Gene-Environment Interactions: The Case of Asbestosis

It is becoming evident that both environmental/lifestyle and genetic factors may influence the development of many diseases. This chapter highlights the importance of considering gene-environment interactions, which is shown on the example of our studies into asbestosis, one of the most frequent asbestos-related diseases. Asbestos fibres induce generation of reactive oxygen and nitric species (ROS and RNS), and it is generally accepted that ROS and RNS are involved in the pathogenesis of asbestos-related diseases. Human tissues contain specific enzymes that metabolise ROS and RNS, such as superoxide dismutases (SODs), catalase (CAT), glutathione-S-transferases (GSTs) and inducible nitric oxide synthase (iNOS). As these enzymes are encoded by polymorphic genes, genetic variability in an individual’s capacity to detoxify these reactive species may modify the risk for disease. Our previous studies into asbestosis showed that the associations between the risk of asbestosis and MnSOD Ala-9Val polymorphism and between asbestosis and iNOS genotypes were modified by CAT −262C>T polymorphism. A strong interaction was also found between smoking (lifestyle factor) and GSTM1-null polymorphism, between smoking and iNOS (CCTTT)n polymorphism and between cumulative asbestos exposure (environmental factor) and iNOS (CCTTT)n polymorphism. The findings of our studies and other studies indicate that in addition to environmental and/or occupational exposure to different hazards and lifestyle factors, genetic factors as well as the interactions between different genotypes, between genotypes and lifestyle factors and between genotypes and environmental/occupational exposure to hazards may also have an important role on the development of diseases and should be further investigated

The madness of history

In this novel, the main character/narrator is used as a vehicle to make sense of the atrocities in the former Yugoslavia

Asbestos-Related Diseases and Blood Biomarkers

Asbestos-related diseases, including asbestosis, benign pleural diseases, lung cancer, other types of cancer, and especially malignant mesothelioma (MM), still represent an enormous problem all over the world and are among the most investigated occupational diseases. Considering that MM is a highly aggressive and severe malignant cancer of pleura, peritoneum and other serosal surfaces, new blood biomarkers for earlier diagnosis, following response to treatment and disease progression, have been intensively investigated. Several studies suggested that soluble mesothelin-related peptides, fibulin-3, survivin, osteopontin, vimentin, calretinin, and many others could be helpful in diagnosis, detecting the progression of MM and evaluating tumour response to treatment; however, these biomarkers have not been validated in clinical practice. Therefore, search for novel better stand-alone or composite biomarkers is under way. The aim of this chapter is to present the importance of blood biomarkers in evaluating the risk of developing asbestos-related diseases, early diagnosis, following the response to treatment and progression of these diseases, with special emphasis on MM

Berättelser om skolans arbete med barn i missbruksmiljöer. En kvalitativ studie.

The purpose of this study was to analyze narratives of school counselors and nurses’ on how they identify children who live in abusive environments and the actions they have taken. We used a qualitative method and the study consisted of eight semistructed interviews with four school counselors and four school nurses. We have analyzed our material using Goffmans theory about the theater metaphor and Michael Lipskys street-level bureaucracy. The following questions guided our study: how do the professionals describe their work with children who are in abusive environments, how do the professionals describe the prevention work and how do the professionals describe the actions taken by them when they have identified children in abusive environments. The main finding of this study was that all of the informants found it difficult to identify these children and decide whether or not abuse goes on in the family. The majority of the informants highlight the fact that there are an unrecorded number of students who live in those environments, but few discuss how they can identify the children better. Reports from school counselors and nurses reveal that they would like to be around the children more than they currently do, so that they may identify those children better. All of the informants described the importance of prevention work in school, but that the resources and time are limited

Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening

Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility

Prenatal Excess Glucocorticoid Exposure and Adult Affective Disorders:A Role for Serotonergic and Catecholamine Pathways

Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal ‘programming’ of adult affective behaviours such as depression and anxiety. Indeed, the glucocorticoid metabolising enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is highly expressed in the placenta and the developing fetus, acts as a protective barrier from the high maternal glucocorticoids which may alter developmental trajectories. The programmed changes resulting from maternal stress or bypass or from the inhibition of 11β-HSD2 are frequently associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Hence, circulating glucocorticoid levels are increased either basally or in response to stress accompanied by CNS region-specific modulations in the expression of both corticosteroid receptors (mineralocorticoid and glucocorticoid receptors). Furthermore, early-life glucocorticoid exposure also affects serotonergic and catecholamine pathways within the brain, with changes in both associated neurotransmitters and receptors. Indeed, global removal of 11β-HSD2, an enzyme that inactivates glucocorticoids, increases anxiety‐ and depressive-like behaviour in mice; however, in this case the phenotype is not accompanied by overt perturbation in the HPA axis but, intriguingly, alterations in serotonergic and catecholamine pathways are maintained in this programming model. This review addresses one of the potential adverse effects of glucocorticoid overexposure in utero, i.e. increased incidence of affective behaviours, and the mechanisms underlying these behaviours including alteration of the HPA axis and serotonergic and catecholamine pathways

The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding

α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors

Development of a small molecule that corrects misfolding and increases secretion of Z α1 -antitrypsin.

Severe α1 -antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1 -antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high-throughput screen to identify small molecules that bind to, and stabilise Z α1 -antitrypsin. The lead compound blocks Z α1 -antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1 -antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1 -antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that "mutation ameliorating" small molecules can block the aberrant polymerisation that underlies Z α1 -antitrypsin deficiency

Lack of Renal 11 Beta-Hydroxysteroid Dehydrogenase Type 2 at Birth, a Targeted Temporal Window for Neonatal Glucocorticoid Action in Human and Mice

International audienceBackground Glucocorticoid hormones play a major role in fetal organ maturation. Yet, excessive glucocorticoid exposure in utero can result in a variety of detrimental effects, such as growth retardation and increased susceptibility to the development of hypertension. To protect the fetus, maternal glucocorticoids are metabolized into inactive compounds by placental 11beta-hydroxysteroid dehydrogenase type2 (11βHSD2). This enzyme is also expressed in the kidney, where it prevents illicit occupation of the mineralocorticoid receptor by glucocorticoids. We investigated the role of renal 11βHSD2 in the control of neonatal glucocorticoid metabolism in the human and mouse. Methods Cortisol (F) and cortisone (E) concentrations were measured in maternal plasma, umbilical cord blood and human newborn urine using HPLC. 11βHSD2 activity was indirectly assessed by comparing the F/E ratio between maternal and neonatal plasma (placental activity) and between plasma and urine in newborns (renal activity). Direct measurement of renal 11βHSD2 activity was subsequently evaluated in mice at various developmental stages. Renal 11βHSD2 mRNA and protein expression were analyzed by quantitative RT-PCR and immunohistochemistry during the perinatal period in both species. Results We demonstrate that, at variance with placental 11βHSD2 activity, renal 11βHSD2 activity is weak in newborn human and mouse and correlates with low renal mRNA levels and absence of detectable 11βHSD2 protein. Conclusions We provide evidence for a weak or absent expression of neonatal renal 11βHSD2 that is conserved among species. This temporal and tissue-specific 11βHSD2 expression could represent a physiological window for glucocorticoid action yet may constitute an important predictive factor for adverse outcomes of glucocorticoid excess through fetal programming

Adult-Onset Obesity Reveals Prenatal Programming of Glucose-Insulin Sensitivity in Male Sheep Nutrient Restricted during Late Gestation

BACKGROUND: Obesity invokes a range of metabolic disturbances, but the transition from a poor to excessive nutritional environment may exacerbate adult metabolic dysfunction. The current study investigated global maternal nutrient restriction during early or late gestation on glucose tolerance and insulin sensitivity in the adult offspring when lean and obese. METHODS/PRINCIPAL FINDINGS: Pregnant sheep received adequate (1.0M; CE, n = 6) or energy restricted (0.7M) diet during early (1-65 days; LEE, n = 6) or late (65-128 days; LEL, n = 7) gestation (term approximately 147 days). Subsequent offspring remained on pasture until 1.5 years when all received glucose and insulin tolerance tests (GTT & ITT) and body composition determination by dual energy x-ray absorptiometry (DXA). All animals were then exposed to an obesogenic environment for 6-7 months and all protocols repeated. Prenatal dietary treatment had no effect on birth weight or on metabolic endpoints when animals were 'lean' (1.5 years). Obesity revealed generalised metabolic 'inflexibility' and insulin resistance; characterised by blunted excursions of plasma NEFA and increased insulin(AUC) (from 133 to 341 [s.e.d. 26] ng.ml(-1).120 mins) during a GTT, respectively. For LEL vs. CE, the peak in plasma insulin when obese was greater (7.8 vs. 4.7 [s.e.d. 1.1] ng.ml(-1)) and was exacerbated by offspring sex (i.e. 9.8 vs. 4.4 [s.e.d. 1.16] ng.ml(-1); LEL male vs. CE male, respectively). Acquisition of obesity also significantly influenced the plasma lipid and protein profile to suggest, overall, greater net lipogenesis and reduced protein metabolism. CONCLUSIONS: This study indicates generalised metabolic dysfunction with adult-onset obesity which also exacerbates and 'reveals' programming of glucose-insulin sensitivity in male offspring prenatally exposed to maternal undernutrition during late gestation. Taken together, the data suggest that metabolic function appears little compromised in young prenatally 'programmed' animals so long as weight is adequately controlled. Nutritional excess in adulthood exacerbates any programmed phenotype, indicating greater vigilance over weight control is required for those individuals exposed to nutritional thrift during gestation