Putative Biomarkers of Environmental Enteric Disease Fail to Correlate in a Cross-Sectional Study in Two Study Sites in Sub-Saharan Africa.

Environmental enteric dysfunction (EED) is an elusive, inflammatory syndrome of the small intestine thought to be associated with enterocyte loss and gut leakiness and lead to stunted child growth. To date, the gold standard for diagnosis is small intestine biopsy followed by histology. Several putative biomarkers for EED have been proposed and are widely used in the field. Here, we assessed in a cross-sectional study of children aged 2-5 years for a large set of biomarkers including markers of protein exudation (duodenal and fecal alpha-1-antitrypsin (AAT)), inflammation (duodenal and fecal calprotectin, duodenal, fecal and blood immunoglobulins, blood cytokines, C-reactive protein (CRP)), gut permeability (endocab, lactulose-mannitol ratio), enterocyte mass (citrulline) and general nutritional status (branched-chain amino acids (BCAA), insulin-like growth factor) in a group of 804 children in two Sub-Saharan countries. We correlated these markers with each other and with anemia in stunted and non-stunted children. AAT and calprotectin, CRP and citrulline and citrulline and BCAA correlated with each other. Furthermore, BCAA, citrulline, ferritin, fecal calprotectin and CRP levels were correlated with hemoglobin levels. Our results show that while several of the biomarkers are associated with anemia, there is little correlation between the different biomarkers. Better biomarkers and a better definition of EED are thus urgently needed.

Neurotransmitters and Behavioral Alterations Induced by Nickel Exposure.

BACKGROUND: Nickel ions (Ni2+) are a heavy metal with wide industrial uses. Environmental and occupational exposures to Ni are potential risk factors for brain dysfunction and behavioral and neurological symptoms in humans. METHODS: We reviewed the current evidence about neurochemical and behavioral alterations associated with Ni exposure in laboratory animals and humans. RESULTS: Ni2+ exposure can alter (both inhibition and stimulation) dopamine release and inhibit glutamate NMDA receptors. Few reports claim an effect of Ni2+ at the level of GBA and serotonin neurotransmission. At behavioral levels, exposure to Ni2+ in rodents alters motor activity, learning and memory as well as anxiety and depressive-like symptoms. However, no analysis of the dose-dependent relationship has been carried out regarding these effects and the levels of the Ni2+ in the brain, in blood or urine. CONCLUSION: Further research is needed to correlate the concentration of Ni2+ in biological fluids with specific symptoms/deficits. Future studies addressing the impact of Ni2+ under environmental or occupational exposure should consider the administration protocols to find Ni2+ levels similar in the general population or occupationally exposed workers.

Differential protein expression of hippocampal cells associated with heavy metals (Pb, As, and MeHg) neurotoxicity: Deepening into the molecular mechanism of neurodegenerative diseases.

Chronic exposure to heavy metals such as Pb, As, and MeHg can be associated with an increased risk of developing neurodegenerative diseases. Our in vitro bioassays results showed the potency of heavy metals in the order of Pb < As < MeHg on hippocampal cells. The main objective of this study was combining in vitro label free proteomics and systems biology approach for elucidating patterns of biological response, discovering underlying mechanisms of Pb, As, and MeHg toxicity in hippocampal cells. The omics data was refined by using different filters and normalization and multilevel analysis tools were employed to explore the data visualization. The functional and pathway visualization was performed by using Gene ontology and PathVisio tools. Using these all integrated approaches, we identified significant proteins across treatments within the mitochondrial dysfunction, oxidative stress, ubiquitin proteome dysfunction, and mRNA splicing related to neurodegenerative diseases. The systems biology analysis revealed significant alterations in proteins implicated in Parkinson's disease (PD) and Alzheimer's disease (AD). The current proteomics analysis of three metals support the insight into the proteins involved in neurodegeneration and the altered proteins can be useful for metal-specific biomarkers of exposure and its adverse effects. SIGNIFICANCE: The proteomics techniques have been claimed to be more sensitive than the conventional toxicological assays, facilitating the measurement of responses to heavy metals (Pb, As, and MeHg) exposure before obvious harm has occurred demonstrating their predictive value. Also, proteomics allows for the comparison of responses between Pb, As, and MeHg metals, permitting the evaluation of potency differences hippocampal cells of the brain. Hereby, the molecular information provided by pathway and gene functional analysis can be used to develop a more thorough understanding of each metal mechanism at the protein level for different neurological adverse outcomes (e.g. Parkinson's disease, Alzheimer's diseases). Efforts are put into developing proteomics based toxicity testing methods using in vitro models for improving human risk assessment. Some of the key proteins identified can also potentially be used as biomarkers in epidemiologic studies. These heavy metal response patterns shed new light on the mechanisms of mRNA splicing, ubiquitin pathway role in neurodegeneration, and can be useful for the development of molecular biomarkers of heavy metals exposure.

Immune System: An Emerging Player in Mediating Effects of Endocrine Disruptors on Metabolic Health.

The incidence of metabolic disorders like type 2 diabetes and obesity continues to increase. In addition to the well-known contributors to these disorders, such as food intake and sedentary lifestyle, recent research in the exposure science discipline provides evidence that exposure to endocrine-disrupting chemicals like bisphenol A and phthalates via multiple routes (e.g., food, drink, skin contact) also contribute to the increased risk of metabolic disorders. Endocrine-disrupting chemicals (EDCs) can disrupt any aspect of hormone action. It is becoming increasingly clear that EDCs not only affect endocrine function but also adversely affect immune system function. In this review, we focus on human, animal, and in vitro studies that demonstrate EDC exposure induces dysfunction of the immune system, which, in turn, has detrimental effects on metabolic health. These findings highlight how the immune system is emerging as a novel player by which EDCs may mediate their effects on metabolic health. We also discuss studies highlighting mechanisms by which EDCs affect the immune system. Finally, we consider that a better understanding of the immunomodulatory roles of EDCs will provide clues to enhance metabolic function and contribute toward the long-term goal of reducing the burden of environmentally induced diabetes and obesity.

Desensitization to chemical and food sensitivities by low-dose immunotherapy ascertained by provocation neutralization is associated with reduced influx of calcium ions into lymphocytes.

Background Food and chemical sensitivities have detrimental effects on health and the quality of life. The natural course of such sensitivities can potentially be altered through various types of allergen-specific immunotherapy, including low-dose immunotherapy. The molecular mechanism by which low-dose immunotherapy causes desensitization has not thus far been elucidated. While resting lymphocytes maintain a low cytosolic calcium ion concentration, antigen receptor signaling results in calcium ion influx, predominantly via store-operated calcium channels. We therefore hypothesized that desensitization by low-dose immunotherapy is associated with reduced influx of calcium ions into lymphocytes. The aim of this study was to test this hypothesis. Methods Intracellular lymphocytic calcium ion concentrations were assayed in a total of 47 patients, following incubation with picogram amounts of the test allergens, using a cell-permeable calcium-sensing ratiometric fluorescent dye and fluorescence spectroscopy, both at baseline and following successful provocation neutralization treatment with low-dose immunotherapy. Results Low-dose immunotherapy was associated with a reduction in lymphocytic intracellular calcium ion concentration following treatment of: 23 % for metabisulfite sensitivity (p<0.0004); 12 % for salicylate sensitivity (p<0.01); 23 % for benzoate sensitivity (p<0.01); 30 % for formaldehyde sensitivity (p<0.0001); 16 % for sensitivity to petrol exhaust (p<0.003); 16 % for natural gas sensitivity (p<0.001); 13 % for nickel sensitivity (p<0.05); 30 % for sensitivity to organophosphates (p<0.01); and 24 % for sensitivity to nitrosamines (p<0.05). Conclusions Low-dose immunotherapy may affect baseline levels of intracellular calcium in lymphocytes, supporting the premise that allergens affect cell signaling in immune cells and provocation neutralization immunotherapy helps to promote more normal immune cell signaling.

Oxidative Signaling Response to Cadmium Exposure.

Changes in the intracellular thiol-disulfide balance are considered major determinants in the redox status/signaling of the cell. Cellular signaling is very sensitive to both exogenous and intracellular redox status and respond to many exogenous pro-oxidative or oxidative stresses. Redox status has dual effects on upstream signaling systems and downstream transcription factors. Redox signaling pathways use reactive oxygen species (ROS) to transfer signals from different sources to the nucleus to regulate such functions as growth, differentiation, proliferation, and apoptosis. Mitogen-activated protein kinases are activated by numerous cellular stresses and ligand-receptor bindings. An imbalance in the oxidant/antioxidant system, either resulting from excessive ROS/reactive nitrogen species production and/or antioxidant system impairment, leads to oxidative stress. Glutathione (GSH) is known to play a critical role in the cellular defense against unregulated oxidative stress in mammalian cells and involvement of large molecular antioxidants include classical antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). Cadmium (Cd), a potent toxic heavy metal, is a widespread environmental contaminant. It is known to cause renal dysfunction, hepatic toxicity, genotoxicity, and apoptotic effects depending on the dose, route, and duration of exposure. This review examines the signaling pathways and mechanisms of activation of transcription factors by Cd-induced oxidative stress thus representing an important basis for understanding the mechanisms of Cd effect on the cells.

Breath biomarkers in toxicology.

Exhaled breath has joined blood and urine as a valuable resource for sampling and analyzing biomarkers in human media for assessing exposure, uptake metabolism, and elimination of toxic chemicals. This article focuses current use of exhaled gas, aerosols, and vapor in human breath, the methods for collection, and ultimately the use of the resulting data. Some advantages of breath are the noninvasive and self-administered nature of collection, the essentially inexhaustible supply, and that breath sampling does not produce potentially infectious waste such as needles, wipes, bandages, and glassware. In contrast to blood and urine, breath samples can be collected on demand in rapid succession and so allow toxicokinetic observations of uptake and elimination in any time frame. Furthermore, new technologies now allow capturing condensed breath vapor directly, or just the aerosol fraction alone, to gain access to inorganic species, lung pH, proteins and protein fragments, cellular DNA, and whole microorganisms from the pulmonary microbiome. Future applications are discussed, especially the use of isotopically labeled probes, non-targeted (discovery) analysis, cellular level toxicity testing, and ultimately assessing "crowd breath" of groups of people and the relation to dose of airborne and other environmental chemicals at the population level.

Experimentally increased temperature and hypoxia affect stability of social hierarchy and metabolism of the Amazonian cichlid Apistogramma agassizii.

The primary goal of this study was to understand how changes in temperature and oxygen could influence social behaviour and aerobic metabolism of the Amazonian dwarf cichlid Apistogramma agassizii. Social hierarchies were established over a period of 96h by observing the social interactions, feeding behaviour and shelter use in groups of four males. In the experimental environment, temperature was increased to 29°C in the high-temperature treatment, and oxygen lowered to 1.0mg·L(-1)O2 in the hypoxia treatment. Fish were maintained at this condition for 96h. The control was maintained at 26°C and 6.6mg·L(-1)O2. After the experimental exposure, metabolism was measured as routine metabolic rate (RMR) and electron transport system (ETS) activity. There was a reduction in hierarchy stability at high-temperature. Aggression changed after environmental changes. Dominant and subdominant fish at high temperatures increased their biting, compared with control-dominant. In contrast, hypoxia-dominant fish decreased their aggressive acts compared with all other fish. Shelter use decreased in control and hypoxic dominant fish. Dominant fish from undisturbed environments eat more than their subordinates. There was a decrease of RMR in fish exposed to the hypoxic environment when compared with control or high-temperature fish, independent of social position. Control-dominant fish had higher RMR than their subordinates. ETS activity increased in fish exposed to high temperatures; however, there was no effect on social rank. Our study reinforces the importance of environmental changes for the maintenance of hierarchies and their characteristics and highlights that most of the changes occur in the dominant position.

Preliminary study to explore gene-PM2.5 interactive effects on respiratory system in traffic policemen.

OBJECTIVES: Traffic-related particulate matter (PM) is one of the major sources of air pollution in metropolitan areas. This study is to observe the interactive effects of gene and fine particles (particles smaller than 2.5 µm - PM2.5) on the respiratory system and explore the mechanisms linking PM2.5 and pulmonary injury. MATERIAL AND METHODS: The participants include 110 traffic policemen and 101 common populations in Shanghai, China. Continuous 24 h individual-level PM2.5 is detected and the pulmonary function, high-sensitivity C-reactive protein (hs-CRP), Clara cell protein 16 (CC16) and the polymorphism in CXCL3, NME7 and C5 genes are determined. The multiple linear regression method is used to analyze the association between PM2.5 and health effects. Meanwhile, the interactive effects of gene and PM2.5 on lung function are analyzed. RESULTS: The individual PM2.5 exposure for traffic policemen was higher than that in the common population whereas the forced expiratory volume in 1 s (FEV1), the ratio of FEV1 to forced vital capacity (FEV1/FVC) and lymphocytes are lower. In contrast, the hs-CRP level is higher. In the adjusted analysis, PM2.5 exposure was associated with the decrease in lymphocytes and the increase in hs-CRP. The allele frequencies for NME7 and C5 have significant differences between FEV1/FVC ≤ 70% and FEV1/FVC > 70% participants. The results didn't find the interaction effects of gene and PM2.5 on FEV1/FVC in all the 3 genes. CONCLUSIONS: The results indicated that traffic exposure to high levels of PM2.5 was associated with systemic inflammatory response and respiratory injury. Traffic policemen represent a high risk group suffering from the respiratory injury.

[The content of protein regulators of apoptosis Bcl-2 and bad in regional lymph nodes of the liver under the influence of 50 Hz a magnetic field].

There was investigated the expression of molecular and cellular regulators of apoptosis Bcl-2 and Bad in the regional lymph nodes of the liver in rats exposed to the magnetic field of 50 Hz during 14 days. There was revealed a reduction in the protein expression of regulators of apoptosis Bcl-2 in the cortical area of the regional lymph nodes of the liver in animals exposed to the magnetic field.

Interplay between Dioxin-mediated signaling and circadian clock: a possible determinant in metabolic homeostasis.

The rotation of the earth on its axis creates the environment of a 24 h solar day, which organisms on earth have used to their evolutionary advantage by integrating this timing information into their genetic make-up in the form of a circadian clock. This intrinsic molecular clock is pivotal for maintenance of synchronized homeostasis between the individual organism and the external environment to allow coordinated rhythmic physiological and behavioral function. Aryl hydrocarbon receptor (AhR) is a master regulator of dioxin-mediated toxic effects, and is, therefore, critical in maintaining adaptive responses through regulating the expression of phase I/II drug metabolism enzymes. AhR expression is robustly rhythmic, and physiological cross-talk between AhR signaling and circadian rhythms has been established. Increasing evidence raises a compelling argument that disruption of endogenous circadian rhythms contributes to the development of disease, including sleep disorders, metabolic disorders and cancers. Similarly, exposure to environmental pollutants through air, water and food, is increasingly cited as contributory to these same problems. Thus, a better understanding of interactions between AhR signaling and the circadian clock regulatory network can provide critical new insights into environmentally regulated disease processes. This review highlights recent advances in the understanding of the reciprocal interactions between dioxin-mediated AhR signaling and the circadian clock including how these pathways relate to health and disease, with emphasis on the control of metabolic function.

Interactions between zinc deficiency and environmental enteropathy in developing countries.

Zinc deficiency affects one-fifth of the world's population and leads to substantial morbidity and mortality. Environmental enteropathy (EE), a subclinical pathology of altered intestinal morphology and function, is almost universal among people living in developing countries and affects long-term growth and health. This review explores the overlapping nature of these 2 conditions and presents evidence for their interaction. EE leads to impaired zinc homeostasis, predominantly due to reduced absorptive capacity arising from disturbed intestinal architecture, and zinc deficiency exacerbates several of the proposed pathways that underlie EE, including intestinal permeability, enteric infection, and chronic inflammation. Ongoing zinc deficiency likely perpetuates the adverse outcomes of EE by worsening malabsorption, reducing intestinal mucosal immune responses, and exacerbating systemic inflammation. Although the etiology of EE is predominantly environmental, zinc deficiency may also have a role in its pathogenesis. Given the impact of both EE and zinc deficiency on morbidity and mortality in developing countries, better understanding the relation between these 2 conditions may be critical for developing combined interventions to improve child health.

Atmospheric pressure chemical ionization mass spectrometry of pyridine and isoprene: potential breath exposure and disease biomarkers.

Volatile organic compounds (VOCs) in exhaled human breath can serve as potential disease-specific and exposure biomarkers and therefore can reveal information about a subject's health and environment. Pyridine, a VOC marker for exposure to tobacco smoke, and isoprene, a liver disease biomarker, were studied using atmospheric pressure chemical ionization mass spectrometry (APCI-MS). While both molecules could be detected in low-ppb levels, interactions of the ionized analytes with their neutral forms and ambient air led to unusual ion/molecule chemistry. The result was a highly dynamic system and a nonlinear response to changes in analyte concentration. Increased presence of ambient water was found to greatly enhance the detection limit of pyridine and only slightly decrease that of isoprene. APCI-MS is shown to be a promising analytical tool in breath analysis with good detection limits, but its application requires a better understanding of the ion/molecule chemistry that may affect VOC quantification from a chemically complex system such as human breath.

Detection of mycotoxins in patients with chronic fatigue syndrome.

Over the past 20 years, exposure to mycotoxin producing mold has been recognized as a significant health risk. Scientific literature has demonstrated mycotoxins as possible causes of human disease in water-damaged buildings (WDB). This study was conducted to determine if selected mycotoxins could be identified in human urine from patients suffering from chronic fatigue syndrome (CFS). Patients (n = 112) with a prior diagnosis of CFS were evaluated for mold exposure and the presence of mycotoxins in their urine. Urine was tested for aflatoxins (AT), ochratoxin A (OTA) and macrocyclic trichothecenes (MT) using Enzyme Linked Immunosorbent Assays (ELISA). Urine specimens from 104 of 112 patients (93%) were positive for at least one mycotoxin (one in the equivocal range). Almost 30% of the cases had more than one mycotoxin present. OTA was the most prevalent mycotoxin detected (83%) with MT as the next most common (44%). Exposure histories indicated current and/or past exposure to WDB in over 90% of cases. Environmental testing was performed in the WDB from a subset of these patients. This testing revealed the presence of potentially mycotoxin producing mold species and mycotoxins in the environment of the WDB. Prior testing in a healthy control population with no history of exposure to a WDB or moldy environment (n = 55) by the same laboratory, utilizing the same methods, revealed no positive cases at the limits of detection.

[Testing of the system of biochemical and immunological indices of the state of population health in the survey of residents of Moscow, exposed to ambient air pollution].

New biomarkers of effect of some controlled ambient air pollutants (formaldehyde, carbon monoxide and TSP) were found in two surveys of Moscow residents (apparently healthy and outpatients with allergic diseases) with a help of screening system of biochemical and immunological parameters. Possible mechanisms of the effects, including interference of atmospheric carbon monoxide and sulfur dioxide with corresponding endogenous second messengers, are discussed.

[Assessment of actual nutrition of Arctic migrants sympathoadrenal and the activity of the sympathoadrenal system].

The complex of extreme factors of the Arctic and unbalanced diet have an adverse effect on a human and alter the functional activity of his sympathoadrenal system. Representative sample of migrants in the Arctic was examined to study the structure of nutrition as a factor of influence on the activity of the sympathoadrenal system. The actual nutrition of migrants in the Arctic plays a role of a stressing factor that increases the tone of the sympathoadrenal system.

[The inflammatory response as a manifestation of the influence of environmental chemical factors].

The paper shows that a chronic slowly developing inflammation manifesting itself as adipokine imbalance and lipid metabolism abnormalities in the body under the influence of unfavorable environmental factors.

[The content of metals in hair and blood in the child population of cities of Aktobe region].

The content of metal carcinogens in hair and blood in children's population in thee cities of Aktobe area has been studied. These data indicate that levels of carcinogens in children living in the Khromtau and Aktobe cities are 2 times higher than levels of carcinogens in children living in the Alga city.