Biological embedding of early life exposures and disease risk in humans: a role for DNA methylation.

BACKGROUND: Following wider acceptance of "the thrifty phenotype" hypothesis and the convincing evidence that early life exposures can influence adult health even decades after the exposure, much interest has been placed on the mechanisms through which early life exposures become biologically embedded. METHODS: In this review, we summarize the current literature regarding biological embedding of early life experiences. To this end we conducted a literature search to identify studies investigating early life exposures in relation to DNA methylation changes. In addition, we summarize the challenges faced in investigations of epigenetic effects, stemming from the peculiarities of this emergent and complex field. A proper systematic review and meta-analyses were not feasible given the nature of the evidence. RESULTS: We identified 7 studies on early life socioeconomic circumstances, 10 studies on childhood obesity, and 6 studies on early life nutrition all relating to DNA methylation changes that met the stipulated inclusion criteria. The pool of evidence gathered, albeit small, favours a role of epigenetics and DNA methylation in biological embedding, but replication of findings, multiple comparison corrections, publication bias, and causality are concerns remaining to be addressed in future investigations. CONCLUSIONS: Based on these results, we hypothesize that epigenetics, in particular DNA methylation, is a plausible mechanism through which early life exposures are biologically embedded. This review describes the current status of the field and acts as a stepping stone for future, better designed investigations on how early life exposures might become biologically embedded through epigenetic effects. This article is protected by copyright. All rights reserved.

Modelling of Mercury’s surface composition and remote detection from the orbit with the BepiColombo Mercury Planetary Orbiter

It can be assumed that the composition of Mercury’s thin gas envelope (exosphere) is related to thecomposition of the planets crustal materials. If this relationship is true, then inferences regarding the bulkchemistry of the planet might be made from a thorough exospheric study. The most vexing of allunsolved problems is the uncertainty in the source of each component. Historically, it has been believedthat H and He come primarily from the solar wind, while Na and K originate from volatilized materialspartitioned between Mercury’s crust and meteoritic impactors. The processes that eject atoms andmolecules into the exosphere of Mercury are generally considered to be thermal vaporization, photonstimulateddesorption (PSD), impact vaporization, and ion sputtering. Each of these processes has its owntemporal and spatial dependence. The exosphere is strongly influenced by Mercury’s highly ellipticalorbit and rapid orbital speed. As a consequence the surface undergoes large fluctuations in temperatureand experiences differences of insolation with longitude. We will discuss these processes but focus moreon the expected surface composition and solar wind particle sputtering which releases material like Caand other elements from the surface minerals and discuss the relevance of composition modelling

Insights into low fish mercury bioaccumulation in a mercury-contaminated reservoir, Guizhou, China.

We examined Hg biogeochemistry in Baihua Reservoir, a system affected by industrial wastewater containing mercury (Hg). As expected, we found high levels of total Hg (THg, 664-7421 ng g(-1)) and monomethylmercury (MMHg, 3-21 ng g(-1)) in the surface sediments (0-10 cm). In the water column, both THg and MMHg showed strong vertical variations with higher concentrations in the anoxic layer (>4m) than in the oxic layer (0-4 m), which was most pronounced for the dissolved MMHg (p < 0.001). However, mercury levels in biota samples (mostly cyprinid fish) were one order of magnitude lower than common regulatory values (i.e. 0.3-0.5 mg kg(-1)) for human consumption. We identified three main reasons to explain the low fish Hg bioaccumulation: disconnection of the aquatic food web from the high MMHg zone, simple food web structures, and biodilution effect at the base of the food chain in this eutrophic reservoir.

Impact of biological and environmental variabilities on biological monitoring: an approach using toxicokinetic models

Biological monitoring of occupational exposure is characterized by important variability, due both to variability in the environment and to biological differences between workers. A quantitative description and understanding of this variability is important for a dependable application of biological monitoring. This work describes this variability,using a toxicokinetic model, for a large range of chemicals for which reference biological reference values exist. A toxicokinetic compartmental model describing both the parent compound and its metabolites was used. For each chemical, compartments were given physiological meaning. Models were elaborated based on physiological, physicochemical, and biochemical data when available, and on half-lives and central compartment concentrations when not available. Fourteen chemicals were studied (arsenic, cadmium, carbon monoxide, chromium, cobalt, ethylbenzene, ethyleneglycol monomethylether, fluorides, lead, mercury, methyl isobutyl ketone, penthachlorophenol, phenol, and toluene), representing 20 biological indicators. Occupational exposures were simulated using Monte Carlo techniques with realistic distributions of both individual physiological parameters and exposure conditions. Resulting biological indicator levels were then analyzed to identify the contribution of environmental and biological variability to total variability. Comparison of predicted biological indicator levels with biological exposure limits showed a high correlation with the model for 19 out of 20 indicators. Variability associated with changes in exposure levels (GSD of 1.5 and 2.0) is shown to be mainly influenced by the kinetics of the biological indicator. Thus, with regard to variability, we can conclude that, for the 14 chemicals modeled, biological monitoring would be preferable to air monitoring. For short half-lives (less than 7 hr), this is very similar to the environmental variability. However, for longer half-lives, estimated variability decreased. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: tables detailing the CBTK models for all 14 chemicals and the symbol nomenclature that was used.] [Authors]

Occupational respiratory exposures to irritating and sensitizing volatile compounds deriving from cleaning products

Recent findings suggest an association between exposure to cleaning products and respiratory dysfunctions including asthma. However, little information is available about quantitative airborne exposures of professional cleaners to volatile organic compounds deriving from cleaning products. During the first phases of the study, a systematic review of cleaning products was performed. Safety data sheets were reviewed to assess the most frequently added volatile organic compounds. It was found that professional cleaning products are complex mixtures of different components (compounds in cleaning products: 3.5 ± 2.8), and more than 130 chemical substances listed in the safety data sheets were identified in 105 products. The main groups of chemicals were fragrances, glycol ethers, surfactants, solvents; and to a lesser extent phosphates, salts, detergents, pH-stabilizers, acids, and bases. Up to 75% of products contained irritant (Xi), 64% harmful (Xn) and 28% corrosive (C) labeled substances. Hazards for eyes (59%), skin (50%) and by ingestion (60%) were the most reported. Monoethanolamine, a strong irritant and known to be involved in sensitizing mechanisms as well as allergic reactions, is frequently added to cleaning products. Monoethanolamine determination in air has traditionally been difficult and air sampling and analysis methods available were little adapted for personal occupational air concentration assessments. A convenient method was developed with air sampling on impregnated glass fiber filters followed by one step desorption, gas chromatography and nitrogen phosphorous selective detection. An exposure assessment was conducted in the cleaning sector, to determine airborne concentrations of monoethanolamine, glycol ethers, and benzyl alcohol during different cleaning tasks performed by professional cleaning workers in different companies, and to determine background air concentrations of formaldehyde, a known indoor air contaminant. The occupational exposure study was carried out in 12 cleaning companies, and personal air samples were collected for monoethanolamine (n=68), glycol ethers (n=79), benzyl alcohol (n=15) and formaldehyde (n=45). All but ethylene glycol mono-n-butyl ether air concentrations measured were far below (<1/10) of the Swiss eight hours occupational exposure limits, except for butoxypropanol and benzyl alcohol, where no occupational exposure limits were available. Although only detected once, ethylene glycol mono-n-butyl ether air concentrations (n=4) were high (49.5 mg/m3 to 58.7 mg/m3), hovering at the Swiss occupational exposure limit (49 mg/m3). Background air concentrations showed no presence of monoethanolamine, while the glycol ethers were often present, and formaldehyde was universally detected. Exposures were influenced by the amount of monoethanolamine in the cleaning product, cross ventilation and spraying. The collected data was used to test an already existing exposure modeling tool during the last phases of the study. The exposure estimation of the so called Bayesian tool converged with the measured range of exposure the more air concentrations of measured exposure were added. This was best described by an inverse 2nd order equation. The results suggest that the Bayesian tool is not adapted to predict low exposures. The Bayesian tool should be tested also with other datasets describing higher exposures. Low exposures to different chemical sensitizers and irritants should be further investigated to better understand the development of respiratory disorders in cleaning workers. Prevention measures should especially focus on incorrect use of cleaning products, to avoid high air concentrations at the exposure limits. - De récentes études montrent l'existence d'un lien entre l'exposition aux produits de nettoyages et les maladies respiratoires telles que l'asthme. En revanche, encore peu d'informations sont disponibles concernant la quantité d'exposition des professionnels du secteur du nettoyage aux composants organiques volatiles provenant des produits qu'ils utilisent. Pendant la première phase de cette étude, un recueil systématique des produits professionnels utilisés dans le secteur du nettoyage a été effectué. Les fiches de données de sécurité de ces produits ont ensuite été analysées, afin de répertorier les composés organiques volatiles les plus souvent utilisés. Il a été mis en évidence que les produits de nettoyage professionnels sont des mélanges complexes de composants chimiques (composants chimiques dans les produits de nettoyage : 3.5 ± 2.8). Ainsi, plus de 130 substances listées dans les fiches de données de sécurité ont été retrouvées dans les 105 produits répertoriés. Les principales classes de substances chimiques identifiées étaient les parfums, les éthers de glycol, les agents de surface et les solvants; dans une moindre mesure, les phosphates, les sels, les détergents, les régulateurs de pH, les acides et les bases ont été identifiés. Plus de 75% des produits répertoriés contenaient des substances décrites comme irritantes (Xi), 64% nuisibles (Xn) et 28% corrosives (C). Les risques pour les yeux (59%), la peau (50%) et par ingestion (60%) était les plus mentionnés. La monoéthanolamine, un fort irritant connu pour être impliqué dans les mécanismes de sensibilisation tels que les réactions allergiques, est fréquemment ajouté aux produits de nettoyage. L'analyse de la monoéthanolamine dans l'air a été habituellement difficile et les échantillons d'air ainsi que les méthodes d'analyse déjà disponibles étaient peu adaptées à l'évaluation de la concentration individuelle d'air aux postes de travail. Une nouvelle méthode plus efficace a donc été développée en captant les échantillons d'air sur des filtres de fibre de verre imprégnés, suivi par une étape de désorption, puis une Chromatographie des gaz et enfin une détection sélective des composants d'azote. Une évaluation de l'exposition des professionnels a été réalisée dans le secteur du nettoyage afin de déterminer la concentration atmosphérique en monoéthanolamine, en éthers de glycol et en alcool benzylique au cours des différentes tâches de nettoyage effectuées par les professionnels du nettoyage dans différentes entreprises, ainsi que pour déterminer les concentrations atmosphériques de fond en formaldéhyde, un polluant de l'air intérieur bien connu. L'étude de l'exposition professionnelle a été effectuée dans 12 compagnies de nettoyage et les échantillons d'air individuels ont été collectés pour l'éthanolamine (n=68), les éthers de glycol (n=79), l'alcool benzylique (n=15) et le formaldéhyde (n=45). Toutes les substances mesurées dans l'air, excepté le 2-butoxyéthanol, étaient en-dessous (<1/10) de la valeur moyenne d'exposition aux postes de travail en Suisse (8 heures), excepté pour le butoxypropanol et l'alcool benzylique, pour lesquels aucune valeur limite d'exposition n'était disponible. Bien que détecté qu'une seule fois, les concentrations d'air de 2-butoxyéthanol (n=4) étaient élevées (49,5 mg/m3 à 58,7 mg/m3), se situant au-dessus de la frontière des valeurs limites d'exposition aux postes de travail en Suisse (49 mg/m3). Les concentrations d'air de fond n'ont montré aucune présence de monoéthanolamine, alors que les éthers de glycol étaient souvent présents et les formaldéhydes quasiment toujours détectés. L'exposition des professionnels a été influencée par la quantité de monoéthanolamine présente dans les produits de nettoyage utilisés, par la ventilation extérieure et par l'emploie de sprays. Durant la dernière phase de l'étude, les informations collectées ont été utilisées pour tester un outil de modélisation de l'exposition déjà existant, l'outil de Bayesian. L'estimation de l'exposition de cet outil convergeait avec l'exposition mesurée. Cela a été le mieux décrit par une équation du second degré inversée. Les résultats suggèrent que l'outil de Bayesian n'est pas adapté pour mettre en évidence les taux d'expositions faibles. Cet outil devrait également être testé avec d'autres ensembles de données décrivant des taux d'expositions plus élevés. L'exposition répétée à des substances chimiques ayant des propriétés irritatives et sensibilisantes devrait être investiguée d'avantage, afin de mieux comprendre l'apparition de maladies respiratoires chez les professionnels du nettoyage. Des mesures de prévention devraient tout particulièrement être orientées sur l'utilisation correcte des produits de nettoyage, afin d'éviter les concentrations d'air élevées se situant à la valeur limite d'exposition acceptée.

MERCURY QUANTIFICATION IN SOILS USING THERMAL DESORPTION AND ATOMIC ABSORPTION SPECTROMETRY: PROPOSAL FOR AN ALTERNATIVE METHOD OF ANALYSIS

Despite the considerable environmental importance of mercury (Hg), given its high toxicity and ability to contaminate large areas via atmospheric deposition, little is known about its activity in soils, especially tropical soils, in comparison with other heavy metals. This lack of information about Hg arises because analytical methods for determination of Hg are more laborious and expensive compared to methods for other heavy metals. The situation is even more precarious regarding speciation of Hg in soils since sequential extraction methods are also inefficient for this metal. The aim of this paper is to present a technique of thermal desorption associated with atomic absorption spectrometry, TDAAS, as an efficient tool for quantitative determination of Hg in soils. The method consists of the release of Hg by heating, followed by its quantification by atomic absorption spectrometry. It was developed by constructing calibration curves in different soil samples based on increasing volumes of standard Hg2+ solutions. Performance, accuracy, precision, and quantification and detection limit parameters were evaluated. No matrix interference was detected. Certified reference samples and comparison with a Direct Mercury Analyzer, DMA (another highly recognized technique), were used in validation of the method, which proved to be accurate and precise.

A novel in vitro metabolomics approach for neurotoxicity testing, proof of principle for methyl mercury chloride and caffeine

There is a need for more efficient methods giving insight into the complex mechanisms of neurotoxicity. Testing strategies including in vitro methods have been proposed to comply with this requirement. With the present study we aimed to develop a novel in vitro approach which mimics in vivo complexity, detects neurotoxicity comprehensively, and provides mechanistic insight. For this purpose we combined rat primary re-aggregating brain cell cultures with a mass spectrometry (MS)-based metabolomics approach. For the proof of principle we treated developing re-aggregating brain cell cultures for 48h with the neurotoxicant methyl mercury chloride (0.1-100muM) and the brain stimulant caffeine (1-100muM) and acquired cellular metabolic profiles. To detect toxicant-induced metabolic alterations the profiles were analysed using commercial software which revealed patterns in the multi-parametric dataset by principal component analyses (PCA), and recognised the most significantly altered metabolites. PCA revealed concentration-dependent cluster formations for methyl mercury chloride (0.1-1muM), and treatment-dependent cluster formations for caffeine (1-100muM) at sub-cytotoxic concentrations. Four relevant metabolites responsible for the concentration-dependent alterations following methyl mercury chloride treatment could be identified using MS-MS fragmentation analysis. These were gamma-aminobutyric acid, choline, glutamine, creatine and spermine. Their respective mass ion intensities demonstrated metabolic alterations in line with the literature and suggest that the metabolites could be biomarkers for mechanisms of neurotoxicity or neuroprotection. In addition, we evaluated whether the approach could identify neurotoxic potential by testing eight compounds which have target organ toxicity in the liver, kidney or brain at sub-cytotoxic concentrations. PCA revealed cluster formations largely dependent on target organ toxicity indicating possible potential for the development of a neurotoxicity prediction model. With such results it could be useful to perform a validation study to determine the reliability, relevance and applicability of this approach to neurotoxicity screening. Thus, for the first time we show the benefits and utility of in vitro metabolomics to comprehensively detect neurotoxicity and to discover new biomarkers.

Induction of apoptosis by mercury compounds depends on maturation and is not associated with microglial activation

The earliest sign of neurotoxicity observed after exposure of three-dimensional brain cell cultures to low concentrations of mercury compounds is a microglial reaction. We hypothesized that an induction of apoptosis by mercury compounds could be an activating signal of the microglial reaction. Aggregating brain cell cultures of fetal rat telencephalon were treated for 10 days with either mercury chloride or monomethylmercury chloride at noncytotoxic concentrations during two developmental periods: from day 5 to 15, corresponding to an immature stage, and from day 25 to 35 corresponding to a mature stage. Apoptosis was evaluated by the TUNEL technique. It was found that both mercury compounds caused a significant increase in the number of apoptotic cells, but exclusively in immature cultures exhibiting also spontaneous apoptosis. Double staining by the TUNEL technique combined with either neuronal or astroglial markers revealed that the proportion of cells undergoing apoptosis was highest for astrocytes. Furthermore neither an association nor a colocalization was found between apoptotic cells and microglial cells. In conclusion, it appears that the induction of apoptosis by mercury compounds in immature cells is only an acceleration of a spontaneously occurring process, and that it is not a directly related to the early microglial reaction.

Biological embedding of early-life exposures and disease risk in humans : a role for DNA methylation

BACKGROUND: Following wider acceptance of 'the thrifty phenotype' hypothesis and the convincing evidence that early-life exposures can influence adult health even decades after the exposure, much interest has been placed on the mechanisms through which early-life exposures become biologically embedded. MATERIALS AND METHODS: In this review, we summarize the current literature regarding biological embedding of early-life experiences. To this end, we conducted a literature search to identify studies investigating early-life exposures in relation to DNA methylation changes. In addition, we summarize the challenges faced in investigations of epigenetic effects, stemming from the peculiarities of this emergent and complex field. A proper systematic review and meta-analyses were not feasible given the nature of the evidence. RESULTS: We identified seven studies on early-life socio-economic circumstances, 10 studies on childhood obesity and six studies on early-life nutrition all relating to DNA methylation changes that met the stipulated inclusion criteria. The pool of evidence gathered, albeit small, favours a role of epigenetics and DNA methylation in biological embedding, but replication of findings, multiple comparison corrections, publication bias and causality are concerns remaining to be addressed in future investigations. CONCLUSIONS: Based on these results, we hypothesize that epigenetics, in particular DNA methylation, is a plausible mechanism through which early-life exposures are biologically embedded. This review describes the current status of the field and acts as a stepping stone for future, better designed investigations on how early-life exposures might become biologically embedded through epigenetic effects.

The importance of environmental exposures to physical, mental and social well-being

"Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity" states the WHO. However, the current focus in this important area seems to be on reducing diseases, while less attention is paid on aspects how to increase the well-being of populations. This paper reviews three examples where well-being has drawn attention of the public and policy makers, and compares the policies of two wealthy countries. The first example is noise. Noise can reduce sleep quality and cause physiological, mental, and social effects. In Switzerland, noise receives a lot of attention by the public. Swiss laws are extensive, e.g., they prohibit trucks and planes from traveling at night. In the USA, there is little public attention and no national strategy against environmental noise. The second example is aesthetics and recreation. Many humans seek contact with the beauty of nature. The USA and Switzerland have similar strategies for achieving clear waters, while the protection of scenic views is approached very differently. Lifestyle is the last example. In the USA, the desire for individual freedom is a leading cause for suburban sprawl, a car-dependent sedentary lifestyle resulting in obesity, asthma and loss of community spirit. In Switzerland, a strict land use planning seeks to balance individual and public interests and stresses public transportation, which seems to be a more promising approach. Paying attention to aspects of well-being while developing political strategies might be a promising model to tackle environmental problems. Successful strategies employed so far seem to include the public, local authorities, politicians and scientists in this process, which might have been a key for their success. [Authors]