Friedreich ataxia (FA) is an autosomal recessive disease with a complex neurological phenotype, but the most common cause of death is heart failure. This study presents a systematic analysis of 15 ...fixed and 13 frozen archival autopsy tissues of FA hearts and 10 normal controls (8 frozen) by measurement of cardiomyocyte hypertrophy; tissue frataxin assay; X-ray fluorescence (XRF) of iron (Fe) and zinc (Zn) in polyethylene glycol-embedded samples of left and right ventricular walls (LVW, RVW) and ventricular septum (VS); metal quantification in bulk digests by inductively-coupled plasma optical emission spectrometry (ICP-OES); Fe histochemistry; and immunohistochemistry and immunofluorescence of cytosolic and mitochondrial ferritins and of the inflammatory markers CD68 and hepcidin. FA cardiomyocytes were significantly larger than normal and surrounded by fibrotic endomysium. Frataxin in LVW was reduced to less than 15 ng/g wet weight (normal 235.4 ± 75.1 ng/g). All sections displayed characteristic Fe-reactive inclusions in cardiomyocytes, and XRF confirmed significant regional Fe accumulation in LVW and VS. In contrast, ICP-OES analysis of bulk extracts revealed normal total Fe levels in LVW, RVW, and VS. Cardiac Zn remained normal by XRF and assay of bulk digests. Cytosolic and mitochondrial ferritins exhibited extensive co-localization in cardiomyocytes, representing translational and transcriptional responses to Fe, respectively. Fe accumulation progressed from a few small granules to coarse aggregates in phagocytized cardiomyocytes. All cases met the "Dallas criteria" of myocarditis. Inflammatory cells contained CD68 and cytosolic ferritin, and most also expressed the Fe-regulatory hormone hepcidin. Inflammation is an important factor in the pathogenesis of FA cardiomyopathy but may be more evident in advanced stages of the disease. Hepcidin-induced failure of Fe export from macrophages is a likely contributory cause of damage to the heart in FA. Frataxin replacement and anti-inflammatory agents are potential therapies in FA cardiomyopathy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Included 627 children between the ages of 2–5 from CHARGE, a case-control study.•Measured 44 environmental compounds and metabolites in urine.•Estimated risks of autism spectrum disorder (ASD) and ...developmental delay (DD).•Conducted a weighted quantile sum regression analysis and single chemical analyses.•Higher concentrations increased odds of ASD and DD compared to typical.
To determine if higher exposures measured in early childhood to environmental phenols, phthalates, pesticides, and/or trace elements, are associated with increased odds of having a diagnosis of Autism Spectrum Disorder (ASD), Developmental Delay (DD), or Other Early Concerns (OEC) compared to typically developing children (TD).
This study included 627 children between the ages of 2–5 who participated in the Childhood Autism Risks from Genetics and Environment (CHARGE) study. Urine samples were collected at the same study visit where diagnostic assessments to confirm diagnosis indicated during the recruitment process were performed. Adjusted multinomial regression models of each chemical with diagnosis as the outcome were conducted. Additionally, two methods were used to analyze mixtures: repeated holdout multinomial weighted quantile sum (WQS) regression for each chemical class; and a total urinary mixture effect was assessed with repeated holdout random subset WQS.
Many urinary chemicals were associated with increased odds of ASD, DD or OEC compared to TD; however, most did not remain significant after false discovery rate adjustment. Repeated holdout WQS indices provided evidence for associations of both a phenol/paraben mixture effect and a trace element mixture effect on DD independently. In analyses adjusted for confounders and other exposures, results suggested an association of a pesticide mixture effect with increased risk for ASD. Results also suggested associations of a total urinary mixture with greater odds of both ASD and DD separately.
Higher concentrations of urinary biomarkers were associated with ASD, DD, and OEC compared to TD, with consistency of the results comparing single chemical analyses and mixture analyses. Given that the biospecimens used for chemical analysis were generally collected many months after diagnoses were made, the direction of any causal association is unknown. Hence findings may reflect higher exposures among children with non-typical development than TD children due to differences in behaviors, metabolism, or toxicokinetics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Manganese (Mn) plays a vital role in brain growth and development, yet excessive exposure can result in neurotoxicity. Marietta, Ohio, is home to the nation's longest-operating ferromanganese ...refinery, and community concern about exposure led to the development of the research study.
Our overall goal was to address the community's primary research question: "Does Mn affect cognitive development of children?" We evaluated the relationships between Mn exposure as measured by blood and hair Mn, along with other neurotoxicants including blood lead (Pb) and serum cotinine, and child cognition.
Children 7-9 years of age were enrolled (n = 404) in the Communities Actively Researching Exposure Study (CARES) from Marietta and Cambridge, Ohio, and their surrounding communities from October 2008 through March 2013. Blood and hair were analyzed for Mn and Pb, and serum was analyzed for cotinine. We used penalized splines to assess potential nonlinear associations between biological measures and IQ subscale scores, followed by multivariable regression models with categorical variables based on quartiles of the distribution for biological measures with nonlinear associations and continuous variables for biological measures with linear associations.
Geometric mean blood (n = 327) and hair Mn (n = 370) concentrations were 9.67 ± 1.27 μg/L and 416.51 ± 2.44 ng/g, respectively. After adjusting for potential confounders, both low and high blood and hair Mn concentrations were associated with lower Full Scale IQ and subscale scores, with significant negative associations between the highest quartile and middle two quartiles of blood Mn (β -3.51; 95% CI: -6.64, -0.38) and hair Mn (β -3.66; 95% CI: -6.9, -0.43%) and Full Scale IQ.
Both low and high Mn concentrations in blood and hair were negatively associated with child IQ scores. Serum cotinine was negatively associated with child cognitive function.
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CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Lead is ubiquitous in the environment and exposure can have adverse health effects even at low concentrations, particularly in young children. Blood Pb levels are the best indicator of recent Pb ...exposure. The Centers for Disease Control and Prevention (CDC) recently lowered the blood Pb reference value from 5 μg/dL to 3.5 μg/dL, based on data calculated from the 97.5th percentile of children 1–5 years old in the National Health and Nutrition Examination Survey (NHANES). The established method for determining Pb in blood by GFAAS has an estimated detection limit (LOD) of ≈1 μg/dL. This presents an analytical challenge for its clinical use in the US, given that the current population mean blood Pb level is 0.82 μg/dL. Accuracy and precision may be insufficient to quantitate low blood Pb levels in the 1–5 μg/dL range, which is essential now that the CDC blood Pb reference value is 3.5 μg/dL.
The original GFAAS method for blood Pb published in 1993 has been significantly improved to achieve a lower LOD of 0.2 μg/dL, with the ability to quantitate blood Pb levels down to 1 μg/dL. This method is fit for the purpose of detecting blood Pb levels currently, with excellent accuracy and precision in the 1–5 μg/dL range. Results from analyzing SRMs, PT materials and human blood samples were in good agreement between two different GFAAS platforms, as well as with results obtained by ICP-MS. The improvements provide evidence of an GFAAS method capable of achieving lower LODs with improved accuracy and precision at lower blood Pb levels, which can support the lower blood Pb reference value for children at 3.5 μg/dL.
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•Determination of Pb in blood by GFAAS with W-Rh permanent modifier•Commutability of blood-based reference materials for the determination of Pb by GFAAS•Improved LOD and method validation for blood Pb by GFAAS suitable for the new CDC blood lead reference value at 3.5 μg/dL
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GEOZS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The X-linked BCL-6 co-repressor (BCOR) gene encodes a key constituent of a variant polycomb repressive complex (PRC) that is mutated or translocated in human cancers. Here we report on the ...identification of somatic internal tandem duplications (ITDs) clustering in the C terminus of BCOR in 23 of 27 (85%) pediatric clear cell sarcomas of the kidney (CCSK) from two independent cohorts. We profile CCSK tumours using a combination of whole-exome, transcriptome and targeted sequencing. Identical ITD mutations are found in primary and relapsed tumour pairs but not in adjacent normal kidney or blood. Mutant BCOR transcripts and proteins are markedly upregulated in ITD-positive tumours. Transcriptome analysis of ITD-positive CCSKs reveals enrichment for PRC2-regulated genes and similarity to undifferentiated sarcomas harbouring BCOR-CCNB3 fusions. The discovery of recurrent BCOR ITDs defines a major oncogenic event in this childhood sarcoma with significant implications for diagnostic and therapeutic approaches to this tumour.
The potential harm from exposure to nonessential metals, particularly mercury (Hg) and lead (Pb), has been the focus of research for years. Initial interest focused on relatively high exposures; ...however, recent evidence suggests that even background exposures might have adverse consequences for child development. Identifying the extent of these consequences is now a priority.
We assessed blood Pb and Hg levels in a biracial sample of 9–11 year-old children (N = 203). Neurodevelopment and psychological functioning assessments included hostility, disruptive behaviors, emotion regulation, and autism spectrum disorder behaviors. Parasympathetic (vagal) responses to acute stress were indexed by heart rate variability (HRV) at rest and during stress.
With increasing Pb levels, children exhibit higher levels of hostile distrust and oppositional defiant behaviors, were more dissatisfied and uncertain about their emotions, and had difficulties with communication. These significant associations were found within a range of blood Pb levels from 0.19 to 3.25 μg/dL, well below the “reference value” for children of >5 μg/dL. Vagal reactivity interacted with Hg such that increasing Hg was associated with increasing autism spectrum behaviors for those children with sustained vagal tone during acute stress.
This study is the first to demonstrate an association between very low-level Pb exposure and fundamental psychological mechanisms that might explain prior associations with more complex outcomes such as delinquency. Analyses of vagal reactivity yielded entirely novel associations suggesting that Hg may increase autism spectrum behaviors in children with sustained vagal tone during acute stress. The novelty of these later findings requires additional research for confirmation and the cross-sectional nature of the data caution against assumptions of causality without further research.
•Pb and Hg, psychological outcomes, and vagal responses were measured in children.•Pb levels were associated with hostility, ODD, and poor emotional regulation.•Hg was associated with autism spectrum for those with sustained vagal tone.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum ...manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objectives: We assessed the extent of exposure to lead, cadmium, and mercury in the New York City (NYC) adult population. Methods: We measured blood metal concentrations in a representative sample of ...1,811 NYC residents as part of the NYC Health and Nutrition Examination Survey, 2004. Results: The geometric mean blood mercury concentration was 2.73 µg/L 95% confidence interval (CI), 2.58-2.89; blood lead concentration was 1.79 µg/dL (95% CI, 1.73-1.86); and blood cadmium concentration was 0.77 µg/L (95% CI, 0.75-0.80). Mercury levels were more than three times that of national levels. An estimated 24.8% (95% CI, 22.2-27.7%) of the NYC adult population had blood mercury concentration at or above the 5 µg/L New York State reportable level. Across racial/ethnic groups, the NYC Asian population, and the foreign-born Chinese in particular, had the highest concentrations of all three metals. Mercury levels were elevated 39% in the highest relative to the lowest income group (95% CI, 21-58%). Blood mercury concentrations in adults who reported consuming fish or shellfish 20 times or more in the last 30 days were 3.7 times the levels in those who reported no consumption (95% CI, 3.0-4.6); frequency of consumption explained some of the elevation in Asians and other subgroups. Conclusions: Higher than national blood mercury exposure in NYC adults indicates a need to educate New Yorkers about how to choose fish and seafood to maximize health benefits while minimizing potential risks from exposure to mercury. Local biomonitoring can provide valuable information about environmental exposures.
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