Replication of Integrative Data Analysis for Adipose Tissue Dysfunction, Low-Grade Inflammation, Postprandial Responses and OMICs Signatures in Symptom-Free Adults.

We previously reported preliminary characterization of adipose tissue (AT) dysfunction through the adiponectin/leptin ratio (ALR) and fasting/postprandial (F/P) gene expression in subcutaneous (SQ) adipose tissue (AT) biopsies obtained from participants in the GEMM study, a precision medicine research project. Here we present integrative data replication of previous findings from an increased number of GEMM symptom-free (SF) adults (N = 124) to improve characterization of early biomarkers for cardiovascular (CV)/immunometabolic risk in SF adults with AT dysfunction. We achieved this goal by taking advantage of the rich set of GEMM F/P 5 h time course data and three tissue samples collected at the same time and frequency on each adult participant (F/P blood, biopsies of SQAT and skeletal muscle (SKM)). We classified them with the presence/absence of AT dysfunction: low (<1) or high (>1) ALR. We also examined the presence of metabolically healthy (MH)/unhealthy (MUH) individuals through low-grade chronic subclinical inflammation (high sensitivity C-reactive protein (hsCRP)), whole body insulin sensitivity (Matsuda Index) and Metabolic Syndrome criteria in people with/without AT dysfunction. Molecular data directly measured from three tissues in a subset of participants allowed fine-scale multi-OMIC profiling of individual postprandial responses (RNA-seq in SKM and SQAT, miRNA from plasma exosomes and shotgun lipidomics in blood). Dynamic postprandial immunometabolic molecular endophenotypes were obtained to move towards a personalized, patient-defined medicine. This study offers an example of integrative translational research, which applies bench-to-bedside research to clinical medicine. Our F/P study design has the potential to characterize CV/immunometabolic early risk detection in support of precision medicine and discovery in SF individuals.

Association of glutathione S-transferase Ω 1-1 polymorphisms (A140D and E208K) with the expression of interleukin-8 (IL-8), transforming growth factor beta (TGF-ß), and apoptotic protease-activating factor 1 (Apaf-1) in humans chronically exposed to arsenic in drinking water.

Human exposure to arsenicals is associated with inflammatory-related diseases including different kinds of cancer as well as non-cancerous diseases like neuro-degenerative diseases, atherosclerosis, hypertension, and diabetes. Interindividual susceptibility has been mainly addressed by evaluating the role of genetic polymorphism in metabolic enzymes in inorganic arsenic (iAs) metabolism. Glutathione S-transferase omega 1-1 (GSTO1-1), which had been associated with iAs metabolism, is also known to participate in inflammatory and apoptotic cellular responses. The polymorphism A140D of GSTO1-1 has been not only associated with distinct urinary profile of arsenic metabolites in populations chronically exposed to iAs in drinking water, but also with higher risk of childhood leukemia and lung disease in non-exposed populations, suggesting that GSTO1-1 involvement in other physiologic processes different from toxics metabolism could be more relevant than is thought. We evaluated the association of the presence of A140D and E208K polymorphisms of GSTO1-1 gene with the expression of genes codifying for proteins involved in the inflammatory and apoptotic response in a human population chronically exposed to iAs through drinking water. A140D polymorphism was associated with higher expression of genes codifying for IL-8 and Apaf-1 mainly in heterozygous individuals, while E208K was associated with higher expression of IL-8 and TGF- gene, in both cases, the association was independently of iAs exposure level; however, the exposure to iAs increased slightly but significantly the influence of A140D and E208K polymorphisms on such genes expression. These results suggest an important role of GSTO1-1 in the inflammatory response and the apoptotic process and indicate that A140D and E208K polymorphisms could increase the risk of developing inflammatory and apoptosis-related diseases in As-exposed populations.

Chronic exposure to arsenic sensitizes CD3+ and CD56+ human cells to sodium arsenite-mediated apoptosis.

Despite the relevance of immune responses in cancer development, little is known about arsenite-induced apoptosis on different immune effectors cells. In this work, we determined the effect of in vitro exposure to sodium arsenite on apoptosis rates of blood lymphocytes, monocytes and NK cells. Blood was obtained from six healthy non-exposed donors, and also from a woman chronically exposed to arsenic. The results indicated that in vitro exposure of mononuclear cells (MNC) from non-exposed donors to sodium arsenite showed no increase in apoptosis as compared to non-treated cells. In contrast, cells obtained from the exposed-donor showed a significant increase in apoptosis after the treatment with sodium arsenite as compared to non-treated cells. This effect was observed in CD3+ and CD56+ but not in CD14+ cells. In addition, we found a preexisting high basal level of apoptosis in MNC from the exposed-donor. These results indicate that chronic exposure to arsenic increases the sensitivity of immune cells to in vitro sodium arsenite-mediated apoptosis.

Effect of oral chronic intoxication with sodium arsenite on murine giardiasis.

Chronic exposure to toxicants alters immune function that can affect the ability of the host to mount a response to infection. Giardiasis is a gastrointestinal disease in which subtle alteration in immunity of the host can transform the normal acute infection into a chronic one. In this work we used a murine giardiasis model to evaluate the effect of chronic oral intoxication with sodium arsenite on the characteristics of giardiasis. BALB/c mice were intoxicated during 45 days with water containing 50, 125 or 250 microg/mL sodium arsenite. Each group was then inoculated with G. muris cysts. Cysts excreted in the feces were isolated and quantified. The toxic effect of arsenic on intestinal trophozoites was evaluated using G. lamblia trophozoites cultured in vitro with different arsenic concentrations, corresponding to equivalent concentrations of arsenic found in the gut lumen of intoxicated mice. Mice intoxicated with 125 and 250 microg/mL of sodium arsenite and infected with G. muris cysts displayed a shorter period of cysts excretion and were resistant to secondary infection with the parasite. In vitro studies showed that G. lamblia trophozoites were able to grow in presence of high sodium arsenite concentrations, suggesting the absence of a direct toxic effect on the parasite in the gut. Since a longer period of Giardia cysts excretion is associated with suppression of the immune system, the earlier clearance of primary G. muris infection in intoxicated mice suggests the induction of an immune modification that leads to an improved ability of mice to overcome the infection.