Mechanisms of Immunotoxicity: Stressors and Evaluators.

The immune system defends the body against certain tumor cells and against foreign agents such as fungi, parasites, bacteria, and viruses. One of its main roles is to distinguish endogenous components from non-self-components. An unproperly functioning immune system is prone to primary immune deficiencies caused by either primary immune deficiencies such as genetic defects or secondary immune deficiencies such as physical, chemical, and in some instances, psychological stressors. In the manuscript, we will provide a brief overview of the immune system and immunotoxicology. We will also describe the biochemical mechanisms of immunotoxicants and how to evaluate immunotoxicity.

Epigenome-wide association study reveals methylation pathways associated with childhood allergic sensitization.

Epigenetic mechanisms integrate both genetic variability and environmental exposures. However, comprehensive epigenome-wide analysis has not been performed across major childhood allergic phenotypes. We examined the association of epigenome-wide DNA methylation in mid-childhood peripheral blood (Illumina HumanMethyl450K) with mid-childhood atopic sensitization, environmental/inhalant and food allergen sensitization in 739 children in two birth cohorts (Project Viva-Boston, and the Generation R Study-Rotterdam). We performed covariate-adjusted epigenome-wide association meta-analysis and employed pathway and regional analyses of results. Seven-hundred and five methylation sites (505 genes) were significantly cross-sectionally associated with mid-childhood atopic sensitization, 1411 (905 genes) for environmental and 45 (36 genes) for food allergen sensitization (FDR<0.05). We observed differential methylation across multiple genes for all three phenotypes, including genes implicated previously in innate immunity (DICER1), eosinophilic esophagitis and sinusitis (SIGLEC8), the atopic march (AP5B1) and asthma (EPX, IL4, IL5RA, PRG2, SIGLEC8, CLU). In addition, most of the associated methylation marks for all three phenotypes occur in putative transcription factor binding motifs. Pathway analysis identified multiple methylation sites associated with atopic sensitization and environmental allergen sensitization located in/near genes involved in asthma, mTOR signaling, and inositol phosphate metabolism. We identified multiple differentially methylated regions associated with atopic sensitization (8 regions) and environmental allergen sensitization (26 regions). A number of nominally significant methylation sites in the cord blood analysis were epigenome-wide significant in the mid-childhood analysis, and we observed significant methylation - time interactions among a subset of sites examined. Our findings provide insights into epigenetic regulatory pathways as markers of childhood allergic sensitization.

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.

[Rare-earth metals as a factor in mutagenicity].

Both the regions of the Orenburg Region area and individual examined streams and reservoirs were shown to be characterized by a varying load index for rare earth elements. The total level of rare earth elements was directly correlated with different types of mutations.

Frontiers in occupational and environmental lung disease research.

Two central challenges in the field of occupational and environmental epidemiology include accurately measuring biologic responses to exposure and preventing subsequent disease. As exposure-related lung diseases continue to be identified, advances in exposure biology have introduced toxicogenomic approaches that detect biomarkers of exposure at the gene, protein, and metabolite levels. Moreover, genetic epidemiology research has focused more recently on common, low-penetrant (ie, low-relative-risk) genetic variants that may interact with commonly encountered exposures. A number of such gene by environment interactions have been identified for airways and interstitial lung diseases, with the goal of preventing disease among susceptible populations that may not otherwise have been identified. Exhaled breath condensate analysis has provided another noninvasive means of assessing toxicant exposures and systemic effects. As these technologies become more refined, clinicians and public health practitioners will need to appreciate the social implications of the individual- and population-level risks conferred by certain genetic polymorphisms or by biomarker evidence of exposure. At present, the primary approach to occupational and environmental lung disease prevention remains elimination or reduction of known hazardous exposures and requires continued application of local and international resources toward exposure control.

On information coded in gene-environment independence in case-control studies.

For analysis of case-control genetic association studies, it has recently been shown that gene-environment independence in the population can be leveraged to increase efficiency for estimating gene-environment interaction effects in comparison with the standard prospective analysis. However, for the special case in which data on the binary phenotype and genetic and environmental risk factors can be summarized in a 2 × 2 × 2 table, the authors show here that there is no efficiency gain for estimating interaction effects, nor is there an efficiency gain for estimating the genetic and environmental main effects. This contrasts with the well-known result assuming that rare phenotype prevalence and gene-environment independence in the control population for the same data can lead to efficiency gain. This discrepancy is counterintuitive, since the 2 likelihoods are also approximately equal when the phenotype is rare. An explanation for the paradox based on a theoretical analysis is provided. Implications of these results for data analyses are also examined, and practical guidance on analyzing such case-control studies is offered.

[The cytogenetic status of children living in the vicinity of a pulp-and-paper mill].

To evaluate the cytogenetic and cytotoxic effects of a set of pollutions in the town of Koryazhma, the investigators made a complete karyological analysis (cytogenetic, apoptotic, and indirect proliferation parameters) of buccal and nasal epithelial exfoliative cells in two groups of old school age children living at various distances from a pulp-and-paper mill (PPM). The residential area that is adjacent to the PPM can be considered to be poor in the influence of genotoxic factors since there were 1.6- and 1.65-fold increases in cytogenetic disorders and cells with an atypically shaped nucleus, respectively, with a 1.57-fold reduction in the level of cell apoptosis. Karyological changes were revealed in the nasal mucosa, rather than in the buccal mucosa, which permitted one to recommend for the evaluation of the influence of environmental factors, the impact of ambient air pollution in particular, and to conduct cytogenetic studies on the cells of not only the buccal epithelium (that has been better studied), but also those of the nasal epithelium.

[Effect of toxins of cyanobacteria of the Microcystis genus from the Shershnevo Reservoir on DNA, cell cycle, and apoptosis of bone marrow cells in CBA mice].

The effect of toxins of a Cyanobacterium sample of the Shershnevo Reservoir on DNA, which was presented by cyanobacteria of the Microcystis genera, on the bone marrow of male CBA mice (whose age was 3 months and weight 24 g) was evaluated. With intraperitoneal administration, LD50 and LD16 of this sample for male CBA mice were 48.4 and 42.1 mg/kg, respectively. Administration of Microcystis cyanobacterial sample from the Shershnevo Reservoir in doses of 1/10 of LD16 and 1/2 of LD16, and LD16 was found to cause a dose-dependent reduction in the number of bone marrow nucleated cells, a dose-dependent increase in the rate of cell apoptotic death, a reduction in the duration of a cell cycle (within the first 12 hours), which gave way to an increase in the duration of the cycle 24 hours after administration, a dose-dependent increase in the frequency of micronuclei in the murine bone marrow eryphrocytes, and a dose-dependent decrease in the polychromatophil/normochromatophil ratio in the murine bone marrow.

Gene-environment interactions in environmental lung diseases.

Lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS) have complex etiologies. It is generally agreed that genetic background has an important role in susceptibility to these diseases, and the genetic contribution to disease phenotypes varies between populations. Linkage analyses have identified some predisposing genes. However, genetic background cannot account for all of the inter-individual variation in disease susceptibility. Interaction between genetic background and exposures to environmental stimuli, and understanding of the mechanisms through which environmental exposure interact with susceptibility genes, is critical to disease prevention. Use of animal models, particularly inbred mice, has provided important insight to understand human disease etiologies because genetic background and environmental exposures can be controlled. We have utilized a positional cloning approach in inbred mice to identify candidate susceptibility genes for oxidant-induced lung injury. Subsequent investigations with cell models identified functional polymorphisms in human homologues that confer enhanced risk of lung injury in humans. This 'bench to bedside' approach may provide an understanding of gene-environment interactions in complex lung diseases is essential to the development of new strategies for lung disease prevention and treatment.

Sequencing and its consequences: path dependence and the relationships between genetics and medicalization.

Both advocacy for and critiques of the Human Genome Project assume a self-sustaining relationship between genetics and medicalization. However, this assumption ignores the ways in which the meanings of genetic research are conditional on its position in sequences of events. Based on analyses of three conditions for which at least one putative gene or genetic marker has been identified, this article argues that critical junctures in the institutional stabilization of phenotypes and the mechanisms that sustain such classifications over time configure the practices and meanings of genetic research. Path dependence is critical to understanding the lack of consistent fit between genetics and medicalization.

[Buccal epithelial micronuclear test in the comprehensive assessment of children's ecological well-being in Moscow].

In the buccal epithelial micronuclear test, only the higher frequency of cells with any nuclear degenerative changes is considered to be attributable to the adverse influence of environmental factors. Comprehensive examination of 223 children of 5-7 years of age, going to kindergartens and schools has indicated that the frequency of cells with nuclear chromatin condensation and incomplete nuclear lysis decreased when ambient air contamination was increased in the territories of children's establishments and when the child's throat was contaminated with Staphylococcus aureus or the pharyngeal resident microflora inhibited. Some poor conditions of the nasal and buccal mucosae were also associated with the increase or decrease of cell frequencies. It is suggested that nuclear chromatin condensation and nuclear lysis (rather than other signs of cell degeneration and death) reflect natural cell aging. A moderate toxic effect causes epitheliocytic physiological development retardation and a more intensive effect accelerates aging of cells and induces their death.

[Evaluation of the mutagenic effects of environmental factors using polyorgan micronuclear test].

The author reviews the results of studies in which mutagenic effects of environmental factors were investigated using polyorgan micronuclear test, and substantiates the application of this test. This new approach enables fulfillment of various hygienic tasks, such as evaluation of the mutagenic activity of individual factors and mixtures (evaluation of total mutagenic activity), and detection of the level of human genetic lesions.

[A modification factor of spontaneous chromosomal aberrations in miner's towns and settlements].

The level and qualitative spectrum of spontaneous chromosomal aberrations (CA) were comparatively analyzed in the lymphocytes of 655 children and adolescents from the Kemerovo Region. The presented sample was divided into 3 groups according to the type of an inhabited locality: 1) small miner's towns; 2) large industrial towns; and 3) rural localities. The maximum frequency of CA (3.77 +/- 0.22%) was noted in a group of dwellers in the miner's towns; its minimum frequency (2.68 +/- 0.17%) among the rural inhabitants. The significant clastogenic effects (including the markers of radiation exposure) were detected in the miner's towns located in the southern part of the region, which represented mountain and submountain areas. At the same time, in the northern and western parts of the Kemerovo Region, the average frequencies of CA in children and adolescents did not exceed the control background values. Thus, the residence in the inhabited localities specializing in mining is not a factor of absolute toxicogenetic risk.

PopGen: population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships.

OBJECTIVE: Patient samples used for mapping complex human disease genes are unlikely to be representative of the phenotype spectrum of the respective population as a whole. On the other hand, most ongoing prospective studies are probably too small for evaluating polygenic disease markers. DESIGN: Precise estimates of population-specific genotypic risks can be obtained efficiently through the complete ascertainment of patients in a geographically confined area. The PopGen project uses the most northern part of Germany as a target region for such a pursuit. RESULTS: PopGen currently pursues recruitment, sampling and processing activities in close collaboration with a multitude of clinical partners, covering cardiovascular, neuropsychiatric and environmental diseases. CONCLUSION: PopGen has successfully established itself as a large-scale genetic epidemiological project of international recognition.

Fibrinogen and CRP in Israeli families: genetic and environmental sources of concentrations and longitudinal changes.

OBJECTIVE: To estimate the genetic and environmental determinants of plasma fibrinogen and C-reactive protein (CRP). METHODS AND RESULTS: A complex segregation analysis was undertaken in a sample of 142 kindreds residing in Kibbutz settlements in Israel. In addition, included in this analysis were family members who were examined 10 years earlier in the framework of this study. Analysis indicated a major locus in addition to polygenic effect that explained the sex- and age-adjusted levels and longitudinal changes in plasma fibrinogen. A non-transmitted environmental major factor with no polygenic effect explained the adjusted variation in levels and change of CRP. Both the particular genotypes determined by the major genetic factor associated with fibrinogen levels and the particular ousiotypes determined by the major environmental factor associated with CRP levels were sex- and age-dependent. In addition, our results demonstrated significant interactions between polygenotype and gender, age and environmental factors such as smoking and BMI on fibrinogen and CRP levels. CONCLUSIONS: Our models that consider interactions between genotypes and gender, age and environmental exposures have the potential to improve our understanding of the genetics of fibrinogen and CRP levels.

Genetic aspects of pulmonary responses to inhaled pollutants.

Air pollution continues to be a major public health concern in industrialized cities throughout the world. Recent population and epidemiological studies that have associated ozone and particulate exposures with morbidity and mortality outcomes underscore the important detrimental effects of these pollutants on the lung. Inter-individual variation in human responses to air pollutants suggests that some subpopulations are at increased risk to the detrimental effects of pollutant exposure, and it has become clear that genetic background is an important susceptibility factor. Environmental exposures to inhaled pollutants and genetic factors associated with disease risk likely interact in a complex fashion that varies from one population to another. The relationships between the genetic background and disease risk and severity is often evaluated through traditional family-based linkage studies and positional cloning techniques. Case-control studies based on association of disease or disease subphenotypes with candidate genes may have certain advantages over family pedigree studies, and have become useful for understanding complex disease phenotypes. This is based in part on continued development of quantitative analysis and development of mapping technologies. Linkage analyses with genetically standardized animal models are useful to identify genetic determinants of host responses to environmental stimuli. For example, linkage analyses using inbred mice have identified chromosomal segments (quantitative trait loci, QTL) that contain genes that control susceptibility to the lung inflammatory and immune dysfunction responses to ozone, nitrogen dioxide, zinc oxide, and sulfate-associated particles. Candidate genes within the pollutant susceptibility QTLs have been tested for proof-of-concept using gene-targeting and overexpression models. Importantly, significant homology exists between the human and mouse genomes. Therefore, comparative mapping between the human and mouse genomes should yield candidate susceptibility genes that may be tested by association studies in humans. The combined human studies and mouse modeling will provide important insight to understanding genetic factors that contribute to differential susceptibility to pollutants in human populations.

La acumulación de alteraciones genéticas y epigenéticas: un proceso causal clave entre el medio ambiente y las enfermedades de etiología compleja / Accumulation of genetic and epigenetic alterations: a key causal process between the environment and diseases of complex etiology

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[Current problems of hygiene and epidemiology]. / Problemy higieny i epidemiologii, takze molekularnej.

In this review, the data available in the literature concerning determinants of human health from the public health point of view have been summarized. Presented newest concepts of human health include genomic and proteomic perspectives in the complex web of interactions between genes and environment. In 2002 epidemiologist and hygienist also has an access to an almost complete description of a single human genome but the challenges remain to move from the description to understanding the function of the genome. Studying the role of molecular determinants of human health is an area of research that has gained attention, particularly during the past 50 years, since the structure of DNA helix has solved. This field will become more dynamic one in the near future and the important data will rapidly accumulate. Further researches are clearly needed to determine not only carcinogenic potential of human ecosystems, but also to establish new methods of risk assessment. The knowledge gained will be crucial in prophylactic health care systems.