Lung function in adults following in utero and childhood exposure to arsenic in drinking water: preliminary findings

PurposeEvidence suggests that arsenic in drinking water causes non-malignant lung disease, but nearly all data concern exposed adults. The desert city of Antofagasta (population 257,976) in northern Chile had high concentrations of arsenic in drinking water (>800 μg/l) from 1958 until 1970, when a new treatment plant was installed. This scenario, with its large population, distinct period of high exposure, and accurate data on past exposure, is virtually unprecedented in environmental epidemiology. We conducted a pilot study on early-life arsenic exposure and long-term lung function. We present these preliminary findings because of the magnitude of the effects observed.MethodsWe recruited a convenience sample consisting primarily of nursing school employees in Antofagasta and Arica, a city with low drinking water arsenic. Lung function and respiratory symptoms in 32 adults exposed to >800 μg/l arsenic before age 10 were compared to 65 adults without high early-life exposure.ResultsEarly-life arsenic exposure was associated with 11.5% lower forced expiratory volume in 1 s (FEV(1)) (P = 0.04), 12.2% lower forced vital capacity (FVC) (P = 0.04), and increased breathlessness (prevalence odds ratio = 5.94, 95% confidence interval 1.36-26.0). Exposure-response relationships between early-life arsenic concentration and adult FEV(1) and FVC were also identified (P trend = 0.03).ConclusionsEarly-life exposure to arsenic in drinking water may have irreversible respiratory effects of a magnitude similar to smoking throughout adulthood. Given the small study size and non-random recruitment methods, further research is needed to confirm these findings

PrognoScan: a new database for meta-analysis of the prognostic value of genes

<p>Abstract</p> <p>Background</p> <p>In cancer research, the association between a gene and clinical outcome suggests the underlying etiology of the disease and consequently can motivate further studies. The recent availability of published cancer microarray datasets with clinical annotation provides the opportunity for linking gene expression to prognosis. However, the data are not easy to access and analyze without an effective analysis platform.</p> <p>Description</p> <p>To take advantage of public resources in full, a database named "PrognoScan" has been developed. This is 1) a large collection of publicly available cancer microarray datasets with clinical annotation, as well as 2) a tool for assessing the biological relationship between gene expression and prognosis. PrognoScan employs the minimum <it>P</it>-value approach for grouping patients for survival analysis that finds the optimal cutpoint in continuous gene expression measurement without prior biological knowledge or assumption and, as a result, enables systematic meta-analysis of multiple datasets.</p> <p>Conclusion</p> <p>PrognoScan provides a powerful platform for evaluating potential tumor markers and therapeutic targets and would accelerate cancer research. The database is publicly accessible at <url>http://gibk21.bse.kyutech.ac.jp/PrognoScan/index.html</url>.</p

Effects of two common polymorphisms in the 3' untranslated regions of estrogen receptor β on mRNA stability and translatability

Estrogen signaling is mediated by estrogen receptors (ERs), ERα and ERβ. Aberrant estrogen signaling is involved in breast cancer development. ERα is one of the key biomarkers for diagnosis and treatment of breast cancer. Unlike ERα, ERβ is still not introduced as a marker for diagnosis and established as a target of therapy. Numerous studies suggest antiproliferative effects of ERβ, however its role remains to be fully explored. Albeit important, ERα is not a perfect marker, and some aspects of ERα function are still unclear. This thesis aims to characterize distinct molecular facets of ER action relevant for breast cancer and provide valuable information for ER-based diagnosis and treatment design. In PAPER I, we analyzed the functionality of two common single nucleotide polymorphisms in the 3’ untranslated regions of ERβ, rs4986938 and rs928554, which have been extensively investigated for association with various diseases. A significant difference in allelic expression was observed for rs4986938 in breast tumor samples from heterozygous individuals. However, no difference in mRNA stability or translatability between the alleles was observed. In PAPER II, we provided a more comprehensive understanding of ERβ function independent of ERα. A global gene expression analysis in a HEK293/ERβ cell model identified a set of ERβ-regulated genes. Gene Ontology (GO) analysis showed that they are involved in cell-cell signaling, morphogenesis and cell proliferation. Moreover, ERβ expression resulted in a significant decrease in cell proliferation. In PAPER III, using the human breast cancer MCF-7/ERβ cell model, we demonstrated, for the first time, the binding of ERα/β heterodimers to various DNA-binding regions in intact chromatin. In PAPER IV, we investigated a potential cross-talk between estrogen signaling and DNA methylation by identifying their common target genes in MCF-7 cells. Gene expression profiling identified around 150 genes regulated by both 17β- estradiol (E2) and a hypomethylating agent 5-aza-2’-deoxycytidine. Based on GO analysis, CpG island prediction analysis and previously reported ER binding regions, we selected six genes for further analysis. We identified BTG3 and FHL2 as direct target genes of both pathways. However, our data did not support a direct molecular interplay of mediators of estrogen and epigenetic signaling at promoters of regulated genes. In PAPER V, we further explored the interactions between estrogen signaling and DNA methylation, with focus on DNA methyltransferases (DNMT1, DNMT3a and DNMT3b). E2, via ERα, up-regulated DNMT1 and down-regulated DNMT3a and DNMT3b mRNA expression. Furthermore, DNMT3b interacted with ERα. siRNA-mediated DNMT3b depletion increased the expression of two genes, CDKN1A and FHL2. We proposed that the molecular mechanism underlying regulation of FHL2 and CDKN1A gene expression involves interplay of DNMT3b and ERα. In conclusion, the studies presented in this thesis contribute to the knowledge of ERβ function, and give additional insight into the cross-talk mechanisms underlying ERα signaling with ERβ and with DNA methylation pathways

Expression Patterns of Protein Kinases Correlate with Gene Architecture and Evolutionary Rates

Protein kinase (PK) genes comprise the third largest superfamily that occupy ∼2% of the human genome. They encode regulatory enzymes that control a vast variety of cellular processes through phosphorylation of their protein substrates. Expression of PK genes is subject to complex transcriptional regulation which is not fully understood.Our comparative analysis demonstrates that genomic organization of regulatory PK genes differs from organization of other protein coding genes. PK genes occupy larger genomic loci, have longer introns, spacer regions, and encode larger proteins. The primary transcript length of PK genes, similar to other protein coding genes, inversely correlates with gene expression level and expression breadth, which is likely due to the necessity to reduce metabolic costs of transcription for abundant messages. On average, PK genes evolve slower than other protein coding genes. Breadth of PK expression negatively correlates with rate of non-synonymous substitutions in protein coding regions. This rate is lower for high expression and ubiquitous PKs, relative to low expression PKs, and correlates with divergence in untranslated regions. Conversely, rate of silent mutations is uniform in different PK groups, indicating that differing rates of non-synonymous substitutions reflect variations in selective pressure. Brain and testis employ a considerable number of tissue-specific PKs, indicating high complexity of phosphorylation-dependent regulatory network in these organs. There are considerable differences in genomic organization between PKs up-regulated in the testis and brain. PK genes up-regulated in the highly proliferative testicular tissue are fast evolving and small, with short introns and transcribed regions. In contrast, genes up-regulated in the minimally proliferative nervous tissue carry long introns, extended transcribed regions, and evolve slowly.PK genomic architecture, the size of gene functional domains and evolutionary rates correlate with the pattern of gene expression. Structure and evolutionary divergence of tissue-specific PK genes is related to the proliferative activity of the tissue where these genes are predominantly expressed. Our data provide evidence that physiological requirements for transcription intensity, ubiquitous expression, and tissue-specific regulation shape gene structure and affect rates of evolution

A case-control study of GST polymorphisms and arsenic related skin lesions

BACKGROUND: Polymorphisms in GSTT1, GSTM1 and GSTP1 impact detoxification of carcinogens by GSTs and have been reported to increase susceptibility to environmentally related health outcomes. Individual factors in arsenic biotransformation may influence disease susceptibility. GST activity is involved in the metabolism of endogenous and exogenous compounds, including catalyzing the formation of arsenic-GSH conjugates. METHODS: We investigated whether polymorphisms in GSTT1, GSTP1 and GSTM1 were associated with risk of skin lesions and whether these polymorphisms modify the relationship between drinking water arsenic exposure and skin lesions in a case control study of 1200 subjects frequency matched on age and gender in community clinics in Pabna, Bangladesh in 2001–2002. RESULTS AND DISCUSSION: GSTT1 homozygous wildtype status was associated with increased odds of skin lesions compared to the null status (OR1.56 95% CI 1.10–2.19). The GSTP1 GG polymorphism was associated with greater odds of skin lesions compared to GSTP1 AA, (OR 1.86 (95%CI 1.15–3.00). No evidence of effect modification by GSTT1, GSTM1 or GSTP1 polymorphisms on the association between arsenic exposure and skin lesions was detected. CONCLUSION: GSTT1 wildtype and GSTP1 GG are associated with increased risk of skin lesions

Vernonia cinerea Less. supplementation and strenuous exercise reduce smoking rate: relation to oxidative stress status and beta-endorphin release in active smokers

<p>Abstract</p> <p>Purpose</p> <p>The aim of this study was to evaluate the effects of <it>Vernonia cinerea </it>Less. (VC) supplementation and exercise on oxidative stress biomarkers, beta-endorphin release, and the rate of cigarette smoking.</p> <p>Methods</p> <p>Volunteer smokers were randomly divided into four groups: group 1: VC supplement; group 2: exercise with VC supplement; group 3: exercise; and group 4: control. VC was prepared by wash and dry techniques and taken orally before smoking, matching the frequency of strenuous exercise (three times weekly). Before and after a two month period, exhaled carbon monoxide (CO), blood oxidative stress (malondialdehyde [MDA], nitric oxide [NOx], protein hydroperoxide [PrOOH] and total antioxidant capacity [TAC]), beta-endorphin and smoking rate were measured, and statistically analyzed.</p> <p>Results</p> <p>In Group 1, MDA, PrOOH, and NOx significantly decreased, whereas TAC increased (p < 0.05). In Group 2, MDA and PrOOH decreased (p < 0.05), with no other changes noted (p > 0.05). In Group 3, MDA, PrOOH, NOx, TAC, and beta-endorphin levels increased significantly (p < 0.05). Group 4 showed no change in oxidative stress variables or beta-endorphine levels (p > 0.05). All groups had lower levels of CO after the intervention. The smoking rate for light cigarette decreased in group 2(62.7%), 1(59.52%), 3 (53.57%) and 4(14.04%), whereas in self-rolled cigarettes it decreased in group 1 (54.47%), 3 (42.30%), 2 (40%) and 4 (9.2%).</p> <p>Conclusion</p> <p>Supplementation with <it>Vernonia cinerea </it>Less and exercise provided benefit related to reduced smoking rate, which may be related to oxidaive stress and beta-endorphine levels.</p

Rule-Based Cell Systems Model of Aging using Feedback Loop Motifs Mediated by Stress Responses

Investigating the complex systems dynamics of the aging process requires integration of a broad range of cellular processes describing damage and functional decline co-existing with adaptive and protective regulatory mechanisms. We evolve an integrated generic cell network to represent the connectivity of key cellular mechanisms structured into positive and negative feedback loop motifs centrally important for aging. The conceptual network is casted into a fuzzy-logic, hybrid-intelligent framework based on interaction rules assembled from a priori knowledge. Based upon a classical homeostatic representation of cellular energy metabolism, we first demonstrate how positive-feedback loops accelerate damage and decline consistent with a vicious cycle. This model is iteratively extended towards an adaptive response model by incorporating protective negative-feedback loop circuits. Time-lapse simulations of the adaptive response model uncover how transcriptional and translational changes, mediated by stress sensors NF-κB and mTOR, counteract accumulating damage and dysfunction by modulating mitochondrial respiration, metabolic fluxes, biosynthesis, and autophagy, crucial for cellular survival. The model allows consideration of lifespan optimization scenarios with respect to fitness criteria using a sensitivity analysis. Our work establishes a novel extendable and scalable computational approach capable to connect tractable molecular mechanisms with cellular network dynamics underlying the emerging aging phenotype