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A P-type ATPase importer that discriminates between essential and toxic transition metals.

ABSTRACT: Transition metals, although being essential cofactors in many physiological processes, are toxic at elevated concentrations. Among the membrane-embedded transport proteins that maintain appropriate intracellular levels of transition metals are ATP-driven pumps belonging to the P-type ATPase superfamily. These metal transporters may be differentiated according to their substrate specificities, where the majority of pumps can extrude either silver and copper or zinc, cadmium, and lead. In the present report, we have established the substrate specificities of nine previously uncharacterized prokaryotic transition-metal P-type ATPases. We find that all of the newly identified exporters indeed fall into one of the two above-mentioned categories. In addition to these exporters, one importer, Pseudomonas aeruginosa Q9I147, was also identified. This protein, designated HmtA (heavy metal transporter A), exhibited a different substrate recognition profile from the exporters. In vivo metal susceptibility assays, intracellular metal measurements, and transport experiments all suggest that HmtA mediates the uptake of copper and zinc but not of silver, mercury, or cadmium. The substrate selectivity of this importer ensures the high-affinity uptake of essential metals, while avoiding intracellular contamination by their toxic counterparts.

SUBMITTER: Lewinson O

PROVIDER: S-EPMC2651836 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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A P-type ATPase importer that discriminates between essential and toxic transition metals.

Lewinson Oded O Lee Allen T AT Rees Douglas C DC

Proceedings of the National Academy of Sciences of the United States of America 20090305 12

Transition metals, although being essential cofactors in many physiological processes, are toxic at elevated concentrations. Among the membrane-embedded transport proteins that maintain appropriate intracellular levels of transition metals are ATP-driven pumps belonging to the P-type ATPase superfamily. These metal transporters may be differentiated according to their substrate specificities, where the majority of pumps can extrude either silver and copper or zinc, cadmium, and lead. In the pres ...[more]

PMID: 19264958

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Project description:Introduction Cerebral palsy (CP) is the most common motor disability in childhood, but its causes are only partly known. Early-life exposure to toxic metals and inadequate or excess amounts of essential elements can adversely affect brain and nervous system development. However, little is still known about these as perinatal risk factors for CP. This study aims to investigate the associations between second trimester maternal blood levels of toxic metals, essential elements, and mixtures thereof, with CP diagnoses in children. Methods In a large, population-based prospective birth cohort (The Norwegian Mother, Father, and Child Cohort Study), children with CP diagnoses were identified through The Norwegian Patient Registry and Cerebral Palsy Registry of Norway. One hundred forty-four children with CP and 1,082 controls were included. The relationship between maternal blood concentrations of five toxic metals and six essential elements and CP diagnoses were investigated using mixture approaches: elastic net with stability selection to identify important metals/elements in the mixture in relation to CP; then logistic regressions of the selected metals/elements to estimate odds ratio (OR) of CP and two-way interactions among metals/elements and with child sex and maternal education. Finally, the joint effects of the mixtures on CP diagnoses were estimated using quantile-based g-computation analyses. Results The essential elements manganese and copper, as well as the toxic metal Hg, were the most important in relation to CP. Elevated maternal levels of copper (OR = 1.40) and manganese (OR = 1.20) were associated with increased risk of CP, while Hg levels were, counterintuitively, inversely related to CP. Metal/element interactions that were associated with CP were observed, and that sex and maternal education influenced the relationships between metals/elements and CP. In the joint mixture approach no significant association between the mixture of metals/elements and CP (OR = 1.00, 95% CI = [0.67, 1.50]) was identified. Conclusion Using mixture approaches, elevated levels of copper and manganese measured in maternal blood during the second trimester could be related to increased risk of CP in children. The inverse associations between maternal Hg and CP could reflect Hg as a marker of maternal fish intake and thus nutrients beneficial for foetal brain development.

Project description:BackgroundToxic heavy metals such as chromium (Cr), arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) are known to be priority pollutants due to their high degrees of toxicity and widespread presence in the environment. This review aimed to explore the association between heavy metals and noncancerous thyroid diseases by synthesizing findings from observational and experimental studies. This review addressed a critical intersection of environmental health, endocrinology, and public health. The findings would be of interest to a wide range of disciplines given the ubiquitous presence of toxic heavy metals in the environment and their potential to disrupt endocrine systems. The evidence-based information from diverse fields generated from this review will provide insights into the health implications of heavy metal exposure on thyroid function and guide the necessary interdisciplinary research and collaborative interventions.MethodThree databases were searched, namely PubMed, Web of Science, and Scopus. The Arksey and O'Malley (2005) framework was used as a guide in conducting this scoping review. The reporting was carried out based on the Preferred Reporting Items for Systematic Reviews and the Meta-Analyses Extension for Scoping Reviews (PRISMA). The literature search retrieved 552 articles and 29 articles were included in the final review.ResultsAs high as 83% of the 29 included studies followed an observational study design while the rest were experimental animal studies. Among the observational studies, two-thirds (66%) were cross-sectional studies while the rest were case-control studies (31%) and cohort studies (n = 1, 3%). Few number of studies in this review reported a significant association between Cr, As, Cd, Hg, and Pb with noncancerous thyroid diseases (2, 3, 16, 8, and 12) while another few (5, 8, 9, 5, and 11) did not show any significant association.ConclusionA heterogeneous and diverse sample population in the included studies could have potentially led to mixed findings about the association between toxic heavy metals and thyroid diseases in this review. Therefore, future research should prioritize longitudinal studies and controlled clinical trials to better elucidate the causative mechanisms and long-term impact of heavy metal exposure on thyroid health.

Project description:BackgroundComprehensive examinations of placental metal concentrations and correlations with infant parameters are under-investigated. Chattanooga, Tennessee's consistently high incidence of low birth weight and potential for metal exposure provides an ideal opportunity to investigate potential correlations.ObjectivesTo investigate the associations between a wide variety of metals in placental tissue and multiple infant parameters.MethodsA total of 31 elements were screened via ICP-MS in 374 individual placental samples. Of those, 14 were quantifiable in > 86% of the samples. We examined correlations between metal concentrations and infant parameters (birth weight, gestational age, birth weight centile, placental weight, birth length and head circumference). We fit multivariable regression models to estimate the covariate-adjusted associations of birth weight with ln-transformed concentrations of each of the 14 metals and used generalized additive models to examine nonlinear relationships.ResultsSome of the strongest relationships with infant parameters came from several lesser-studied metals. Placental rhodium concentrations were negatively correlated with almost all infant parameters. In the fully adjusted regression model, birth weight was significantly associated with several metals. On an IQR (25th to the 75th percentile) basis, estimated changes in birthweight were: for cobalt (82.5 g, IQR=6.05 µg/kg, p = 0.006), iron (-51.5 g, IQR = 171800 µg/kg, p = 0.030), manganese (-27.2 g, IQR=152.1 µg/kg, p = 0.017), lead (-72.7 g, IQR=16.55 µg/kg, p = 0.004) and rhodium (-1365.5 g, IQR = 0.33 µg/kg, p < 0.001). Finally, a generalized additive model showed significant nonlinear relationships between birth weight and concentrations of Co and Rh.ConclusionsOur comprehensive examination of placental metals illustrate many strong associations between lesser-studied metals and infant parameters. These data, in combination with our correlations of well-studied metals, illustrate a need to consider in utero exposure to a broad array of metals when considering fetal development.

Project description:OBJECTIVE:Damage to locus ceruleus neurons could play a part in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis because of impairment of the blood-brain barrier and enhanced neuroinflammation. The locus ceruleus has connections throughout the brain and spinal cord, so the characteristic widespread multifocal pathology in these disorders could be due to damage to different subsets of locus ceruleus neurons. Previous studies have shown that only certain locus ceruleus neurons accumulate the neurotoxic metal mercury. To find out if concentrations of other toxic metals or of essential trace elements also vary between individual locus ceruleus neurons, we used synchrotron X-ray fluorescence microscopy on frozen sections of locus ceruleus neurons taken from people with multiple sclerosis, in whom the locus ceruleus is structurally intact. MATERIALS AND METHODS:Paraffin embedded sections containing the locus ceruleus from seven people with multiple sclerosis were stained with autometallography that demonstrates accumulations of mercury, silver and bismuth. These were compared to maps of multiple elements obtained from frozen sections of locus ceruleus neurons from the same people using X-ray fluorescence microscopy. Neurons in the anterior pons from three of these donors were used as internal controls. RESULTS:Autometallography staining was observed in scattered locus ceruleus neurons from three of the seven donors. X-ray fluorescence microscopy showed variations among individual locus ceruleus neurons in levels of mercury, selenium, iron, copper, lead, bromine, and rubidium. Variations between donors of locus ceruleus neuronal average levels of mercury, iron, copper, and bromine were also detected. Anterior pons neurons contained no mercury, had varied levels of iron, and had lower copper levels than locus ceruleus neurons. CONCLUSIONS:Individual human locus ceruleus neurons contain varying levels of toxic metals and essential trace elements. In contrast, most toxic metals are absent or at low levels in nearby anterior pons neurons. The locus ceruleus plays a role in numerous central nervous system functions, including maintaining the blood-brain-barrier and limiting neuroinflammation. Toxic metals, or alterations in essential trace metals within individual locus ceruleus neurons, could be one factor determining the non-random destruction of locus ceruleus neurons in normal aging and neurodegenerative diseases, and subsequently the sites of the widespread multifocal central nervous system pathology in these disorders.

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A P-type ATPase importer that discriminates between essential and toxic transition metals.

Publications

A P-type ATPase importer that discriminates between essential and toxic transition metals.

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