The mutagenesis moonshot: The propitious beginnings of the environmental mutagenesis and genomics society

A mutagenesis moonshot addressing the influence of the environment on our genetic wellbeing was launched just 2 months before astronauts landed on the moon. Its impetus included the discovery that X-rays (Muller HJ. [1927]: Science 64:84–87) and chemicals (Auerbach and Robson. [1946]: Nature 157:302) were germ-cell mutagens, the introduction of a growing number of untested chemicals into the environment after World War II, and an increasing awareness of the role of environmental pollution on human health. Due to mounting concern from influential scientists that germ-cell mutagens might be ubiquitous in the environment, Alexander Hollaender and colleagues founded in 1969 the Environmental Mutagen Society (EMS), now the Environmental Mutagenesis and Genomics Society (EMGS); Frits Sobels founded the European EMS in 1970. As Fred de Serres noted, such societies were necessary because protecting populations from environmental mutagens could not be addressed by existing scientific societies, and new multidisciplinary alliances were required to spearhead this movement. The nascent EMS gathered policy makers and scientists from government, industry, and academia who became advocates for laws requiring genetic toxicity testing of pesticides and drugs and helped implement those laws. They created an electronic database of the mutagenesis literature; established a peer-reviewed journal; promoted basic and applied research in DNA repair and mutagenesis; and established training programs that expanded the science worldwide. Despite these successes, one objective remains unfulfilled: identification of human germ-cell mutagens. After 50 years, the voyage continues, and a vibrant EMGS is needed to bring the mission to its intended target of protecting populations from genetic hazards. Environ. Mol. Mutagen. 61:8–24, 2020. © 2019 Wiley Periodicals, Inc.     

Building on the past,shaping the future: The environmental mutagenesis and genomics society

In late 2012, the members of the Environmental Mutagen Society voted to change its name to the Environmental Mutagenesis and Genomics Society. Here, we describe the thought process that led to adoption of the new name, which both respects the rich history of a Society founded in 1969 and reflects the many advances in our understanding of the nature and breadth of gene‐environment interactions during the intervening 43 years. Environ. Mol. Mutagen. 54:153–157, 2013. © 2013 Wiley Periodicals, Inc.     

Chromosomal aberrations and sister chromatid exchange tests in Chinese hamster ovary cells in vitro. IV. Results with 15 chemicals

The National Toxicology Program has undertaken a study to assess the ability of four genetic toxicology assays to predict the carcinogenicity of chemicals in 2-year rodent studies [Tennant et al.: Science 236:933-941, 1987]. Two of the assays, used for evaluating in vitro cytogenetic damage, were the SCE and chromosome aberration assays in Chinese hamster ovary cells. The results and data for 15 of the chemicals tested in these two assays are presented here. Each chemical was tested with and without exogenous metabolic activation. The chemicals tested were bisphenol A, 2-chloroethanol, C.I. acid orange 10, C.I. disperse yellow 3, C.I. solvent yellow 14, cytembena, D&C red 9, 1,2-dibromoethane, FD&C yellow 6, malaoxon, D,L-menthol, phenol, sulfisoxazole, titanium dioxide, and tris(2-ethylhexyl)phosphate. In vitro cytogenetic results from the other chemicals presented by Tennant et al. (Science 236:933-941, 1987) have been published by Galloway et al. (Environmental and Molecular Mutagenesis 10(Suppl 10): 1-175, 1987), Gulati et al. (Environmental and Molecular Mutagenesis 13:133-193, 1989), and Love-day et al. (Environmental Mutagenesis 13:60-94).     

Editorial changes

I am pleased to welcome Toshihiro Ohta, of the Tokyo Universityof Life Science, as a new Senior Editor of Mutagenesis. Toshihirohas previously been an Associate Editor of the journal and has     

噬菌体突变库技术在蛋白质改造中的应用

噬菌体展示突变蛋白库是以噬菌粒为载体,对蛋白质序列中的位点(特异或随机)在DNA水平上进行突变而构建的次级文库。突变蛋白库构建策略包括:寡核苷酸介导的直接位点突变、盒式突变、DNA shuffling以及错倾PCR。蛋白突变库主要应用于提高蛋白亲和力、延长半衰期、确定蛋白关键残基。     

Editor's note

This special issue of Teratogenesis Carcinogenesis and Mutagenesis departs somewhat from the usual format of the journal. Following discussions with Dr. Parviz Pour, one of the discoverers of carcinogens that are capable of inducing pancreatic cancer, we concluded that a comprehensive group of articles on this elusive problem would be of general interest. The current series of papers gathered together by Dr. Pour are the result of the stimulus that his original studies have provided.     

Variations in ploidy among isolates of Botrytis cinerea: implications for genetic and molecular analyses

Field isolates and laboratory strains of Botrytis cinerea, an ascomycetous fungus causing considerable economic losses, e.g., as grey mould of vine, were compared for differences in ploidy level by determining their DNA content per nucleus. Strain SAS56, an ascospore line used routinely for genetic analyses, is probably polyploid, since treatment with benomyl causes a significant reduction in DNA content per nucleus. This conclusion is substantiated by the increased sensitivity of the putative haploid derivatives to mutagens (UV and EMS). Molecular analyses (RAPD) of the haploidized strains indicate a very limited degree of heterozygosis of the parent strain SAS56. Analysis of field isolates of B. cinerea showed that their DNA content per nucleus varied considerably, indicating that aneuploidy/polyploidy is a widespread phenomenon in this species. This can explain both the variability and phenotypic instability of many field isolates of this fungus and the unusual difficulties faced by researchers in recovering stable recessive laboratory mutants. Since the haploid derivatives of SAS56 resemble the parent strain in their parasitic and physiological properties they should provide a good basis for classical and molecular genetic studies.     

The role of environmental exposures and the epigenome in health and disease

The genetic material of every organism exists within the context of regulatory networks that govern gene expression, collectively called the epigenome. Epigenetics has taken center stage in the study of diseases such as cancer and diabetes, but its integration into the field of environmental health is still emerging. As the Environmental Mutagenesis and Genomics Society (EMGS) celebrates its 50th Anniversary this year, we have come together to review and summarize the seminal advances in the field of environmental epigenomics. Specifically, we focus on the role epigenetics may play in multigenerational and transgenerational transmission of environmentally induced health effects. We also summarize state of the art techniques for evaluating the epigenome, environmental epigenetic analysis, and the emerging field of epigenome editing. Finally, we evaluate transposon epigenetics as they relate to environmental exposures and explore the role of noncoding RNA as biomarkers of environmental exposures. Although the field has advanced over the past several decades, including being recognized by EMGS with its own Special Interest Group, recently renamed Epigenomics, we are excited about the opportunities for environmental epigenetic science in the next 50 years. Environ. Mol. Mutagen. 61:176–192, 2020. © 2019 Wiley Periodicals, Inc.     

The link between immunity,autoimmunity and endometriosis: a literature update

Endometriosis (EMS), an estrogen-dependent inflammatory disorder affects approximately 5–10% of the general female population of reproductive age and 20–90% of women with pelvic pain and infertility. Many immunological factors are known to contribute significantly to the pathogenesis and pathophysiology of EMS, and both chronic local inflammation and autoantibodies in EMS shares many similarities with autoimmune diseases (AD). However, the autoimmune etiology in EMS remains controversial, and its evidence on autoimmune basis may be limited. Here we aim to review the current understanding between autoimmunity and EMS to provide important knowledge to develop future potential immunomodulatory therapy for the treatment of EMS.     

In vivo animal studies help achieve international consensus on standards and guidelines for health risk estimates for chronic exposure to low levels of tritium in drinking water

Existing and future nuclear fusion technologies involve the production and use of large quantities of tritium, a highly volatile, but low toxicity beta‐emitting isotope of hydrogen. Tritium has received international attention because of public and scientific concerns over its release to the environment and the potential health impact of its internalization. This article provides a brief summary of the current state of knowledge of both the biological and regulatory aspects of tritium exposure; it also explores the gaps in this knowledge and provides recommendations on the best ways forward for improving our understanding of the health effects of low‐level exposure to it. Linking health effects specifically to tritium exposure is challenging in epidemiological studies due to high uncertainty in tritium dosimetry and often suboptimal cohort sizes. We therefore argued that limits for tritium in drinking water should be based on evidence derived from controlled in vivo animal tritium toxicity studies that use realistically low levels of tritium. This article presents one such mouse study, undertaken within an international collaboration, and discusses the implications of its main findings, such as the similarity of the biokinetics of tritiated water (HTO) and organically bound tritium (OBT) and the higher biological effectiveness of OBT. This discussion is consistent with the position expressed in this article that in vivo animal tritium toxicity studies carried out within large, multi‐partner collaborations allow evaluation of a great variety of health‐related endpoints and essential to the development of international consensus on the regulation of tritium levels in the environment. Environ. Mol. Mutagen. 59:586–594, 2018. © 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society     

N-Terminal deletions of rKv1.4 channels affect the voltage dependence of channel availability

Rat Kv1.4 potassium channels undergo rapid inactivation, which is mediated by the N-terminal structure of the polypeptide. This inactivation can be removed by N-terminal deletion of about 20 residues. However, more substantial deletion (e.g. 37 residues) restores inactivation suggesting a second inactivating domain [Kondoh et al. J Biol Chem 272:19333–19338, 1997]. Here we provide evidence that this inactivation shares all properties with N-type inactivation. Pore mutations, which are supposed to affect C-type inactivation, have no effect. In addition, the redox regulation of inactivation, which is typical for Kv1.4 channels, can be conferred to the inactivation of the deleted constructs by incorporation of an N-terminal cysteine residue. The most remarkable feature of this secondary inactivation is the existence of two components in the steady-state voltage dependence of inactivation. For mutant rKv1.4Δ2–37 about 90% of the channels only activate when the holding membrane potential is more negative than about –120 mV; the remaining 10% show the typical threshold at –60 mV. Mutagenesis of the truncated channel affected the relative amplitudes of these two components, but not the voltage dependence. The results suggest that the secondary ball structures of rKv1.4 channels interact with the protein structures responsible for activation. Received: 3 February 1999 / Accepted: 15 March 1999     

A new way of looking at environmental variables that may affect the age at menopause

Environmental variables that might affect the age at menopause were analysed by means of the segmentation method AID. Marital status, occupation, smoking habits, age at last pregnancy and height were shown to be significant discriminating variables. The material and design of the study and the method of analysis are given and its results are discussed. A proposal is made concerning the nature of a ‘secular trend’.     

Early Maladaptive Schemas and Schema Modes in clinical disorders: A systematic review

Purpose

Although schema therapy has been predominantly applied to treat personality disorders, interest into its application in other clinical disorders is growing. Central to schema therapy are Early Maladaptive Schemas (EMS) and Schema Modes. Since existing EMS and Schema Modes were primarily developed in the context of personality disorders, their relevance for clinical disorders is unclear.

Methods

We conducted a systematic review of the presence of EMS and Schema Modes in clinical disorders according to DSM criteria. Per disorder, we evaluated which EMS and Schema Modes were more pronounced in comparison with clinical as well as non-clinical control groups and which EMS and Schema Modes were most highly endorsed within the disorder.

Results

Although evidence concerning EMS was scarce for several disorders, and only few studies on Schema Modes survived inclusion criteria, we identified meaningful relationships and patterns for EMS and Schema Modes in various clinical disorders.

Conclusions

The present review highlights the relevance of EMS and Schema Modes for clinical disorders beyond personality disorders. Depending on the theme of the representation, EMS act as vulnerabilities both across diagnoses and for specific disorders. Thus, EMS and resulting Schema Modes are potential, valuable targets for the prevention and treatment of clinical disorders.     

UKEMS/Dutch EMS-sponsored workshop on biomarkers of exposure and oxidative DNA damage & 7th GUM-32P-postlabelling workshop, University of Münster, Münster, Germany, 28-29 March 2011

Environmental exposures are a major concern for human cancer. However, the precise contribution of specific risk factors and their interactions, both with each other and with genotype, continue to be difficult to elucidate. The exposome is the comprehensive characterisation of an individual's lifetime exposure history (Wild, C. P. (2009) Environmental exposure measurement in cancer epidemiology. Mutagenesis, 24, 117-125). Unravelling complex environmental and genetic aetiologies in order to plan effective public health interventions demands that both environmental exposures and genetic variations are reliably measured. The development, validation and application of biomarkers of exposure are manifestly critical to the future of cancer epidemiology. The aim of this workshop at the University of Münster was to discuss the current status of exposure biomarkers in cancer molecular epidemiology as well as new findings achieved by applying the methods to studies of mechanisms of human cancer. Day 1 focused on biomarkers of exposure (i.e. carcinogen DNA adducts), effect and susceptibility to gain greater understanding of environmental cancer risks and their modulation. Day 2 focused on the role of oxidative stress and DNA damage in human carcinogenesis including methodologies used for the measurement of oxidatively induced DNA lesions in human cells or tissues and the possible use of these lesions as cancer biomarkers.     

Calibration of the single cell gel electrophoresis assay, flow cytometry analysis and forward mutation in Chinese hamster ovary cells

The induction kinetics of genetic damage were measured in oneclone of a mammalian cell line (CHO AS52) with three genotoxicityassays, the single cell gel electrophoresis (Comet) assay, laserbeam flow cytometry and forward mutation. The first two assaysallow for the rapid analysis of genotoxic damage in individualnuclei. The alkaline Comet assay detects DNA strand breaks,alkali-labile sites and incomplete excision repair sites. Flowcytometry measures chromosome damage that results in an unequaldistribution of nuclear DNA in daughter cells. We calibratedthese assays to compare acute DNA damage and longer term clastogenicitywith forward mutation at the gpt^– locus using ethyl methanesulfonate(EMS). The EMS treatments were conducted in F12 medium for 2h. AS52 cells carry a single functional gpt gene which providesfor quantitation of gpt mutants by selecting for 6-thioguanineresistance. EMS induced a concentration-dependent response withmedian Comet tail moment values of 1.06 µm for the negativecontrol and 64.6 µm with 20 mM. The coefficient of variation(CV) of the negative control with flow cytometry was 233; theCV value increased to 4.87 in cells treated with 20 mM EMS.EMS (8 mM) induced a mutant frequency of 779.8 x10^–6 ata relative survival of 64.4%. Genetic response factors werecalculated and the data demonstrate that the induction kineticsof genetic damage as measured by the Comet assay (15.6) andflow cytometry (14.2) were more closely related than that determinedfor mutation induction (7.9). These three assays measure a widespectrum of genetic events at the level of DNA, the gene andthe chromosome and demonstrate the usefulness of the Comet assayand flow cytometry as two relatively rapid procedures to detectgenotoxic damage in mammalian cells. ³To whom correspondence should be addressed at: 364 Environmental and Agricultural Sciences Building, 1101 West Peabody Drive, Urbana, IL 61801-4178, USA. Tel: +1 217 333 3614; Fax: +1 217 333 8046; Email: m-plewa{at}uiuc.edu     

Linear relationship between lethal mutation yield and intake of ethyl methanesulfonate in Drosophila melanogaster

Males of Drosophila melanogaster were fed sucrose solutions containing various concentrations of EMS (from 0.25 to 10 mM) for 24 hr. To measure the intake of an EMS solution, 3H-labeled sucrose was added to the feeding solution, and the 3H activity inside the flies was used as a measure for the intake volume of EMS solution. Each absorbed dose of EMS was estimated from the intake volume of an EMS solution multiplied by its EMS concentration in the feeding solution in a way similar to that described in a previous report [Ayaki et al, 1984]. The relationship between the estimated absorbed dose and the exposure concentration was almost linear in a low concentration range but became concave with a downward curvature in a high concentration range. The dose-response relationship between the frequency of sex-linked recessive lethals and the estimated absorbed dose showed no deviation from linearity at all the five absorbed doses tested. It may be concluded that the absorbed doses thus estimated were very close to true absorbed doses, indicating the usefulness of the present method for dosimetry of chemicals to be given to flies.     

Exploring the relationships among early maladaptive schemas,psychological mindedness and self‐reported college adjustment

Objectives . The primary aim of this research was to study the statistical effects of psychological mindedness (PM) upon the relationship between early maladaptive schemas (EMS) and self‐reported college adjustment. Design . A cross‐sectional design was employed to assess correlations among study variables and to assess the role of PM as moderator or mediator in the relationship between EMS and adjustment. Methods . Into this study, 264 undergraduate students were recruited in partial fulfilment of research requirements in introductory psychology class. Participants completed the Young Schema Questionnaire, the Psychological Mindedness Scale and the Student Adaptation to College Questionnaire. Results . At the level of bivariate correlations, EMS were inversely associated with college adjustment and with PM, and PM was positively associated with adjustment. In a multiple regression equation with PM and EMS entered separately and then as an interaction term as predictors of adjustment, PM was not a significant moderator. However, in a path analysis, the indirect effect of EMS on adjustment through PM was significant, suggesting that PM is a significant mediator. Conclusions . These findings suggest that the assessment of EMS and PM may enhance an understanding of problems with college adjustment and that interventions to reduce the negative effects of EMS may indeed benefit from efforts to improve PM and its correlates.     

Quality improvement of health care services in Croatian emergency medicine

Emergency medical services (EMS) in the Republic of Croatia are currently organized as part of the existing health care system and delivered in the form of pre-hospital and hospital EMS. The pre-hospital EMS are delivered by standalone EMS Centers, EMS units set up in community health centers, and by general practitioners working in shifts and on call in remote and scarcely populated areas. In hospitals, each ward usually has its own emergency reception area, and only in a couple of cases there is an integrated emergency admission unit for the entire hospital. The current EMS structure does not meet the basic requirements that would make an EMS system optimal, i.e. equal quality, equal access, effectiveness and appropriate equipment. The EMS Restructuring Project is part of the Croatian health care system reform and is addressed by the National Health Development Strategy 2006-2011. As part of restructuring efforts, the Croatian National Institute of Emergency Medicine, 21 County Institutes of Emergency Medicine and county-level call centers are going to be set up. In addition, the project will introduce the following: integrated emergency admission areas at hospitals; telemedicine as part of emergency medicine; emergency medicine specialty for physicians and additional specialized training for nurses/technicians; separation of emergency and non-emergency transport; standards for vehicles and equipment and guidelines/protocols/algorithms for care. The Croatian National Institute of Emergency Medicine is an umbrella EMS organization. It shapes the EMS in Croatia and proposes, plans, monitors and analyzes EMS actions in Croatia. In addition, it submits a proposal of the Emergency Medicine Network to the minister, sets standards for EMS transport, and coordinates, guides and supervises the work of County Institutes of Emergency Medicine. County Institutes organize and deliver pre-hospital EMS in their counties. Integrated hospital emergency admission units represent a single point of entry for all emergencies at a particular hospital. Upon triage, depending on the level of emergency, patients are provided with appropriate care and treatment. The introduction of EMS specialty for physicians and additional specialized training for nurses/ technicians is going to increase competencies of all EMS team members. The main objectives of the EMS Restructuring Project to be achieved in the 5-year period are the following: to reduce the response time of pre-hospital EMS teams to 10 minutes in urban areas and 20 minutes in rural areas in 20% of team interventions; to bring patients to hospital within the "golden hour" in 80% of cases; to have 200 physicians specialized in emergency medicine; and to have 220 nurses/technicians that have successfully completed their specialized training in emergency medicine. The objectives are going to be monitored through indicators as part of the World Bank Project for which data have already been collected throughout Croatia: number of interventions; number of emergency interventions; time between call receipt and arrival to scene; time between call receipt and arrival to hospital emergency reception area; percentage of arrivals to hospital by EMS vehicles within 12 hours of symptom onset; polytrauma and cardiac arrest survival rate before admission to hospital; time spent in hospital emergency reception areas and integrated hospital emergency admission units; polytrauma and cardiac arrest survival rate within 24 hours of hospital admission; number of integrated hospital emergency admission units per county; and number of pre-hospital EMS teams per capita.     

丰富环境改善抑郁的基础与临床研究进展

抑郁是一种常见的情感性精神障碍,具有高发病率、高致残率、高复发率的特点。抑郁的发病机制复杂,涉及生物、心理、社会等多方面因素,其中环境因素在抑郁发生中占重要比例,可对抑郁患者大脑结构和功能的可塑性产生双面影响。丰富环境是提供运动、感觉与社会交流等良性刺激的一种特殊干预手段,能够改善异常的躯体与精神症状,对精神障碍如抑郁症的恢复具有积极作用。本文总结了近些年来关于丰富环境改善抑郁的基础与临床研究,以期为今后的研究应用提供新的思路。     

Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment

Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose–response data (Gollapudi et al., 2013), here we present analyses of 1‐ethyl‐1‐nitrosourea (ENU) and 1‐methyl‐1‐nitrosourea (MNU) dose–response data and additional approaches for the determination of genetic toxicity point‐of‐departure (PoD) metrics. We previously described methods to determine the no‐observed‐genotoxic‐effect‐level (NOGEL), the breakpoint‐dose (BPD; previously named Td), and the benchmark dose (BMD₁₀) for genetic toxicity endpoints. In this study we employed those methods, along with a new approach, to determine the non‐linear slope‐transition‐dose (STD), and alternative methods to determine the BPD and BMD, for the analyses of nine ENU and 22 MNU datasets across a range of in vitro and in vivo endpoints. The NOGEL, BMDL₁₀ and BMDL_1SD PoD metrics could be readily calculated for most gene mutation and chromosomal damage studies; however, BPDs and STDs could not always be derived due to data limitations and constraints of the underlying statistical methods. The BMDL₁₀ values were often lower than the other PoDs, and the distribution of BMDL₁₀ values produced the lowest median PoD. Our observations indicate that, among the methods investigated in this study, the BMD approach is the preferred PoD for quantitatively describing genetic toxicology data. Once genetic toxicology PoDs are calculated via this approach, they can be used to derive reference doses and margin of exposure values that may be useful for evaluating human risk and regulatory decision making. Environ. Mol. Mutagen. 55:609–623, 2014. © 2014 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.