimination factors (reported as Δ), vary considerably by species and tissue. Variations in discrimination factors used in stableisotope mixing models can lead to inaccurate estimates of diets. Therefore, determining accurate discrimination factors specific to species and tissue is important. We established the Δ13C and Δ15N values between diet and blood and feathers from chicks and juveniles of the California Condor (Gymnogyps californianus). Hatchlings were fed rats for 76-119 days, whereas juveniles were fed dairy calves for 64 days. The mean Δ13C and Δ15N values ( ± SD) between chick feathers and rat muscle were 0.4 ± 0.4‰ and 3.1 ± 0.2‰, respectively; those between chicks' whole blood and rat muscle were -0.7 ± 0.1‰ and 1.7 ± 0.1‰, respectively. The mean Δ13C and Δ15N values between juvenile condors' plasma and calf muscle were 0.9 ± 0.2‰ and 3.3 ± 0.7‰, respectively; those between juveniles' red blood cells and calf muscle were 0.3 ± 0.3‰ and 1.8 ± 0.1‰, respectively; and those between juveniles' whole blood and calf muscle were 0.3 ± 0.3‰ and 1.9 ± 0.2‰, respectively. We report the first discrimination factors for the Cathartidae (New World vultures), and our findings will have important applications in studies of the critically endangered California Condor's foraging ecology. © The Cooper Ornithological Society 2013.

Endangered species recovery programs seek to restore populations to self-sustaining levels. Nonetheless, many recovering species require continuing management to compensate for persistent threats in their environment. Judging true recovery in the face of this management is often difficult, impeding thorough analysis of the success of conservation programs. We illustrate these challenges with a multidisciplinary study of one of the world's rarest birds-the California condor (Gymnogyps californianus). California condors were brought to the brink of extinction, in part, because of lead poisoning, and lead poisoning remains a significant threat today. We evaluated individual lead-related health effects, the efficacy of current efforts to prevent lead-caused deaths, and the consequences of any reduction in currently intensive management actions. Our results show that condors in California remain chronically exposed to harmful levels of lead; 30% of the annual blood samples collected from condors indicate lead exposure (blood lead ≥ 200 ng/mL) that causes significant subclinical health effects, measured as >60% inhibition of the heme biosynthetic enzyme δ-aminolevulinic acid dehydratase. Furthermore, each year, ∼20% of free-flying birds have blood lead levels (≥450 ng/mL) that indicate the need for clinical intervention to avert morbidity and mortality. Lead isotopic analysis shows that lead-based ammunition is the principle source of lead poisoning in condors. Finally, population models based on condor demographic data show that the condor's apparent recovery is solely because of intensive ongoing management, with the only hope of achieving true recovery dependent on the elimination or substantial reduction of lead poisoning rates.