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Mechanisms of mutagenesis: DNA replication in the presence of DNA damage.
Liu B, Xue Q, Tang Y, Cao J, Guengerich FP, Zhang H
(2016) Mutat Res Rev Mutat Res 768: 53-67
MeSH Terms: Animals, DNA Adducts, DNA Damage, DNA Repair, DNA Replication, DNA-Directed DNA Polymerase, Environmental Exposure, Genetic Predisposition to Disease, Humans, Mutagenesis, Mutagens, Mutation, Protein Binding
Show Abstract · Added March 14, 2018
Environmental mutagens cause DNA damage that disturbs replication and produces mutations, leading to cancer and other diseases. We discuss mechanisms of mutagenesis resulting from DNA damage, from the level of DNA replication by a single polymerase to the complex DNA replisome of some typical model organisms (including bacteriophage T7, T4, Sulfolobus solfataricus, Escherichia coli, yeast and human). For a single DNA polymerase, DNA damage can affect replication in three major ways: reducing replication fidelity, causing frameshift mutations, and blocking replication. For the DNA replisome, protein interactions and the functions of accessory proteins can yield rather different results even with a single DNA polymerase. The mechanism of mutation during replication performed by the DNA replisome is a long-standing question. Using new methods and techniques, the replisomes of certain organisms and human cell extracts can now be investigated with regard to the bypass of DNA damage. In this review, we consider the molecular mechanism of mutagenesis resulting from DNA damage in replication at the levels of single DNA polymerases and complex DNA replisomes, including translesion DNA synthesis.
Copyright © 2016 Elsevier B.V. All rights reserved.
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13 MeSH Terms
GLI3 Links Environmental Arsenic Exposure and Human Fetal Growth.
Winterbottom EF, Fei DL, Koestler DC, Giambelli C, Wika E, Capobianco AJ, Lee E, Marsit CJ, Karagas MR, Robbins DJ
(2015) EBioMedicine 2: 536-43
MeSH Terms: Adolescent, Adult, Arsenic, Birth Weight, Child Health, Environmental Exposure, Female, Fetal Development, Gene Expression Profiling, Groundwater, Humans, Kruppel-Like Transcription Factors, Maternal Exposure, Middle Aged, Nerve Tissue Proteins, Octamer Transcription Factor-3, Placenta, Pregnancy, Prenatal Exposure Delayed Effects, Signal Transduction, Water Pollutants, Chemical, Water Pollution, Young Adult, Zinc Finger Protein Gli3
Show Abstract · Added November 2, 2015
Although considerable evidence suggests that in utero arsenic exposure affects children's health, these data are mainly from areas of the world where groundwater arsenic levels far exceed the World Health Organization limit of 10 μg/L. We, and others, have found that more common levels of in utero arsenic exposure may also impact children's health. However, the underlying molecular mechanisms are poorly understood. To address this issue, we analyzed the expression of key developmental genes in fetal placenta in a birth cohort of women using unregulated water supplies in a US region with elevated groundwater arsenic. We identified several genes whose expression associated with maternal arsenic exposure in a fetal sex-specific manner. In particular, expression of the HEDGEHOG pathway component, GLI3, in female placentae was both negatively associated with arsenic exposure and positively associated with infant birth weight. This suggests that modulation of GLI3 in the fetal placenta, and perhaps in other fetal tissues, contributes to arsenic's detrimental effects on fetal growth. We showed previously that arsenic-exposed NIH3T3 cells have reduced GLI3 repressor protein. Together, these studies identify GLI3 as a key signaling node that is affected by arsenic, mediating a subset of its effects on developmental signaling and fetal health.
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24 MeSH Terms
Secondhand Smoke Exposure and Illness Severity among Children Hospitalized with Pneumonia.
Ahn A, Edwards KM, Grijalva CG, Self WH, Zhu Y, Chappell JD, Arnold SR, McCullers JA, Ampofo K, Pavia AT, Bramley AM, Jain S, Williams DJ
(2015) J Pediatr 167: 869-874.e1
MeSH Terms: Child, Child, Preschool, Community-Acquired Infections, Environmental Exposure, Female, Hospitalization, Humans, Infant, Length of Stay, Male, Pneumonia, Proportional Hazards Models, Regression Analysis, Respiration, Artificial, Tennessee, Tobacco Smoke Pollution, Utah
Show Abstract · Added July 27, 2018
OBJECTIVE - To assess the relationship between secondhand smoke (SHS) exposure and disease severity among children hospitalized with community-acquired pneumonia (CAP).
STUDY DESIGN - Children hospitalized with clinical and radiographic CAP were enrolled between January 1, 2010, and June 30, 2012 at 3 hospitals in Tennessee and Utah as part of the Centers for Disease Control and Prevention's Etiology of Pneumonia in the Community study. Household SHS exposure was defined based on the number of smokers in the child's home. Outcomes included hospital length of stay, intensive care unit admission, and mechanical ventilation. Proportional hazards and logistic regression models were used to assess associations between SHS exposure and outcomes. All models were adjusted for age, sex, race/ethnicity, household education level, government insurance, comorbidities, enrollment site, year, and season.
RESULTS - Of the 2219 children included in the study, SHS exposure was reported in 785 (35.4%), including 325 (14.8%) with ≥2 smokers in the home. Compared with nonexposed children, the children exposed to ≥2 smokers had longer length of stay (median, 70.4 hours vs 64.4 hours; adjusted hazard ratio, 0.85; 95% CI, 0.75-0.97) and were more likely to receive intensive care (25.2% vs 20.9%; aOR, 1.44; 95% CI, 1.05-1.96), but not mechanical ventilation. Outcomes in children exposed to only 1 household smoker were similar to those in nonexposed children.
CONCLUSION - Children hospitalized with CAP from households with ≥2 smokers had a longer length of stay and were more likely to require intensive care compared with children from households with no smokers, suggesting that they experienced greater pneumonia severity.
Copyright © 2015 Elsevier Inc. All rights reserved.
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MeSH Terms
Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.
Goodson WH, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, Lasfar A, Carnero A, Azqueta A, Amedei A, Charles AK, Collins AR, Ward A, Salzberg AC, Colacci A, Olsen AK, Berg A, Barclay BJ, Zhou BP, Blanco-Aparicio C, Baglole CJ, Dong C, Mondello C, Hsu CW, Naus CC, Yedjou C, Curran CS, Laird DW, Koch DC, Carlin DJ, Felsher DW, Roy D, Brown DG, Ratovitski E, Ryan EP, Corsini E, Rojas E, Moon EY, Laconi E, Marongiu F, Al-Mulla F, Chiaradonna F, Darroudi F, Martin FL, Van Schooten FJ, Goldberg GS, Wagemaker G, Nangami GN, Calaf GM, Williams G, Wolf GT, Koppen G, Brunborg G, Lyerly HK, Krishnan H, Ab Hamid H, Yasaei H, Sone H, Kondoh H, Salem HK, Hsu HY, Park HH, Koturbash I, Miousse IR, Scovassi AI, Klaunig JE, Vondráček J, Raju J, Roman J, Wise JP, Whitfield JR, Woodrick J, Christopher JA, Ochieng J, Martinez-Leal JF, Weisz J, Kravchenko J, Sun J, Prudhomme KR, Narayanan KB, Cohen-Solal KA, Moorwood K, Gonzalez L, Soucek L, Jian L, D'Abronzo LS, Lin LT, Li L, Gulliver L, McCawley LJ, Memeo L, Vermeulen L, Leyns L, Zhang L, Valverde M, Khatami M, Romano MF, Chapellier M, Williams MA, Wade M, Manjili MH, Lleonart ME, Xia M, Gonzalez MJ, Karamouzis MV, Kirsch-Volders M, Vaccari M, Kuemmerle NB, Singh N, Cruickshanks N, Kleinstreuer N, van Larebeke N, Ahmed N, Ogunkua O, Krishnakumar PK, Vadgama P, Marignani PA, Ghosh PM, Ostrosky-Wegman P, Thompson PA, Dent P, Heneberg P, Darbre P, Sing Leung P, Nangia-Makker P, Cheng QS, Robey RB, Al-Temaimi R, Roy R, Andrade-Vieira R, Sinha RK, Mehta R, Vento R, Di Fiore R, Ponce-Cusi R, Dornetshuber-Fleiss R, Nahta R, Castellino RC, Palorini R, Abd Hamid R, Langie SA, Eltom SE, Brooks SA, Ryeom S, Wise SS, Bay SN, Harris SA, Papagerakis S, Romano S, Pavanello S, Eriksson S, Forte S, Casey SC, Luanpitpong S, Lee TJ, Otsuki T, Chen T, Massfelder T, Sanderson T, Guarnieri T, Hultman T, Dormoy V, Odero-Marah V, Sabbisetti V, Maguer-Satta V, Rathmell WK, Engström W, Decker WK, Bisson WH, Rojanasakul Y, Luqmani Y, Chen Z, Hu Z
(2015) Carcinogenesis 36 Suppl 1: S254-96
MeSH Terms: Animals, Carcinogenesis, Carcinogens, Environmental, Environmental Exposure, Hazardous Substances, Humans, Neoplasms
Show Abstract · Added October 17, 2015
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
© The Author 2015. Published by Oxford University Press.
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7 MeSH Terms
Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis.
Hu Z, Brooks SA, Dormoy V, Hsu CW, Hsu HY, Lin LT, Massfelder T, Rathmell WK, Xia M, Al-Mulla F, Al-Temaimi R, Amedei A, Brown DG, Prudhomme KR, Colacci A, Hamid RA, Mondello C, Raju J, Ryan EP, Woodrick J, Scovassi AI, Singh N, Vaccari M, Roy R, Forte S, Memeo L, Salem HK, Lowe L, Jensen L, Bisson WH, Kleinstreuer N
(2015) Carcinogenesis 36 Suppl 1: S184-202
MeSH Terms: Animals, Carcinogenesis, Carcinogens, Environmental, Environmental Exposure, Hazardous Substances, Humans, Neoplasms, Neovascularization, Pathologic
Show Abstract · Added October 17, 2015
One of the important 'hallmarks' of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential.
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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8 MeSH Terms
TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization.
Caballero MT, Serra ME, Acosta PL, Marzec J, Gibbons L, Salim M, Rodriguez A, Reynaldi A, Garcia A, Bado D, Buchholz UJ, Hijano DR, Coviello S, Newcomb D, Bellabarba M, Ferolla FM, Libster R, Berenstein A, Siniawaski S, Blumetti V, Echavarria M, Pinto L, Lawrence A, Ossorio MF, Grosman A, Mateu CG, Bayle C, Dericco A, Pellegrini M, Igarza I, Repetto HA, Grimaldi LA, Gudapati P, Polack NR, Althabe F, Shi M, Ferrero F, Bergel E, Stein RT, Peebles RS, Boothby M, Kleeberger SR, Polack FP
(2015) J Clin Invest 125: 571-82
MeSH Terms: Animals, Bronchiolitis, Viral, Disease Models, Animal, Environmental Exposure, Female, GATA3 Transcription Factor, Genotype, Humans, Infant, Infant, Newborn, Interferon-gamma, Interleukin-4, Lipopolysaccharides, Male, Mice, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, T-Box Domain Proteins, Th2 Cells, Toll-Like Receptor 4
Show Abstract · Added January 20, 2015
While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.
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20 MeSH Terms
Toward primary prevention of asthma. Reviewing the evidence for early-life respiratory viral infections as modifiable risk factors to prevent childhood asthma.
Feldman AS, He Y, Moore ML, Hershenson MB, Hartert TV
(2015) Am J Respir Crit Care Med 191: 34-44
MeSH Terms: Antibodies, Monoclonal, Humanized, Antiviral Agents, Asthma, Child, Preschool, Diet, Environmental Exposure, Epigenesis, Genetic, Genetic Predisposition to Disease, Humans, Infant, Microbiota, Palivizumab, Primary Prevention, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, Respiratory Tract Infections, Rhinovirus, Risk Factors, Severity of Illness Index, Tobacco Smoke Pollution
Show Abstract · Added January 20, 2015
A first step in primary disease prevention is identifying common, modifiable risk factors that contribute to a significant proportion of disease development. Infant respiratory viral infection and childhood asthma are the most common acute and chronic diseases of childhood, respectively. Common clinical features and links between these diseases have long been recognized, with early-life respiratory syncytial virus (RSV) and rhinovirus (RV) lower respiratory tract infections (LRTIs) being strongly associated with increased asthma risk. However, there has long been debate over the role of these respiratory viruses in asthma inception. In this article, we systematically review the evidence linking early-life RSV and RV LRTIs with asthma inception and whether they could therefore be targets for primary prevention efforts.
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20 MeSH Terms
Cellular manganese content is developmentally regulated in human dopaminergic neurons.
Kumar KK, Lowe EW, Aboud AA, Neely MD, Redha R, Bauer JA, Odak M, Weaver CD, Meiler J, Aschner M, Bowman AB
(2014) Sci Rep 4: 6801
MeSH Terms: Animals, Biological Transport, Dopaminergic Neurons, Environmental Exposure, Homeostasis, Humans, Ions, Manganese, Mice, Signal Transduction, Structure-Activity Relationship
Show Abstract · Added January 24, 2015
Manganese (Mn) is both an essential biological cofactor and neurotoxicant. Disruption of Mn biology in the basal ganglia has been implicated in the pathogenesis of neurodegenerative disorders, such as parkinsonism and Huntington's disease. Handling of other essential metals (e.g. iron and zinc) occurs via complex intracellular signaling networks that link metal detection and transport systems. However, beyond several non-selective transporters, little is known about the intracellular processes regulating neuronal Mn homeostasis. We hypothesized that small molecules that modulate intracellular Mn could provide insight into cell-level Mn regulatory mechanisms. We performed a high throughput screen of 40,167 small molecules for modifiers of cellular Mn content in a mouse striatal neuron cell line. Following stringent validation assays and chemical informatics, we obtained a chemical 'toolbox' of 41 small molecules with diverse structure-activity relationships that can alter intracellular Mn levels under biologically relevant Mn exposures. We utilized this toolbox to test for differential regulation of Mn handling in human floor-plate lineage dopaminergic neurons, a lineage especially vulnerable to environmental Mn exposure. We report differential Mn accumulation between developmental stages and stage-specific differences in the Mn-altering activity of individual small molecules. This work demonstrates cell-level regulation of Mn content across neuronal differentiation.
2 Communities
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11 MeSH Terms
Neurosensory perception of environmental cues modulates sperm motility critical for fertilization.
McKnight K, Hoang HD, Prasain JK, Brown N, Vibbert J, Hollister KA, Moore R, Ragains JR, Reese J, Miller MA
(2014) Science 344: 754-7
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Environmental Exposure, Female, Fertilization, Male, Neurons, Afferent, Neurosecretory Systems, Oocytes, Ovum, Perception, Pheromones, Prostaglandin-Endoperoxide Synthases, Prostaglandins, Sperm Motility, Spermatozoa, Transforming Growth Factor beta
Show Abstract · Added May 19, 2014
Environmental exposures affect gamete function and fertility, but the mechanisms are poorly understood. Here, we show that pheromones sensed by ciliated neurons in the Caenorhabditis elegans nose alter the lipid microenvironment within the oviduct, thereby affecting sperm motility. In favorable environments, pheromone-responsive sensory neurons secrete a transforming growth factor-β ligand called DAF-7, which acts as a neuroendocrine factor that stimulates prostaglandin-endoperoxide synthase [cyclooxygenase (Cox)]-independent prostaglandin synthesis in the ovary. Oocytes secrete F-class prostaglandins that guide sperm toward them. These prostaglandins are also synthesized in Cox knockout mice, raising the possibility that similar mechanisms exist in other animals. Our data indicate that environmental cues perceived by the female nervous system affect sperm function.
Copyright © 2014, American Association for the Advancement of Science.
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18 MeSH Terms
Predictors and variability of repeat measurements of urinary phenols and parabens in a cohort of Shanghai women and men.
Engel LS, Buckley JP, Yang G, Liao LM, Satagopan J, Calafat AM, Matthews CE, Cai Q, Ji BT, Cai H, Engel SM, Wolff MS, Rothman N, Zheng W, Xiang YB, Shu XO, Gao YT, Chow WH
(2014) Environ Health Perspect 122: 733-40
MeSH Terms: Adult, Aged, China, Environmental Exposure, Environmental Monitoring, Environmental Pollutants, Female, Humans, Male, Middle Aged, Parabens, Phenols, Prospective Studies, Reproducibility of Results
Show Abstract · Added March 27, 2014
BACKGROUND - Exposure to certain phenols is ubiquitous because of their use in many consumer and personal care products. However, predictors of exposure have not been well characterized in most populations.
OBJECTIVES - We sought to identify predictors of exposure and to assess the reproducibility of phenol concentrations across serial spot urine samples among Chinese adults.
METHODS - We measured 2,4-dichlorophenol, 2,5-dichlorophenol, butyl paraben, methyl paraben, propyl paraben, benzophenone-3, bisphenol A, and triclosan in urine collected during 1997-2006 from 50 participants of the Shanghai Women's Health Study cohort and during 2002-2006 from 50 participants of the Shanghai Men's Health Study cohort. We investigated predictors of concentrations using the Satterthwaite t-test, and assessed reproducibility among serial samples using intraclass correlation coefficients (ICCs) and Spearman correlation coefficients (SCCs).
RESULTS - Creatinine-corrected phenol concentrations were generally higher among women than men. Participants who had taken medicine within the previous 24 hr had higher concentrations of propyl paraben. Cigarette smoking was associated with lower concentrations of propyl and methyl parabens among men. Bottled water consumption was associated with higher bisphenol A, 2,4-dichlorophenol, and 2,5-dichlorophenol concentrations among women. Among men, reproducibility across serial samples was moderate for 2,4-dichlorophenol and 2,5-dichlorophenol (ICC = 0.54-0.60, SCC = 0.43-0.56), but lower for other analytes (ICC = 0.20-0.29). Reproducibility among women was low (ICC = 0.13-0.39), but increased when restricted to morning-only urine samples.
CONCLUSIONS - Among these 100 Shanghai residents, urinary phenol concentrations varied by sex, smoking, and consumption of bottled water. Our results suggest that a single urine sample may be adequate for ranking exposure to the precursors of 2,4-dichlorophenol and 2,5-dichlorophenol among men and, under certain circumstances, among women.
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14 MeSH Terms